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Mappings

MONDO

MONDO:0100017 pityriasis rubra pilaris Not Yet Curated

The MONDO parent concept covers all six Griffiths clinical types of PRP; this entry covers only the CARD14-defined familial (type V) form.

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Inheritance

1

Autosomal dominant inheritance HP:0000006

Heterozygous CARD14 variants segregate dominantly in multigeneration kindreds and also arise de novo; two of the three type V patients in the first Japanese series carried de novo variants. Penetrance is incomplete and expression ranges from limited plaques to erythroderma within the same family.

Autosomal dominant inheritance Penetrance: INCOMPLETE Expressivity: VARIABLE

Show evidence (3 references)

PMID:22703878 SUPPORT Human clinical

"To identify the genetic cause of familial PRP, we ascertained four unrelated families affected by autosomal-dominant PRP."

Dominant transmission in the four gene-discovery kindreds.

PMID:25734815 SUPPORT BACKGROUND Human clinical

"Most cases of PRP are sporadic and without family history, but a familial form with an autosomal dominant inheritance with partial penetrance represents <6% of all cases."

Records the partial penetrance of the dominant familial form.

PMID:27760266 SUPPORT Human clinical

"Among 3 patients with PRP type V, all were found to have CARD14 mutations: 2 de novo novel mutations (p.Cys127Ser and p.Gln136Leu), and another previously reported mutation (p.Gly117Ser)."

De novo occurrence of the same dominant alleles, so a negative family history does not exclude the diagnosis.

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Discussions and Knowledge Gaps

2

Why does the Card14 C127S knock-in mouse need homozygosity to show PRP-like disease, when every reported patient with the same allele is heterozygous, and does the heterozygous mouse's transient disease mean mouse skin buffers CARD14 gain of function more effectively than human skin?

HUMAN MODEL MISMATCH OPEN fprp_hom_mouse_vs_het_human

Attached to

pathophysiology#Epidermal Hyperproliferation and Abnormal Cornification pathophysiology#IL-23/IL-17 Axis Amplification

The only PRP-allele model recapitulates follicular plugging and palmoplantar hyperkeratosis in homozygotes, with early mortality and barrier failure that have no human counterpart, while heterozygous mice resolve by 6-7 weeks. Mechanism claims drawn from the model (IL-36/inflammasome activation, barrier loss) may reflect the doubled allele dose rather than the human disease state.

Posed by dismech curation Posed 2026-10-23T00:00:00Z

Show evidence (2 references)

DOI:10.21203/rs.3.rs-2513325/v1 Preprint · not peer-reviewed SUPPORT Model organism

"We report the first mouse model of PRP to carry a homozygous knock-in mutation, c.380G>C (p.Cys127Ser) corresponding to a PRP-causative human mutation, in CARD14."

The model that recapitulates PRP is homozygous for an allele that is heterozygous in every reported patient.

PMID:27760266 SUPPORT Human clinical

"2 de novo novel mutations (p.Cys127Ser and p.Gln136Leu), and another previously reported mutation (p.Gly117Ser)"

The human p.Cys127Ser case was heterozygous and de novo.

What determines whether a CARD14 gain-of-function allele produces PRP-like, psoriasis-like or mixed disease, given that p.Gly117Ser causes both and that members of one kindred can carry the same allele with different phenotypes?

KNOWLEDGE GAP OPEN fprp_allele_phenotype_prp_vs_psoriasis

Attached to

pathophysiology#CARD14 Gain-of-Function Variant genetic#CARD14

The functional studies cited in this entry compare each CARD14 allele with wild type, not PRP alleles with psoriasis alleles, so they cannot say whether the two phenotypes differ biochemically; and none of them tests a modifier locus. Until a study does, the familial PRP and PSORS2 entries rest on clinical rather than mechanistic separation.

Posed by dismech curation Posed 2026-10-23T00:00:00Z

Show evidence (2 references)

PMID:22703878 SUPPORT Human clinical

"The present data demonstrate that autosomal-dominant PRP is allelic to familial psoriasis, which was recently shown to also be caused by mutations in CARD14."

The allelism that makes the PRP-versus-psoriasis determinant an open question.

PMID:27760266 SUPPORT Human clinical

"another previously reported mutation (p.Gly117Ser)"

The PSORS2 psoriasis allele p.Gly117Ser recurring in a type V PRP patient.

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Pathophysiology

7

CARD14 Gain-of-Function Variant

Heterozygous missense, in-frame deletion or splice-site variants clustered in the coiled-coil domain of CARD14 (CARMA2), the skin-restricted member of the CARMA scaffold family. The variants disrupt the autoinhibitory contact between the linker region and the CARD/coiled-coil domains, so that the mutant scaffold signals without an upstream stimulus. Gain of function is demonstrated biochemically for the psoriasis alleles p.Glu138Ala and p.Gly117Ser (the latter also a PRP allele) and inferred for the other PRP alleles from their position in the same domain and the NF-kappaB activation seen in patient skin.

keratinocyte CL:0000312

CARD14 hgnc:16446

Genetic context variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: GAIN_OF_FUNCTION

Dominant, usually inherited but sometimes de novo; one homozygous p.Gly117Ser CAPE proband was more severely affected than her heterozygous relatives.

CARD14 signaling adaptor activity, constitutively active GO:0035591 ⇑ GAIN OF FUNCTION

Downstream

Constitutive CARD14-BCL10-MALT1 Complex Assembly With autoinhibition lost, the mutant scaffold binds BCL10 and recruits MALT1 without any receptor stimulus.

Replication Stress-Driven Revertant Mosaicism Mutant CARD14 increases double-strand breaks under replication stress, which favours recombination-mediated loss of the mutant allele in epidermal clones.

Show evidence (3 references)

PMID:22703878 SUPPORT Human clinical

"CARD14 was found to be specifically expressed in the skin."

Skin-restricted expression places the lesion in keratinocytes.

PMID:27071417 SUPPORT INDIRECT In vitro / ex vivo

"These alterations disrupted the inhibitory effect of the CARD14 linker region (LR) on NF-κB activation by facilitating BCL10 binding."

Loss of linker-region autoinhibition shown for the psoriasis alleles p.Glu138Ala and p.Gly117Ser; the latter also causes type V PRP, and the PRP-specific alleles lie in the same coiled-coil region, so the mechanism is inferred for them.

PMID:29980436 SUPPORT INDIRECT Model organism

"Here we showed that Card14E138A/+ and Card14ΔQ136/+ mice developed spontaneous psoriasis-like skin inflammation, which resulted from constitutively activated CARMA2 via self-aggregation leading to the enhanced activation of the IL-23-IL-17A cytokine axis."

Constitutive self-aggregation of mutant CARMA2 in knock-in mice carrying psoriasis alleles from the same domain.

Constitutive CARD14-BCL10-MALT1 Complex Assembly

Mutant CARD14 constitutively associates with BCL10 and the paracaspase MALT1 to form a CBM-type signalosome in keratinocytes, the counterpart of the CARD11-BCL10-MALT1 complex formed in lymphocytes after antigen-receptor stimulation. The complex engages IKK and also activates MALT1 protease activity, which cleaves negative regulators of NF-kappaB; MALT1 deficiency or inhibition blunts mutant CARD14 signalling in keratinocytes and in mice.

keratinocyte CL:0000312

BCL10 hgnc:989 MALT1 hgnc:6819

CARD14-BCL10-MALT1 (CBM) complex GO:0032449

Animal models

Card14 delta-E138 knock-in mouse (psoriasis allele) Mouse perturbs Keratinocyte-specific deletion of MALT1 or BCL10 in the related Card14 E138A/+ knock-in abolishes skin and systemic inflammation, placing the keratinocyte CBM complex upstream of the whole cascade.

Downstream

Keratinocyte NF-kappaB Hyperactivation The assembled CBM signalosome activates IKK, and MALT1 protease activity removes NF-kappaB inhibitors, giving sustained canonical NF-kappaB signalling.

Show evidence (3 references)

PMID:27071417 SUPPORT In vitro / ex vivo

"In contrast with wild-type CARD14, CARD14(E138A) and CARD14(G117S) psoriasis mutants interacted constitutively with BCL10 and MALT1, and triggered BCL10- and MALT1-dependent activation of NF-κB in keratinocytes."

Constitutive CBM assembly by mutant CARD14 in keratinocytes, including the p.Gly117Ser allele shared with type V PRP.

PMID:27113748 SUPPORT In vitro / ex vivo

"Mechanistically, we demonstrate that CARD14 physically interacts with paracaspase MALT1 and activates MALT1 proteolytic activity and inflammatory gene expression, which are enhanced by psoriasis-associated CARD14 mutations."

Physical CARD14-MALT1 interaction and MALT1 protease activation, enhanced by activating alleles.

PMID:33419765 SUPPORT Model organism

"Targeting CBM complex by conditional deletion of MALT1 or BCL10 in keratinocytes abrogated both the cutaneous and systemic inflammation of heterozygous Card14 E138A/+ mice."

Genetic requirement for the keratinocyte CBM complex in a CARD14 knock-in model.

Keratinocyte NF-kappaB Hyperactivation

Canonical NF-kappaB is constitutively active in CARD14-mutant keratinocytes, with nuclear p65 demonstrable in lesional familial PRP skin. ERK1/2 and p38 MAP kinase activation accompanies NF-kappaB and is needed for maximal target-gene induction. Because CARD14 also transduces IL-17A signalling through the ACT1-TRAF6 complex, mutant keratinocytes respond more strongly to the IL-17A that the downstream immune response produces, closing a feed-forward loop.

keratinocyte CL:0000312

RELA (p65) hgnc:9955

canonical NF-kappaB signal transduction GO:0007249 ↑ INCREASED

skin epidermis UBERON:0001003

Downstream

Keratinocyte Chemokine and Cytokine Production NF-kappaB drives transcription of CCL20, CXCL8, IL1B, IL36G and antimicrobial peptides in the mutant keratinocyte.

Show evidence (4 references)

PMID:22703878 SUPPORT Human clinical

"Accordingly, CARD14 levels were increased, and p65 was found to be activated in the skin of PRP-affected individuals."

Activated p65 in lesional skin of the familial PRP kindreds.

PMID:30018619 SUPPORT In vitro / ex vivo

"Immunofluorescent staining of the NFκB p65 subunit and NFκB-luciferase reporter assay demonstrated significantly increased NFκB activity in skin samples and keratinocytes from the PRP patient compared to healthy samples."

Increased NF-kappaB activity in patient skin sections and cultured patient keratinocytes; the patient carried CARD14 variants of uncertain individual effect, so this is a type V phenotype-level observation.

PMID:22521418 SUPPORT INDIRECT In vitro / ex vivo

"CARD14 activates nuclear factor kappa B (NF-kB), and compared with wild-type CARD14, the p.Gly117Ser and p.Glu138Ala substitutions were shown to lead to enhanced NF-kB activation and upregulation of a subset of psoriasis-associated genes in keratinocytes."

Enhanced NF-kappaB reporter activity for the p.Gly117Ser allele, which also causes type V PRP; measured in a psoriasis study.

+ 1 more reference

Keratinocyte Chemokine and Cytokine Production

NF-kappaB-dependent transcription in CARD14-mutant keratinocytes raises CCL20, CXCL8 (IL-8), IL1B, IL36G, S100A8/A9 and antimicrobial peptides. CCL20 recruits CCR6-positive dendritic cells and Th17 cells, and IL-36 and inflammasome products amplify innate inflammation, which the Card14 C127S PRP mouse reproduces in the interfollicular epidermis and follicular outer root sheath. MALT1 protease activity is needed for full CCL20 and IL-8 induction.

keratinocyte CL:0000312

CCL20 hgnc:10619 CXCL8 (IL-8) hgnc:6025 IL1B hgnc:5992

chemokine production GO:0032602 ↑ INCREASED inflammatory response GO:0006954 ↑ INCREASED

Downstream

IL-23/IL-17 Axis Amplification Keratinocyte chemokines recruit dendritic cells and T cells; dendritic-cell IL-23 sustains IL-17- and IL-22-producing T cells.

Show evidence (4 references)

PMID:22521418 SUPPORT In vitro / ex vivo

"These genes included chemokine (C-C motif) ligand 20 (CCL20) and interleukin 8 (IL8)."

The NF-kappaB targets induced by activating CARD14 alleles in keratinocytes.

PMID:27113748 SUPPORT In vitro / ex vivo

"Moreover, we show that MALT1 deficiency or pharmacological inhibition of MALT1 catalytic activity inhibits pathogenic mutant CARD14-induced cytokine and chemokine expression in human primary keratinocytes."

Mutant CARD14-driven cytokine and chemokine output in primary human keratinocytes, and its MALT1 dependence.

DOI:10.21203/rs.3.rs-2513325/v1 Preprint · not peer-reviewed SUPPORT Model organism

"the hyperactivation of innate immunity via the IL-36 signaling and inflammasome pathways, and the excessive activation of the IL-17 axis in the outer root sheath and interfollicular epidermis"

The PRP-allele knock-in mouse shows the IL-36/inflammasome and IL-17 output in the follicular and interfollicular epidermis.

+ 1 more reference

IL-23/IL-17 Axis Amplification

Recruited dendritic cells produce IL-23, which maintains Th17 and other type 17 lymphocytes producing IL-17A, IL-17F and IL-22 in the dermis. The axis is demonstrated genetically in CARD14 knock-in mice, where IL-23p19 neutralisation or anti-IL-17A antibody reduces disease, and is the target of the biologics that work in patients. Human lesional-skin cytokine profiling showing IL-17A/IL-17F/IL-22 elevation comes from sporadic PRP rather than genotyped familial cases.

T-helper 17 cell CL:0000899 dendritic cell CL:0000451

IL23A hgnc:15488 IL17A hgnc:5981 IL17F hgnc:16404

T-helper 17 type immune response GO:0072538 ↑ INCREASED interleukin-17 production GO:0032620 ↑ INCREASED interleukin-23 production GO:0032627 ↑ INCREASED

dermis UBERON:0002067

Animal models

Card14 C127S knock-in mouse (PRP allele) Mouse recapitulates IL-17 axis activation in follicular and interfollicular epidermis, and clinical improvement with anti-IL-17A antibody.

Card14 delta-E138 knock-in mouse (psoriasis allele) Mouse partially recapitulates The IL-23/IL-17-dependent inflammation downstream of a CARD14 gain-of-function allele, in a heterozygous animal.

Downstream

Epidermal Hyperproliferation and Abnormal Cornification IL-17A, IL-22 and IL-36 drive keratinocyte proliferation, altered differentiation and follicular plugging; the mutant keratinocyte's heightened IL-17A responsiveness sustains the loop.

Show evidence (5 references)

PMID:29689250 SUPPORT Model organism

"Disease pathogenesis was driven by the IL-23/IL-17 axis, and neutralization of IL-23p19, the key cytokine in maintaining T helper type 17 cell polarization, significantly reduced skin lesions and the expression of antimicrobial peptides and proinflammatory cytokines."

IL-23 dependence of CARD14 gain-of-function skin disease in mice.

PMID:33419765 SUPPORT Model organism

"Together, our results suggest a sequence of events under CARD14-mutation-induced psoriasis condition that keratinocyte-intrinsic activation of CBM complex initiates the skin inflammation depending on the IL-23/T17 axis."

Orders keratinocyte CBM activation upstream of the IL-23/T17 axis.

DOI:10.21203/rs.3.rs-2513325/v1 Preprint · not peer-reviewed SUPPORT Model organism

"Administering anti-IL-17A neutralizing antibody significantly attenuates the skin symptoms in mutant mice."

IL-17A dependence of skin disease in the PRP-allele knock-in mouse.

+ 2 more references

Epidermal Hyperproliferation and Abnormal Cornification

Acanthosis with broad rete ridges, alternating vertical and horizontal orthokeratosis and parakeratosis (checkerboard pattern), hypergranulosis, follicular plugging and dilated papillary vessels, with a superficial lymphocytic infiltrate. The Card14 C127S knock-in mouse reproduces hair-follicle dilatation, follicular plugs and palmoplantar hyperkeratosis and shows reduced filaggrin expression with barrier dysfunction.

keratinocyte CL:0000312 outer root sheath cell CL:0002561

keratinocyte proliferation GO:0043616 ↑ INCREASED keratinization GO:0031424 ⚠ ABNORMAL establishment of skin barrier GO:0061436 ↓ DECREASED

skin epidermis UBERON:0001003 hair follicle UBERON:0002073

Animal models

Card14 C127S knock-in mouse (PRP allele) Mouse recapitulates Follicular plugging, follicle dilatation and palmoplantar hyperkeratosis, the histological core of the human disease.

Downstream

Follicular hyperkeratosis Follicular plugging by retained cornified material produces the keratotic follicular papules.

Palmoplantar keratoderma Hyperkeratosis of palmar and plantar epidermis.

Orange-red scaling plaques Confluent acanthosis with checkerboard parakeratosis and dilated papillary vessels gives the erythematous scaling plaques.

Facial erythema The same plaque process involving the cheeks, chin and ears.

Erythroderma Generalisation of the plaque process over most of the body surface.

Checkerboard parakeratosis with follicular plugging The histological correlate of the abnormal cornification.

Show evidence (3 references)

PMID:31849081 SUPPORT Human clinical

"Lesional skin biopsies from patients with CARD14-associated papulosquamous eruption consistently showed alternating checkerboard parakeratosis and orthokeratosis, acanthosis without acantholysis, and dilated vessels in the dermal papillae, with some cases also showing follicular plugging."

The epidermal histopathology in genotyped CARD14 patients.

DOI:10.21203/rs.3.rs-2513325/v1 Preprint · not peer-reviewed SUPPORT Model organism

"The Card14C127S/C127S knock-in mice recapitulate key aspects of human PRP, including hair follicle dilatation, follicular plugs, and palmoplantar hyperkeratosis, and show skin barrier dysfunction"

Follicular plugging, palmoplantar hyperkeratosis and barrier loss in the PRP-allele mouse.

PMID:29689250 SUPPORT Model organism

"Here, we report that heterozygous mice harboring a CARD14 gain-of-function mutation (Card14ΔE138) spontaneously develop a chronic psoriatic phenotype with characteristic scaling skin lesions, epidermal thickening, keratinocyte hyperproliferation, hyperkeratosis, and immune cell infiltration."

Epidermal thickening and keratinocyte hyperproliferation from a heterozygous CARD14 gain-of-function allele.

Replication Stress-Driven Revertant Mosaicism

In some patients, clinically normal skin patches arise in which the epidermis has lost the germline CARD14 mutation, mostly through copy-neutral loss of heterozygosity of 17q. Mutant CARD14 increases double-strand breaks under replication stress and suppresses new origin firing, favouring break-induced replication; this is a somatic compensatory branch, not part of the pathogenic chain, and is observed rather than therapeutically exploitable.

keratinocyte CL:0000312

double-strand break repair via homologous recombination GO:0000724 ↑ INCREASED

Show evidence (2 references)

PMID:34004138 SUPPORT Human clinical

"Here we show that heterozygous pathogenic CARD14 mutations causing autoinflammatory skin diseases, including psoriasis and pityriasis rubra pilaris, are repaired mainly via homologous recombination."

Revertant patches in CARD14-mutant patients, including PRP, arise by homologous recombination.

PMID:34004138 SUPPORT In vitro / ex vivo

"Rather than altering the DNA damage response to exogenous stimuli, such as X-irradiation or etoposide treatment, mutant CARD14 increased DNA double-strand breaks under conditions of replication stress."

The cellular mechanism proposed for the reversion events, from cultured cells.

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Pathograph

Use Group by to collapse related nodes into one box. Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

9

Cardiovascular 1

Facial erythema VERY_FREQUENT HP:0001041

Show evidence (2 references)

PMID:29477734 SUPPORT Human clinical

"The most notable characteristic among the group is prominent facial involvement, which was displayed by all but 1 subject and in most cases presented early in the disease course as symmetric, well-demarcated pink-red patches or thin plaques involving the bilateral cheeks and chin with sparing of..."

Facial involvement in 14 of 15 index cases.

PMID:34448248 SUPPORT Human clinical

"As described in 93% of the 31 previously described patients, all of our patients had facial involvement that occurred early as symmetric, well-demarcated pink-red plaques involving the cheeks, chin, and ears with sparing of the infralabial region."

Facial involvement in 93% of reviewed paediatric cases.

Head and Neck 1

Ectropion OCCASIONAL HP:0000656

Show evidence (2 references)

PMID:40766060 SUPPORT Human clinical

"palmar and plantar waxy orange-red keratoderma, bilateral ectropion and extensive thick scaly plaques on the scalp"

Bilateral ectropion in a 3-year-old with a novel CARD14 variant.

PMID:34448248 SUPPORT Human clinical

"Bilateral ectropion, palmoplantar keratoderma, and scleroderma-like changes in the hands were also noted."

Ectropion in one of the three new paediatric cases.

Immune 1

Erythroderma OCCASIONAL HP:0001019

Show evidence (2 references)

PMID:29477734 SUPPORT Human clinical

"The skin phenotype ranged from predominantly psoriasis-like to predominantly PRP-like, with several patients showing features typical of both diseases. Two patients were erythrodermic."

Two of 15 index cases were erythrodermic.

PMID:39104646 SUPPORT Human clinical

"From aged six weeks and throughout childhood she had scaly erythroderma, sparing the flexural surfaces and parts of the back, and yellowish hyperkeratotic palms and soles."

Infantile-onset erythroderma in a genotyped type V patient.

Integument 6

Follicular hyperkeratosis FREQUENT HP:0007502

Show evidence (2 references)

PMID:34448248 SUPPORT Human clinical

"In the 31 previously reported cases, clinical features typical of PRP such as follicular papules were observed in 45%, islands of sparing in 42%, palmoplantar keratoderma in 68%, and sclerodermatous changes of the hands in 6%."

Frequency of follicular papules across reported paediatric CARD14 cases.

PMID:42561834 SUPPORT Human clinical

"Physical examination revealed generalized erythematous, hyperkeratotic, follicular papules and plaques involving the trunk and extremities, with prominent palmoplantar keratoderma"

Follicular papules in a genotyped type V patient.

Palmoplantar keratoderma VERY_FREQUENT HP:0000982

Show evidence (3 references)

PMID:29477734 SUPPORT Human clinical

"Most (12/15) subjects had some degree of palmoplantar keratoderma, and two had scleroderma-like changes of the hands."

Frequency in the 15-kindred series.

PMID:34448248 SUPPORT Human clinical

"In the 31 previously reported cases, clinical features typical of PRP such as follicular papules were observed in 45%, islands of sparing in 42%, palmoplantar keratoderma in 68%, and sclerodermatous changes of the hands in 6%."

Frequency across 31 reviewed paediatric cases.

PMID:39104646 SUPPORT Human clinical

"From aged six weeks and throughout childhood she had scaly erythroderma, sparing the flexural surfaces and parts of the back, and yellowish hyperkeratotic palms and soles."

Palmoplantar hyperkeratosis from infancy in a genotyped type V patient.

Orange-red scaling plaques VERY_FREQUENT Scaling skin HP:0040189

HPO has no term for islands of sparing or for the orange-red plaque of PRP; the binding is to the scaling itself and the specificity is carried in preferred_term.

Show evidence (3 references)

PMID:40766060 SUPPORT Human clinical

"The further physical examination revealed prominent facial involvement of cheeks and ears with erythematosquamous plaques, palmar and plantar waxy orange-red keratoderma, bilateral ectropion and extensive thick scaly plaques on the scalp (Figure 1A)."

Scaly plaques, scalp scale and keratoderma in a 3-year-old with a novel CARD14 variant.

PMID:28301045 SUPPORT Human clinical

"A 49-year-old woman and her 20-year-old son had lifelong, generalized, patchy erythematous scale with a few islands of sparing, as well as minor nail ridging and mild palmoplantar keratoderma, features consistent with generalized PRP."

Generalized erythematous scale with islands of sparing in a p.Met119Arg family.

PMID:34448248 SUPPORT Human clinical

"In the 31 previously reported cases, clinical features typical of PRP such as follicular papules were observed in 45%, islands of sparing in 42%, palmoplantar keratoderma in 68%, and sclerodermatous changes of the hands in 6%."

Frequency of islands of sparing across reviewed paediatric cases.

Patchy macular hyperpigmentation OCCASIONAL Hyperpigmentation of the skin HP:0000953

Show evidence (1 reference)

PMID:27760266 SUPPORT Human clinical

"All 3 patients displayed unique patchy macular brown hyperpigmentation additionally to other typical features of PRP."

The pigmentary feature in all three genotyped type V patients.

Pruritus FREQUENT HP:0000989

Itch is a feature of the inflamed plaque rather than a separately mechanised phenotype; it is left unconnected rather than wired to a node that does not explain it.

Show evidence (1 reference)

PMID:40433052 SUPPORT Human clinical

"Eight of these patients reported pruritus."

Pruritus in all eight genotyped paediatric CAPE patients.

Checkerboard parakeratosis with follicular plugging VERY_FREQUENT HP:0001036

Show evidence (2 references)

PMID:31849081 SUPPORT Human clinical

"Lesional skin biopsies from patients with CARD14-associated papulosquamous eruption consistently showed alternating checkerboard parakeratosis and orthokeratosis, acanthosis without acantholysis, and dilated vessels in the dermal papillae, with some cases also showing follicular plugging."

The defining histopathology in genotyped patients.

PMID:31849081 SUPPORT Human clinical

"CARD14-associated papulosquamous eruption has a range of findings, with a predominance of features typically associated with pityriasis rubra pilaris."

The histology favours PRP over psoriasis.

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Genetic Associations

1

CARD14 (Causative)

Gene: CARD14 hgnc:16446 gene page relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (3 references)

PMID:22703878 SUPPORT Human clinical

"Using a combination of linkage analysis followed by targeted whole-exome sequencing and candidate-gene screening, we identified three different heterozygous mutations in CARD14, which encodes caspase recruitment domain family, member 14."

Gene discovery by linkage and exome sequencing in four dominant kindreds.

PMID:22703878 SUPPORT Human clinical

"The present data demonstrate that autosomal-dominant PRP is allelic to familial psoriasis, which was recently shown to also be caused by mutations in CARD14."

Allelism with PSORS2 psoriasis.

PMID:38159213 SUPPORT REVIEW SYNTHESIS Human clinical

"Type V PRP is often due to inborn CARD14 mutations."

Review placing CARD14 as the cause of the type V clinical form.

Variants (7)

CARD14 p.Leu156Pro (c.467T>C) Pathogenic

single nucleotide variant

Coiled-coil missense allele found in two unrelated gene-discovery families on different haplotypes.

Show evidence (1 reference)

PMID:22703878 SUPPORT Human clinical

"we identified three different heterozygous mutations in CARD14"

One of the three gene-discovery alleles; the abstract does not name the individual alleles, which are given in the body of the paper.

CARD14 p.Cys127Ser Pathogenic

single nucleotide variant

De novo coiled-coil missense allele in a Japanese type V patient; the allele modelled in the Card14 C127S knock-in mouse.

Show evidence (1 reference)

PMID:27760266 SUPPORT Human clinical

"2 de novo novel mutations (p.Cys127Ser and p.Gln136Leu), and another previously reported mutation (p.Gly117Ser)"

De novo p.Cys127Ser in a type V patient.

CARD14 p.Gln136Leu Pathogenic

single nucleotide variant

De novo coiled-coil missense allele in a Japanese type V patient.

Show evidence (1 reference)

PMID:27760266 SUPPORT Human clinical

"2 de novo novel mutations (p.Cys127Ser and p.Gln136Leu), and another previously reported mutation (p.Gly117Ser)"

De novo p.Gln136Leu in a type V patient.

CARD14 p.Gly117Ser (c.349G>A) Pathogenic

single nucleotide variant

Exon 3 terminal missense allele that also alters splicing between exons 3 and 4; the founding PSORS2 psoriasis allele, also found in type V PRP and, in homozygous form, in a severe CAPE proband.

Show evidence (2 references)

PMID:22521418 SUPPORT Human clinical

"The mutations c.349G>A (p.Gly117Ser) (in the family of European descent) and c.349+5G>A (in the Taiwanese family) altered splicing between CARD14 exons 3 and 4."

The allele and its splicing effect in the PSORS2 psoriasis kindred.

PMID:27760266 SUPPORT Human clinical

"another previously reported mutation (p.Gly117Ser)"

The same allele in a type V PRP patient.

CARD14 p.Met119Arg (c.356T>G) Pathogenic

single nucleotide variant

Coiled-coil missense allele in a mother and son with generalized PRP.

Show evidence (1 reference)

PMID:28301045 SUPPORT Human clinical

"Following informed consent, Sanger sequencing of CARD14 in both individuals revealed a new heterozygous single-nucleotide transversion in exon 4, c.356T>G, resulting in the missense mutation p.Met119Arg."

Segregating allele in a two-generation family.

CARD14 p.Met119Thr (c.356T>C) Pathogenic

single nucleotide variant

Coiled-coil missense allele at the same codon as p.Met119Arg and p.Met119Lys.

Show evidence (1 reference)

PMID:42561834 SUPPORT Human clinical

"Whole-exome sequencing identified a heterozygous missense variant in CARD14 (NM_001366385.1: c.356T>C; p.Met119Thr), classified as likely pathogenic per American College of Medical Genetics and Genomics criteria (PM1, PM2, PM5, PP5, BP4), establishing the diagnosis of type 5 PRP."

Allele in a woman with lifelong type V PRP and affected first-degree relatives.

CARD14 p.Glu138Lys (c.412G>A) Pathogenic

single nucleotide variant

Coiled-coil missense allele at the codon that also carries the psoriasis alleles p.Glu138Ala and p.Glu138del; reported in lifelong PRP diagnosed at age 70.

Show evidence (1 reference)

PMID:33431438 SUPPORT Human clinical

"We present a case of lifelong PRP in a 70-year-old woman, where genetic testing revealed a heterozygote missense variant c.412G>A, p.(Glu138Lys) in CARD14."

Allele in a late-diagnosed lifelong case.

💊

Medical Actions

7

Ustekinumab (IL-12/IL-23 p40 blockade)

Action: Pharmacotherapy NCIT:C15986

Agent: ustekinumab NCIT:C84237

Platform: Monoclonal antibody

The best-documented therapy: near-complete clearance in 5 of 6 treated subjects in the 15-kindred series and in several familial PRP families, often after failure of retinoids, methotrexate and TNF inhibitors. Weight-based or more frequent dosing than the psoriasis label has been needed to maintain response.

Mechanism Target:

INHIBITS IL-23/IL-17 Axis Amplification — Binds the shared p40 subunit of IL-12 and IL-23, removing the IL-23 signal that maintains the type 17 response.

Show evidence (1 reference)

PMID:29477734 SUPPORT INDIRECT Human clinical

"Notable is the near complete response to ustekinumab in 5 of 6 subjects treated and partial response in the sixth (subject 5), who had the most severe phenotype and was also notably the heaviest and thus may have required a higher dosage."

Clinical response to p40 blockade as evidence that the axis drives the disease.

Show evidence (4 references)

PMID:29477734 SUPPORT Human clinical

"Notable is the near complete response to ustekinumab in 5 of 6 subjects treated and partial response in the sixth (subject 5), who had the most severe phenotype and was also notably the heaviest and thus may have required a higher dosage."

Response in six genotyped subjects.

PMID:28301045 SUPPORT Human clinical

"Ustekinumab, at a dose of 45 mg every 12 weeks, brought about a significant physical and emotional improvement in both the mother and son within a few days of the initial dose, which was sustained on maintenance dosing."

Sustained response in a p.Met119Arg family.

PMID:33431438 SUPPORT Human clinical

"Therapy with ustekinumab was initiated with remarkable effect, which improved the patient's quality of life significantly."

Response in a p.Glu138Lys patient after a lifetime of disease.

+ 1 more reference

IL-17 blockade (secukinumab, ixekizumab, bimekizumab)

Action: Pharmacotherapy NCIT:C15986

Agent: secukinumab NCIT:C152315 ixekizumab NCIT:C174646 bimekizumab NCIT:C171829

Platform: Monoclonal antibody

Secukinumab gave 84.6%, 76.9% and 68.8% PASI improvement at 52 weeks in three genotyped children, and ixekizumab produced rapid clearance in genotyped type V patients, although one subject in the 15-kindred series had only a partial response to ixekizumab. Three adult CAPE patients reported in the literature improved on the IL-17A/F inhibitor bimekizumab. In the Card14 C127S mouse anti-IL-17A reduced inflammation without restoring barrier function.

Mechanism Target:

INHIBITS IL-23/IL-17 Axis Amplification — Neutralises IL-17A, the effector cytokine of the axis and the ligand of the CARD14-dependent keratinocyte IL-17 receptor pathway.

Show evidence (1 reference)

DOI:10.21203/rs.3.rs-2513325/v1 Preprint · not peer-reviewed SUPPORT Model organism

"Administering anti-IL-17A neutralizing antibody significantly attenuates the skin symptoms in mutant mice."

Preclinical IL-17A dependence of the PRP-allele mouse disease.

Show evidence (6 references)

PMID:40433052 SUPPORT Human clinical

"They achieved 84.6%, 76.9%, and 68.8% improvement in PASI score, respectively."

52-week PASI responses to secukinumab in three genotyped children.

PMID:40433052 SUPPORT REVIEW SYNTHESIS Human clinical

"Following the treatment with IL-17A inhibitors (five pediatric patients receiving secukinumab, two adult patients receiving ixekizumab and three adult patients receiving bimekizumab, an IL-17A/F inhibitor), there was significant improvement in skin lesions, and pruritus was alleviated or resolved."

The authors' pooled summary of their own cases and the reported literature, including the three adults treated with bimekizumab.

PMID:40766060 SUPPORT Human clinical

"Here, we present a case of successful treatment with ixekizumab, a humanized monoclonal anti-IL-17A antibody, in an atypical juvenile PRP (type V) patient with a novel variant of CARD14 mutation."

Ixekizumab response in a genotyped type V child.

+ 3 more references

Systemic retinoids (acitretin, isotretinoin)

Action: Pharmacotherapy NCIT:C15986

Agent: acitretin CHEBI:50172 isotretinoin CHEBI:6067

Platform: Small molecule

Oral retinoids are the conventional first-line systemic therapy for juvenile PRP and control some CARD14 patients, but responses in genotyped series are variable and often partial, and several families failed retinoids before responding to biologics.

Mechanism Target:

MODULATES Epidermal Hyperproliferation and Abnormal Cornification — Retinoids normalise keratinocyte differentiation and cornification without acting on the upstream CARD14 signal.

Show evidence (4 references)

PMID:34075616 SUPPORT Human clinical

"She was refractory to treatment with topical emollients and topical corticosteroids, but responsive to oral acitretin."

Acitretin response in a genotyped toddler.

PMID:39104646 SUPPORT Human clinical

"Her skin was very well controlled on acitretin 20 mg daily for many years."

Long-term acitretin control before a switch for pregnancy planning.

PMID:28301045 REFUTE Human clinical

"Topical steroids, phototherapy and oral retinoids proved ineffective."

Retinoid failure in a p.Met119Arg family.

+ 1 more reference

TNF inhibition (etanercept)

Action: Pharmacotherapy NCIT:C15986

Agent: etanercept NCIT:C2381

Platform: Protein replacement

TNF inhibitors, like topical therapy and methotrexate, give little benefit in most CARD14 patients: of eight subjects treated with etanercept monotherapy in the 15-kindred series, one had a partial response, six minimal response and one worsened. Recorded here as a documented poor response rather than a recommended treatment.

Show evidence (1 reference)

PMID:29477734 REFUTE Human clinical

"Among the eight subjects who had been treated with etanercept as monotherapy, only one subject demonstrated partial response, six had minimal response, and one had worsening."

Poor response to etanercept in genotyped subjects.

Topical therapy (corticosteroids, calcineurin inhibitors, vitamin D analogues)

Action: topical pharmacotherapy Ontology label: Pharmacotherapy NCIT:C15986

Agent: topical corticosteroid CHEBI:50858

Platform: Small molecule

Topical corticosteroids, calcineurin inhibitors, vitamin D analogues, topical retinoids and tar preparations gave universally minimal responses across the 15-kindred series. Recorded as a documented poor response, not a recommended treatment.

Show evidence (1 reference)

PMID:29477734 REFUTE Human clinical

"Response to topical medications, including corticosteroids, calcineurin inhibitors, Vitamin D analogues, topical retinoids, and tar preparations had been universally minimal among the group."

Minimal response to every class of topical therapy in the genotyped series.

Methotrexate

Action: Pharmacotherapy NCIT:C15986

Agent: methotrexate CHEBI:44185

Platform: Small molecule

Methotrexate has been used in CARD14 patients as a conventional psoriasis agent with variable and generally inadequate response in the 15-kindred series, where failure of methotrexate, acitretin or TNF inhibition is treated as part of the picture suggesting CAPE. Recorded as a documented poor response, not a recommended treatment.

Show evidence (2 references)

PMID:29477734 SUPPORT Human clinical

"Responses to other treatments, including phototherapy, oral retinoids, methotrexate, cyclosporine and biological therapies had been variable and are detailed in the Table."

Methotrexate was among the conventional agents used in the series, with variable response.

PMID:29477734 SUPPORT Human clinical

"the constellation of findings are highly suggestive of CAPE, particularly when coupled with inadequate response to conventional psoriasis therapies such as methotrexate, acitretin or TNF-α inhibitors."

The authors treat inadequate response to methotrexate as characteristic of the genotyped disease.

MALT1 protease inhibition (preclinical)

Action: Pharmacotherapy NCIT:C15986

Platform: Small molecule

Genetic deletion or oral pharmacological inhibition of MALT1 protease in keratinocytes suppresses CARD14 E138A-driven skin disease in mice. This is a mechanism-directed rationale established in psoriasis-allele models; no MALT1 inhibitor has been given to a patient with familial PRP.

Mechanism Target:

INHIBITS Constitutive CARD14-BCL10-MALT1 Complex Assembly — Blocks the paracaspase activity of MALT1 within the mutant CARD14 signalosome.

Show evidence (2 references)

PMID:32343482 SUPPORT Model organism

"Keratinocyte-specific MALT1 deletion as well as oral treatment of mice with a specific MALT1 protease inhibitor strongly reduces psoriatic skin disease in CARD14E138A mice."

In vivo proof of concept for MALT1 inhibition against mutant CARD14 signalling.

PMID:27113748 SUPPORT In vitro / ex vivo

"Moreover, we show that MALT1 deficiency or pharmacological inhibition of MALT1 catalytic activity inhibits pathogenic mutant CARD14-induced cytokine and chemokine expression in human primary keratinocytes."

MALT1 inhibition blunts mutant CARD14 output in human keratinocytes.

🔬

Diagnosis

2

CARD14 sequencing

Sequencing of CARD14 coding exons and splice junctions (single-gene, keratinization panel or exome) in a child with early-onset papulosquamous disease, prominent facial involvement, a family history of PRP or psoriasis, and poor response to conventional therapy; deep sequencing of lesional skin can detect mosaic alleles missed in blood.

CARD14 gene sequencing NCIT:C15709

Show evidence (2 references)

PMID:29477734 SUPPORT Human clinical

"Subjects with clinical features suggestive of CAPE should undergo CARD14 sequencing and may benefit from treatment with ustekinumab."

Recommendation for CARD14 sequencing from the largest genotyped series.

PMID:40433052 SUPPORT Human clinical

"Whole-exome sequencing (WES) was performed in all patients to identify the mutation type."

Exome sequencing as the diagnostic route in a paediatric series.

Lesional skin biopsy

Histopathology showing checkerboard parakeratosis and orthokeratosis, acanthosis without acantholysis and follicular plugging supports PRP over psoriasis, but the overlap with psoriasis means biopsy cannot replace genotyping.

Skin biopsy NCIT:C51692

Show evidence (1 reference)

PMID:31849081 SUPPORT Human clinical

"CARD14-associated papulosquamous eruption has a range of findings, with a predominance of features typically associated with pityriasis rubra pilaris."

Biopsy findings in genotyped patients.

📈

Progression

2

Infantile onset

Age: Birth to 3 years (4 to 36 months in the gene-discovery kindreds; before 1 year in most CARD14 index cases)

Facial erythema and scale usually precede truncal and palmoplantar disease.

Show evidence (2 references)

PMID:29477734 SUPPORT Human clinical

"With the exception of 2 subjects, all had onset of their disease at or before one year of age."

Onset timing in the 15-kindred series.

PMID:34448248 SUPPORT REVIEW SYNTHESIS Human clinical

"Patients with CARD14 mutations can be distinguished from more common forms of psoriasis and acquired PRP by the early age of onset (primarily before 1 year of age), prominent facial involvement (cheeks, chin and ears), frequent family history of psoriasis or PRP, and limited response to..."

Early onset as a distinguishing feature of CARD14-related disease.

Chronic persistent course

Age: Childhood through adult life

Unlike classic adult (type I) PRP, which usually remits within a few years, the familial form persists lifelong without treatment, with flares during intercurrent infection; somatic revertant patches can appear but do not generalise.

Show evidence (2 references)

PMID:29477734 SUPPORT Human clinical

"None has experienced remission of disease without treatment."

No spontaneous remission in 15 kindreds.

PMID:33431438 SUPPORT Human clinical

"We present a case of lifelong PRP in a 70-year-old woman, where genetic testing revealed a heterozygote missense variant c.412G>A, p.(Glu138Lys) in CARD14."

Lifelong persistence into the eighth decade.

📊

Prevalence

1

Worldwide (familial cases as a fraction of all PRP)

Unknown Rare

No population prevalence has been measured for the familial form. Familial, autosomal dominant PRP is reported as under 6% of all PRP, itself a rare disease; the largest genotyped series is 15 kindreds.

Show evidence (2 references)

PMID:25734815 SUPPORT BACKGROUND Human clinical

"Most cases of PRP are sporadic and without family history, but a familial form with an autosomal dominant inheritance with partial penetrance represents <6% of all cases."

The familial fraction of PRP, stated as background in a CARD14 polymorphism study of sporadic PRP.

PMID:28301045 SUPPORT BACKGROUND Human clinical

"Pityriasis rubra pilaris (PRP) represents a group of rare chronic inflammatory skin disorders in which around one in 20 affected individuals show autosomal dominant inheritance."

Independent estimate that about one in twenty PRP patients has the dominant familial form.

🐁

Animal Models

2

Card14 C127S knock-in mouse (PRP allele)

The first mouse carrying a PRP-causing human allele. Homozygotes develop generalized scaling, hair-follicle dilatation and plugging, palmoplantar hyperkeratosis, markedly increased transepidermal water loss, IL-36/inflammasome and IL-17-axis activation in the outer root sheath and interfollicular epidermis, and high neonatal mortality; anti-IL-17A improves inflammation but not barrier function. Heterozygotes, the genotype that matches patients, have mild transient disease.

Species

Mouse

Genotype

Card14 c.380G>C (p.Cys127Ser) knock-in, homozygous (heterozygotes show milder, transient disease)

Publication

PMID:39159782

Pathograph links

Epidermal Hyperproliferation and Abnormal Cornification recapitulates fidelity: moderate observes: tissue Follicular plugging, follicle dilatation and palmoplantar hyperkeratosis, the histological core of the human disease.

Limitations: The full phenotype requires homozygosity, whereas patients are heterozygous; heterozygous mice have only mild, self-resolving disease.

Show evidence (1 reference)

DOI:10.21203/rs.3.rs-2513325/v1 Preprint · not peer-reviewed SUPPORT Model organism

"The Card14C127S/C127S knock-in mice recapitulate key aspects of human PRP, including hair follicle dilatation, follicular plugs, and palmoplantar hyperkeratosis"

The follicular and palmoplantar phenotype of the homozygous knock-in.

IL-23/IL-17 Axis Amplification recapitulates fidelity: moderate observes: tissue IL-17 axis activation in follicular and interfollicular epidermis, and clinical improvement with anti-IL-17A antibody.

Limitations: Anti-IL-17A improved inflammation but not transepidermal water loss, so inflammation and barrier dysfunction are separable in this model.

Show evidence (1 reference)

DOI:10.21203/rs.3.rs-2513325/v1 Preprint · not peer-reviewed SUPPORT Model organism

"Administering anti-IL-17A neutralizing antibody significantly attenuates the skin symptoms in mutant mice."

IL-17A dependence of the model's skin disease.

The peer-reviewed report is PMID:39159782 (J Invest Dermatol 2025). The quoted sentences are from the authors' 2023 Research Square preprint of the same study (DOI:10.21203/rs.3.rs-2513325/v1), which reports the same allele, genotype and anti-IL-17A result.

Show evidence (1 reference)

DOI:10.21203/rs.3.rs-2513325/v1 Preprint · not peer-reviewed SUPPORT Model organism

"We report the first mouse model of PRP to carry a homozygous knock-in mutation, c.380G>C (p.Cys127Ser) corresponding to a PRP-causative human mutation, in CARD14."

Establishes the model: a knock-in of a human PRP-causing CARD14 allele.

Card14 delta-E138 knock-in mouse (psoriasis allele)

Heterozygous knock-in of a psoriasis-associated gain-of-function allele from the same coiled-coil region. Mice spontaneously develop chronic psoriasiform scaling, epidermal thickening, keratinocyte hyperproliferation and a neutrophil- and T-cell-rich infiltrate driven by the IL-23/IL-17 axis; IL-23p19 neutralisation reduces disease. Related Card14 E138A knock-ins show that the disease is keratinocyte-intrinsic and depends on the CBM complex.

Species

Mouse

Genotype

Card14 p.Glu138del knock-in, heterozygous

Publication

PMID:29689250

Pathograph links

IL-23/IL-17 Axis Amplification partially recapitulates fidelity: moderate observes: tissue The IL-23/IL-17-dependent inflammation downstream of a CARD14 gain-of-function allele, in a heterozygous animal.

Limitations: The allele is a psoriasis allele and the readout is psoriasiform rather than PRP-like dermatitis, without follicular plugging or palmoplantar keratoderma.

Show evidence (1 reference)

PMID:29689250 SUPPORT Model organism

"Disease pathogenesis was driven by the IL-23/IL-17 axis, and neutralization of IL-23p19, the key cytokine in maintaining T helper type 17 cell polarization, significantly reduced skin lesions and the expression of antimicrobial peptides and proinflammatory cytokines."

IL-23 dependence of the model.

Constitutive CARD14-BCL10-MALT1 Complex Assembly perturbs fidelity: moderate observes: cellular Keratinocyte-specific deletion of MALT1 or BCL10 in the related Card14 E138A/+ knock-in abolishes skin and systemic inflammation, placing the keratinocyte CBM complex upstream of the whole cascade.

Limitations: Shown for the E138A psoriasis allele; the PRP alleles have not been tested this way in vivo.

Show evidence (2 references)

PMID:33419765 SUPPORT Model organism

"Targeting CBM complex by conditional deletion of MALT1 or BCL10 in keratinocytes abrogated both the cutaneous and systemic inflammation of heterozygous Card14 E138A/+ mice."

Genetic epistasis placing the CBM complex upstream in vivo.

+ 1 more reference

Show evidence (1 reference)

PMID:29689250 SUPPORT Model organism

"Here, we report that heterozygous mice harboring a CARD14 gain-of-function mutation (Card14ΔE138) spontaneously develop a chronic psoriatic phenotype with characteristic scaling skin lesions, epidermal thickening, keratinocyte hyperproliferation, hyperkeratosis, and immune cell infiltration."

Establishes the model: a heterozygous knock-in of a psoriasis-associated CARD14 gain-of-function allele with spontaneous skin disease.

{ }

Source YAML

click to show

name: Familial Pityriasis Rubra Pilaris
creation_date: "2026-10-13T12:00:00Z"
category: Mendelian
description: >-
  Familial pityriasis rubra pilaris is the autosomal dominant, CARD14-defined form of
  pityriasis rubra pilaris (PRP), corresponding to Griffiths type V (atypical juvenile)
  PRP and the PRP-like end of the CARD14-associated papulosquamous eruption (CAPE)
  spectrum. Heterozygous gain-of-function CARD14 variants, clustered in and around the
  coiled-coil domain, break the autoinhibition of the keratinocyte scaffold CARD14 so
  that it constitutively assembles with BCL10 and MALT1 and activates NF-kappaB. The
  resulting keratinocyte chemokine and cytokine output recruits and amplifies an
  IL-23/IL-17 response, producing infantile-onset follicular hyperkeratosis, orange-red
  scaling plaques with islands of sparing, prominent facial erythema and palmoplantar
  keratoderma that respond poorly to conventional psoriasis therapy but well to IL-12/23
  and IL-17A blockade. This entry is scoped to the CARD14-defined familial form. The
  sporadic clinical types of PRP (Griffiths types I-IV and the HIV-associated type VI)
  have no single conserved mechanism and are out of scope here; the broader concept
  pityriasis rubra pilaris (MONDO:0100017) is mapped only as a broad match. CARD14
  gain-of-function variants also cause PSORS2 familial psoriasis, which is curated in
  the Psoriasis entry and cross-referenced rather than duplicated.
disease_term:
  preferred_term: familial pityriasis rubra pilaris
  term:
    id: MONDO:0008251
    label: familial pityriasis rubra pilaris
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0100017
      label: pityriasis rubra pilaris
    mapping_predicate: skos:broadMatch
    mapping_source: MONDO
    mapping_justification: >-
      The MONDO parent concept covers all six Griffiths clinical types of PRP; this
      entry covers only the CARD14-defined familial (type V) form.
synonyms:
- hereditary pityriasis rubra pilaris
- pityriasis rubra pilaris, familial type
- PRP type V (atypical juvenile)
- atypical juvenile pityriasis rubra pilaris
- CARD14-associated papulosquamous eruption, PRP-like
parents:
- Hereditary skin disorder
notes: >-
  Orphanet has no familial-specific PRP record, so no ORPHA: structured-source row is
  cited. ClinGen has not published a gene-disease validity assertion for CARD14 in
  pityriasis rubra pilaris, so gene_disease_validity is left absent rather than
  assigned. No GeneReviews chapter exists for this disease (offline Bookshelf index,
  2026-09-10 snapshot). The guselkumab, ixekizumab and secukinumab single-arm trials in
  adult PRP (NCT03975153, NCT03485976, NCT03342573) enrolled no participants with
  pathogenic CARD14 variants and are therefore not recorded as trials of this disease.
  Onset is infantile (4 to 36 months in the gene-discovery kindreds, before one year in
  most CARD14 index cases) and is recorded under progression; HP:0003593 Infantile onset
  is a clinical-course modifier outside the PhenotypeTerm enum and is not bound as a
  phenotype.
prevalence:
- population: Worldwide (familial cases as a fraction of all PRP)
  measure_type: UNKNOWN
  prevalence_class: RARE
  notes: >-
    No population prevalence has been measured for the familial form. Familial,
    autosomal dominant PRP is reported as under 6% of all PRP, itself a rare disease;
    the largest genotyped series is 15 kindreds.
  evidence:
  - reference: PMID:25734815
    reference_title: "Analysis of CARD14 Polymorphisms in Pityriasis Rubra Pilaris: Activation of NF-κB."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Most cases of PRP are sporadic and without family history, but a familial form with an autosomal dominant inheritance with partial penetrance represents <6% of all cases."
    explanation: >-
      The familial fraction of PRP, stated as background in a CARD14 polymorphism
      study of sporadic PRP.
  - reference: PMID:28301045
    reference_title: Beneficial effect of ustekinumab in familial pityriasis rubra pilaris with a new missense mutation in CARD14.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Pityriasis rubra pilaris (PRP) represents a group of rare chronic inflammatory skin disorders in which around one in 20 affected individuals show autosomal dominant inheritance."
    explanation: >-
      Independent estimate that about one in twenty PRP patients has the dominant
      familial form.
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: INCOMPLETE
  expressivity: VARIABLE
  description: >-
    Heterozygous CARD14 variants segregate dominantly in multigeneration kindreds and
    also arise de novo; two of the three type V patients in the first Japanese series
    carried de novo variants. Penetrance is incomplete and expression ranges from
    limited plaques to erythroderma within the same family.
  evidence:
  - reference: PMID:22703878
    reference_title: Familial pityriasis rubra pilaris is caused by mutations in CARD14.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To identify the genetic cause of familial PRP, we ascertained four unrelated families affected by autosomal-dominant PRP."
    explanation: >-
      Dominant transmission in the four gene-discovery kindreds.
  - reference: PMID:25734815
    reference_title: "Analysis of CARD14 Polymorphisms in Pityriasis Rubra Pilaris: Activation of NF-κB."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Most cases of PRP are sporadic and without family history, but a familial form with an autosomal dominant inheritance with partial penetrance represents <6% of all cases."
    explanation: >-
      Records the partial penetrance of the dominant familial form.
  - reference: PMID:27760266
    reference_title: Pityriasis Rubra Pilaris Type V as an Autoinflammatory Disease by CARD14 Mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among 3 patients with PRP type V, all were found to have CARD14 mutations: 2 de novo novel mutations (p.Cys127Ser and p.Gln136Leu), and another previously reported mutation (p.Gly117Ser)."
    explanation: >-
      De novo occurrence of the same dominant alleles, so a negative family history
      does not exclude the diagnosis.
genetic:
- name: CARD14
  gene_term:
    preferred_term: CARD14
    term:
      id: hgnc:16446
      label: CARD14
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  association: Causative
  notes: >-
    Heterozygous gain-of-function variants in CARD14 (caspase recruitment domain family
    member 14, CARMA2), the keratinocyte scaffold that activates NF-kappaB. Familial
    PRP alleles cluster in the coiled-coil domain and the exon 3/4 splice junction, the
    same region that carries the PSORS2 psoriasis alleles; the two diseases are allelic
    and the same gene is curated as causative for PSORS2 familial psoriasis in the
    Psoriasis entry. ClinGen has not classified the CARD14-PRP pair, so no
    gene_disease_validity tier is recorded.
  evidence:
  - reference: PMID:22703878
    reference_title: Familial pityriasis rubra pilaris is caused by mutations in CARD14.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Using a combination of linkage analysis followed by targeted whole-exome sequencing and candidate-gene screening, we identified three different heterozygous mutations in CARD14, which encodes caspase recruitment domain family, member 14."
    explanation: >-
      Gene discovery by linkage and exome sequencing in four dominant kindreds.
  - reference: PMID:22703878
    reference_title: Familial pityriasis rubra pilaris is caused by mutations in CARD14.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The present data demonstrate that autosomal-dominant PRP is allelic to familial psoriasis, which was recently shown to also be caused by mutations in CARD14."
    explanation: >-
      Allelism with PSORS2 psoriasis.
  - reference: PMID:38159213
    reference_title: "Pityriasis Rubra Pilaris: An Updated Review of Clinical Presentation, Etiopathogenesis, and Treatment Options."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Type V PRP is often due to inborn CARD14 mutations."
    explanation: >-
      Review placing CARD14 as the cause of the type V clinical form.
  variants:
  - name: CARD14 p.Leu156Pro (c.467T>C)
    description: >-
      Coiled-coil missense allele found in two unrelated gene-discovery families on
      different haplotypes.
    variant_type: single nucleotide variant
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:22703878
      reference_title: Familial pityriasis rubra pilaris is caused by mutations in CARD14.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "we identified three different heterozygous mutations in CARD14"
      explanation: >-
        One of the three gene-discovery alleles; the abstract does not name the
        individual alleles, which are given in the body of the paper.
  - name: CARD14 p.Cys127Ser
    description: >-
      De novo coiled-coil missense allele in a Japanese type V patient; the allele
      modelled in the Card14 C127S knock-in mouse.
    variant_type: single nucleotide variant
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:27760266
      reference_title: Pityriasis Rubra Pilaris Type V as an Autoinflammatory Disease by CARD14 Mutations.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "2 de novo novel mutations (p.Cys127Ser and p.Gln136Leu), and another previously reported mutation (p.Gly117Ser)"
      explanation: >-
        De novo p.Cys127Ser in a type V patient.
  - name: CARD14 p.Gln136Leu
    description: De novo coiled-coil missense allele in a Japanese type V patient.
    variant_type: single nucleotide variant
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:27760266
      reference_title: Pityriasis Rubra Pilaris Type V as an Autoinflammatory Disease by CARD14 Mutations.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "2 de novo novel mutations (p.Cys127Ser and p.Gln136Leu), and another previously reported mutation (p.Gly117Ser)"
      explanation: >-
        De novo p.Gln136Leu in a type V patient.
  - name: CARD14 p.Gly117Ser (c.349G>A)
    description: >-
      Exon 3 terminal missense allele that also alters splicing between exons 3 and 4;
      the founding PSORS2 psoriasis allele, also found in type V PRP and, in
      homozygous form, in a severe CAPE proband.
    variant_type: single nucleotide variant
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:22521418
      reference_title: PSORS2 is due to mutations in CARD14.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The mutations c.349G>A (p.Gly117Ser) (in the family of European descent) and c.349+5G>A (in the Taiwanese family) altered splicing between CARD14 exons 3 and 4."
      explanation: >-
        The allele and its splicing effect in the PSORS2 psoriasis kindred.
    - reference: PMID:27760266
      reference_title: Pityriasis Rubra Pilaris Type V as an Autoinflammatory Disease by CARD14 Mutations.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "another previously reported mutation (p.Gly117Ser)"
      explanation: >-
        The same allele in a type V PRP patient.
  - name: CARD14 p.Met119Arg (c.356T>G)
    description: Coiled-coil missense allele in a mother and son with generalized PRP.
    variant_type: single nucleotide variant
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:28301045
      reference_title: Beneficial effect of ustekinumab in familial pityriasis rubra pilaris with a new missense mutation in CARD14.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Following informed consent, Sanger sequencing of CARD14 in both individuals revealed a new heterozygous single-nucleotide transversion in exon 4, c.356T>G, resulting in the missense mutation p.Met119Arg."
      explanation: >-
        Segregating allele in a two-generation family.
  - name: CARD14 p.Met119Thr (c.356T>C)
    description: Coiled-coil missense allele at the same codon as p.Met119Arg and p.Met119Lys.
    variant_type: single nucleotide variant
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:42561834
      reference_title: Ixekizumab for genetically confirmed type 5 pityriasis rubra pilaris with a CARD14 p.Met119Thr variant.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Whole-exome sequencing identified a heterozygous missense variant in CARD14 (NM_001366385.1: c.356T>C; p.Met119Thr), classified as likely pathogenic per American College of Medical Genetics and Genomics criteria (PM1, PM2, PM5, PP5, BP4), establishing the diagnosis of type 5 PRP."
      explanation: >-
        Allele in a woman with lifelong type V PRP and affected first-degree relatives.
  - name: CARD14 p.Glu138Lys (c.412G>A)
    description: >-
      Coiled-coil missense allele at the codon that also carries the psoriasis alleles
      p.Glu138Ala and p.Glu138del; reported in lifelong PRP diagnosed at age 70.
    variant_type: single nucleotide variant
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:33431438
      reference_title: "Identification of a pathogenic CARD14 mutation in a 70-year-old woman with pityriasis rubra pilaris: when genetic diagnosis influences choice of treatment strategy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We present a case of lifelong PRP in a 70-year-old woman, where genetic testing revealed a heterozygote missense variant c.412G>A, p.(Glu138Lys) in CARD14."
      explanation: >-
        Allele in a late-diagnosed lifelong case.
pathophysiology:
- name: CARD14 Gain-of-Function Variant
  biological_scale: MOLECULAR
  description: >-
    Heterozygous missense, in-frame deletion or splice-site variants clustered in the
    coiled-coil domain of CARD14 (CARMA2), the skin-restricted member of the CARMA
    scaffold family. The variants disrupt the autoinhibitory contact between the linker
    region and the CARD/coiled-coil domains, so that the mutant scaffold signals without
    an upstream stimulus. Gain of function is demonstrated biochemically for the
    psoriasis alleles p.Glu138Ala and p.Gly117Ser (the latter also a PRP allele) and
    inferred for the other PRP alleles from their position in the same domain and the
    NF-kappaB activation seen in patient skin.
  notes: >-
    GO:0035591 signaling adaptor activity is CARD14's QuickGO molecular-function
    annotation (Q9BXL6, IBA). The modifier is GAIN_OF_FUNCTION rather than INCREASED
    because the mutant scaffold has escaped its linker-region autoinhibition and
    signals independently of any upstream stimulus, a qualitative change in
    regulatory control.
  genetic_context:
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    functional_impact_category: GAIN_OF_FUNCTION
    description: >-
      Dominant, usually inherited but sometimes de novo; one homozygous p.Gly117Ser CAPE
      proband was more severely affected than her heterozygous relatives.
  genes:
  - preferred_term: CARD14
    term:
      id: hgnc:16446
      label: CARD14
  molecular_functions:
  - preferred_term: CARD14 signaling adaptor activity, constitutively active
    modifier: GAIN_OF_FUNCTION
    term:
      id: GO:0035591
      label: signaling adaptor activity
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  evidence:
  - reference: PMID:22703878
    reference_title: Familial pityriasis rubra pilaris is caused by mutations in CARD14.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CARD14 was found to be specifically expressed in the skin."
    explanation: >-
      Skin-restricted expression places the lesion in keratinocytes.
  - reference: PMID:27071417
    reference_title: Psoriasis mutations disrupt CARD14 autoinhibition promoting BCL10-MALT1-dependent NF-κB activation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: "These alterations disrupted the inhibitory effect of the CARD14 linker region (LR) on NF-κB activation by facilitating BCL10 binding."
    explanation: >-
      Loss of linker-region autoinhibition shown for the psoriasis alleles p.Glu138Ala
      and p.Gly117Ser; the latter also causes type V PRP, and the PRP-specific alleles
      lie in the same coiled-coil region, so the mechanism is inferred for them.
  - reference: PMID:29980436
    reference_title: Gain-of-Function Mutation of Card14 Leads to Spontaneous Psoriasis-like Skin Inflammation through Enhanced Keratinocyte Response to IL-17A.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: "Here we showed that Card14E138A/+ and Card14ΔQ136/+ mice developed spontaneous psoriasis-like skin inflammation, which resulted from constitutively activated CARMA2 via self-aggregation leading to the enhanced activation of the IL-23-IL-17A cytokine axis."
    explanation: >-
      Constitutive self-aggregation of mutant CARMA2 in knock-in mice carrying
      psoriasis alleles from the same domain.
  downstream:
  - target: Constitutive CARD14-BCL10-MALT1 Complex Assembly
    causal_link_type: DIRECT
    description: >-
      With autoinhibition lost, the mutant scaffold binds BCL10 and recruits MALT1
      without any receptor stimulus.
    evidence:
    - reference: PMID:27071417
      reference_title: Psoriasis mutations disrupt CARD14 autoinhibition promoting BCL10-MALT1-dependent NF-κB activation.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "In contrast with wild-type CARD14, CARD14(E138A) and CARD14(G117S) psoriasis mutants interacted constitutively with BCL10 and MALT1, and triggered BCL10- and MALT1-dependent activation of NF-κB in keratinocytes."
      explanation: >-
        Constitutive BCL10 and MALT1 binding by activating CARD14 alleles, including p.Gly117Ser.
  - target: Replication Stress-Driven Revertant Mosaicism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Mutant CARD14 increases double-strand breaks under replication stress, which
      favours recombination-mediated loss of the mutant allele in epidermal clones.
    evidence:
    - reference: PMID:34004138
      reference_title: Altered replication stress response due to CARD14 mutations promotes recombination-induced revertant mosaicism.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Rather than altering the DNA damage response to exogenous stimuli, such as X-irradiation or etoposide treatment, mutant CARD14 increased DNA double-strand breaks under conditions of replication stress."
      explanation: >-
        The replication-stress lesion that feeds recombination-mediated reversion.
- name: Constitutive CARD14-BCL10-MALT1 Complex Assembly
  biological_scale: MOLECULAR
  description: >-
    Mutant CARD14 constitutively associates with BCL10 and the paracaspase MALT1 to
    form a CBM-type signalosome in keratinocytes, the counterpart of the
    CARD11-BCL10-MALT1 complex formed in lymphocytes after antigen-receptor
    stimulation. The complex engages IKK and also activates MALT1 protease activity,
    which cleaves negative regulators of NF-kappaB; MALT1 deficiency or inhibition
    blunts mutant CARD14 signalling in keratinocytes and in mice.
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  cellular_components:
  - preferred_term: CARD14-BCL10-MALT1 (CBM) complex
    modifier: INCREASED
    term:
      id: GO:0032449
      label: CBM complex
  genes:
  - preferred_term: BCL10
    term:
      id: hgnc:989
      label: BCL10
  - preferred_term: MALT1
    term:
      id: hgnc:6819
      label: MALT1
  evidence:
  - reference: PMID:27071417
    reference_title: Psoriasis mutations disrupt CARD14 autoinhibition promoting BCL10-MALT1-dependent NF-κB activation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In contrast with wild-type CARD14, CARD14(E138A) and CARD14(G117S) psoriasis mutants interacted constitutively with BCL10 and MALT1, and triggered BCL10- and MALT1-dependent activation of NF-κB in keratinocytes."
    explanation: >-
      Constitutive CBM assembly by mutant CARD14 in keratinocytes, including the
      p.Gly117Ser allele shared with type V PRP.
  - reference: PMID:27113748
    reference_title: The paracaspase MALT1 mediates CARD14-induced signaling in keratinocytes.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Mechanistically, we demonstrate that CARD14 physically interacts with paracaspase MALT1 and activates MALT1 proteolytic activity and inflammatory gene expression, which are enhanced by psoriasis-associated CARD14 mutations."
    explanation: >-
      Physical CARD14-MALT1 interaction and MALT1 protease activation, enhanced by
      activating alleles.
  - reference: PMID:33419765
    reference_title: Intrinsic Abnormalities of Keratinocytes Initiate Skin Inflammation through the IL-23/T17 Axis in a MALT1-Dependent Manner.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Targeting CBM complex by conditional deletion of MALT1 or BCL10 in keratinocytes abrogated both the cutaneous and systemic inflammation of heterozygous Card14 E138A/+ mice."
    explanation: >-
      Genetic requirement for the keratinocyte CBM complex in a CARD14 knock-in model.
  downstream:
  - target: Keratinocyte NF-kappaB Hyperactivation
    causal_link_type: DIRECT
    description: >-
      The assembled CBM signalosome activates IKK, and MALT1 protease activity removes
      NF-kappaB inhibitors, giving sustained canonical NF-kappaB signalling.
    evidence:
    - reference: PMID:27071417
      reference_title: Psoriasis mutations disrupt CARD14 autoinhibition promoting BCL10-MALT1-dependent NF-κB activation.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "In contrast with wild-type CARD14, CARD14(E138A) and CARD14(G117S) psoriasis mutants interacted constitutively with BCL10 and MALT1, and triggered BCL10- and MALT1-dependent activation of NF-κB in keratinocytes."
      explanation: >-
        NF-kappaB activation by mutant CARD14 requires BCL10 and MALT1.
- name: Keratinocyte NF-kappaB Hyperactivation
  biological_scale: CELLULAR
  description: >-
    Canonical NF-kappaB is constitutively active in CARD14-mutant keratinocytes, with
    nuclear p65 demonstrable in lesional familial PRP skin. ERK1/2 and p38 MAP kinase
    activation accompanies NF-kappaB and is needed for maximal target-gene induction.
    Because CARD14 also transduces IL-17A signalling through the ACT1-TRAF6 complex,
    mutant keratinocytes respond more strongly to the IL-17A that the downstream immune
    response produces, closing a feed-forward loop.
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  biological_processes:
  - preferred_term: canonical NF-kappaB signal transduction
    modifier: INCREASED
    term:
      id: GO:0007249
      label: canonical NF-kappaB signal transduction
  genes:
  - preferred_term: RELA (p65)
    term:
      id: hgnc:9955
      label: RELA
  locations:
  - preferred_term: skin epidermis
    term:
      id: UBERON:0001003
      label: skin epidermis
  evidence:
  - reference: PMID:22703878
    reference_title: Familial pityriasis rubra pilaris is caused by mutations in CARD14.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Accordingly, CARD14 levels were increased, and p65 was found to be activated in the skin of PRP-affected individuals."
    explanation: >-
      Activated p65 in lesional skin of the familial PRP kindreds.
  - reference: PMID:30018619
    reference_title: Nuclear Factor κB Activation in a Type V Pityriasis Rubra Pilaris Patient Harboring Multiple CARD14 Variants.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Immunofluorescent staining of the NFκB p65 subunit and NFκB-luciferase reporter assay demonstrated significantly increased NFκB activity in skin samples and keratinocytes from the PRP patient compared to healthy samples."
    explanation: >-
      Increased NF-kappaB activity in patient skin sections and cultured patient
      keratinocytes; the patient carried CARD14 variants of uncertain individual
      effect, so this is a type V phenotype-level observation.
  - reference: PMID:22521418
    reference_title: PSORS2 is due to mutations in CARD14.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: "CARD14 activates nuclear factor kappa B (NF-kB), and compared with wild-type CARD14, the p.Gly117Ser and p.Glu138Ala substitutions were shown to lead to enhanced NF-kB activation and upregulation of a subset of psoriasis-associated genes in keratinocytes."
    explanation: >-
      Enhanced NF-kappaB reporter activity for the p.Gly117Ser allele, which also
      causes type V PRP; measured in a psoriasis study.
  - reference: PMID:29980436
    reference_title: Gain-of-Function Mutation of Card14 Leads to Spontaneous Psoriasis-like Skin Inflammation through Enhanced Keratinocyte Response to IL-17A.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "CARMA2, mainly expressed in keratinocytes, associates with the ACT1-TRAF6 signaling complex and mediates IL-17A-induced NF-κB and MAPK signaling pathway activation, which leads to expression of pro-inflammatory factors."
    explanation: >-
      CARD14 sits in the keratinocyte IL-17A pathway, so the mutant amplifies the
      cytokine response it initiates.
  downstream:
  - target: Keratinocyte Chemokine and Cytokine Production
    causal_link_type: DIRECT
    description: >-
      NF-kappaB drives transcription of CCL20, CXCL8, IL1B, IL36G and antimicrobial
      peptides in the mutant keratinocyte.
    evidence:
    - reference: PMID:22521418
      reference_title: PSORS2 is due to mutations in CARD14.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: "CARD14 activates nuclear factor kappa B (NF-kB), and compared with wild-type CARD14, the p.Gly117Ser and p.Glu138Ala substitutions were shown to lead to enhanced NF-kB activation and upregulation of a subset of psoriasis-associated genes in keratinocytes."
      explanation: >-
        Enhanced NF-kappaB activation by the activating alleles upregulates the chemokine genes in keratinocytes.
- name: Keratinocyte Chemokine and Cytokine Production
  biological_scale: CELLULAR
  description: >-
    NF-kappaB-dependent transcription in CARD14-mutant keratinocytes raises CCL20,
    CXCL8 (IL-8), IL1B, IL36G, S100A8/A9 and antimicrobial peptides. CCL20 recruits
    CCR6-positive dendritic cells and Th17 cells, and IL-36 and inflammasome products
    amplify innate inflammation, which the Card14 C127S PRP mouse reproduces in the
    interfollicular epidermis and follicular outer root sheath. MALT1 protease activity
    is needed for full CCL20 and IL-8 induction.
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  biological_processes:
  - preferred_term: chemokine production
    modifier: INCREASED
    term:
      id: GO:0032602
      label: chemokine production
  - preferred_term: inflammatory response
    modifier: INCREASED
    term:
      id: GO:0006954
      label: inflammatory response
  genes:
  - preferred_term: CCL20
    term:
      id: hgnc:10619
      label: CCL20
  - preferred_term: CXCL8 (IL-8)
    term:
      id: hgnc:6025
      label: CXCL8
  - preferred_term: IL1B
    term:
      id: hgnc:5992
      label: IL1B
  evidence:
  - reference: PMID:22521418
    reference_title: PSORS2 is due to mutations in CARD14.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These genes included chemokine (C-C motif) ligand 20 (CCL20) and interleukin 8 (IL8)."
    explanation: >-
      The NF-kappaB targets induced by activating CARD14 alleles in keratinocytes.
  - reference: PMID:27113748
    reference_title: The paracaspase MALT1 mediates CARD14-induced signaling in keratinocytes.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Moreover, we show that MALT1 deficiency or pharmacological inhibition of MALT1 catalytic activity inhibits pathogenic mutant CARD14-induced cytokine and chemokine expression in human primary keratinocytes."
    explanation: >-
      Mutant CARD14-driven cytokine and chemokine output in primary human
      keratinocytes, and its MALT1 dependence.
  - reference: DOI:10.21203/rs.3.rs-2513325/v1
    reference_title: IL-17 axis is a significant driver of skin inflammation in Card14 mutant pityriasis rubra pilaris model mice
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "the hyperactivation of innate immunity via the IL-36 signaling and inflammasome pathways, and the excessive activation of the IL-17 axis in the outer root sheath and interfollicular epidermis"
    explanation: >-
      The PRP-allele knock-in mouse shows the IL-36/inflammasome and IL-17 output in
      the follicular and interfollicular epidermis.
  - reference: PMID:29689250
    reference_title: CARD14 Gain-of-Function Mutation Alone Is Sufficient to Drive IL-23/IL-17-Mediated Psoriasiform Skin Inflammation In Vivo.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Affected skin of these mice is characterized by elevated expression of anti-microbial peptides, chemokines, and cytokines (including T helper type 17 cell-signature cytokines) and an immune infiltrate rich in neutrophils, myeloid cells, and T cells, reminiscent of human psoriatic skin."
    explanation: >-
      Chemokine, cytokine and antimicrobial-peptide output in a CARD14 gain-of-function
      knock-in model.
  downstream:
  - target: IL-23/IL-17 Axis Amplification
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Keratinocyte chemokines recruit dendritic cells and T cells; dendritic-cell IL-23
      sustains IL-17- and IL-22-producing T cells.
    evidence:
    - reference: PMID:29477734
      reference_title: "CARD14-associated papulosquamous eruption: A spectrum including features of psoriasis and pityriasis rubra pilaris."
      supports: SUPPORT
      quote_role: REVIEW_SYNTHESIS
      evidence_source: HUMAN_CLINICAL
      snippet: "Elevated NF-κB activity leads to increases in chemokines such as IL-8 and CCL20, which lead to recruitment and differentiation of inflammatory cells, including production of IL-23 by dendritic cells and IL-17 and IL-22 by T cells"
      explanation: >-
        The chemokine-to-IL-23/IL-17 step as synthesised in the CAPE series.
- name: IL-23/IL-17 Axis Amplification
  biological_scale: TISSUE
  description: >-
    Recruited dendritic cells produce IL-23, which maintains Th17 and other type 17
    lymphocytes producing IL-17A, IL-17F and IL-22 in the dermis. The axis is
    demonstrated genetically in CARD14 knock-in mice, where IL-23p19 neutralisation or
    anti-IL-17A antibody reduces disease, and is the target of the biologics that work
    in patients. Human lesional-skin cytokine profiling showing IL-17A/IL-17F/IL-22
    elevation comes from sporadic PRP rather than genotyped familial cases.
  cell_types:
  - preferred_term: T-helper 17 cell
    term:
      id: CL:0000899
      label: T-helper 17 cell
  - preferred_term: dendritic cell
    term:
      id: CL:0000451
      label: dendritic cell
  biological_processes:
  - preferred_term: T-helper 17 type immune response
    modifier: INCREASED
    term:
      id: GO:0072538
      label: T-helper 17 type immune response
  - preferred_term: interleukin-17 production
    modifier: INCREASED
    term:
      id: GO:0032620
      label: interleukin-17 production
  - preferred_term: interleukin-23 production
    modifier: INCREASED
    term:
      id: GO:0032627
      label: interleukin-23 production
  genes:
  - preferred_term: IL23A
    term:
      id: hgnc:15488
      label: IL23A
  - preferred_term: IL17A
    term:
      id: hgnc:5981
      label: IL17A
  - preferred_term: IL17F
    term:
      id: hgnc:16404
      label: IL17F
  locations:
  - preferred_term: dermis
    term:
      id: UBERON:0002067
      label: dermis
  evidence:
  - reference: PMID:29689250
    reference_title: CARD14 Gain-of-Function Mutation Alone Is Sufficient to Drive IL-23/IL-17-Mediated Psoriasiform Skin Inflammation In Vivo.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Disease pathogenesis was driven by the IL-23/IL-17 axis, and neutralization of IL-23p19, the key cytokine in maintaining T helper type 17 cell polarization, significantly reduced skin lesions and the expression of antimicrobial peptides and proinflammatory cytokines."
    explanation: >-
      IL-23 dependence of CARD14 gain-of-function skin disease in mice.
  - reference: PMID:33419765
    reference_title: Intrinsic Abnormalities of Keratinocytes Initiate Skin Inflammation through the IL-23/T17 Axis in a MALT1-Dependent Manner.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Together, our results suggest a sequence of events under CARD14-mutation-induced psoriasis condition that keratinocyte-intrinsic activation of CBM complex initiates the skin inflammation depending on the IL-23/T17 axis."
    explanation: >-
      Orders keratinocyte CBM activation upstream of the IL-23/T17 axis.
  - reference: DOI:10.21203/rs.3.rs-2513325/v1
    reference_title: IL-17 axis is a significant driver of skin inflammation in Card14 mutant pityriasis rubra pilaris model mice
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Administering anti-IL-17A neutralizing antibody significantly attenuates the skin symptoms in mutant mice."
    explanation: >-
      IL-17A dependence of skin disease in the PRP-allele knock-in mouse.
  - reference: PMID:28122069
    reference_title: Interleukin 23-Helper T Cell 17 Axis as a Treatment Target for Pityriasis Rubra Pilaris.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "Among adaptive T-cell cytokines, an increase of TH1 cytokines and, in particular, TH17 cytokines IL-17A, IL-17F, and IL-22 was seen in PRP."
    explanation: >-
      Th17 cytokine elevation in lesional PRP skin; the patients were not genotyped
      for CARD14, so this supports the axis in PRP generally rather than in the
      familial form specifically.
  - reference: PMID:29477734
    reference_title: "CARD14-associated papulosquamous eruption: A spectrum including features of psoriasis and pityriasis rubra pilaris."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Elevated NF-κB activity leads to increases in chemokines such as IL-8 and CCL20, which lead to recruitment and differentiation of inflammatory cells, including production of IL-23 by dendritic cells and IL-17 and IL-22 by T cells"
    explanation: >-
      The CAPE series' synthesis of the chemokine-to-IL-23/IL-17 chain that its
      ustekinumab responses support.
  downstream:
  - target: Epidermal Hyperproliferation and Abnormal Cornification
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      IL-17A, IL-22 and IL-36 drive keratinocyte proliferation, altered
      differentiation and follicular plugging; the mutant keratinocyte's heightened
      IL-17A responsiveness sustains the loop.
    evidence:
    - reference: DOI:10.21203/rs.3.rs-2513325/v1
      reference_title: IL-17 axis is a significant driver of skin inflammation in Card14 mutant pityriasis rubra pilaris model mice
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "Administering anti-IL-17A neutralizing antibody significantly attenuates the skin symptoms in mutant mice."
      explanation: >-
        Neutralising IL-17A reduces the epidermal disease of the PRP-allele mouse, placing the axis upstream of the tissue change.
- name: Epidermal Hyperproliferation and Abnormal Cornification
  biological_scale: TISSUE
  description: >-
    Acanthosis with broad rete ridges, alternating vertical and horizontal
    orthokeratosis and parakeratosis (checkerboard pattern), hypergranulosis,
    follicular plugging and dilated papillary vessels, with a superficial lymphocytic
    infiltrate. The Card14 C127S knock-in mouse reproduces hair-follicle dilatation,
    follicular plugs and palmoplantar hyperkeratosis and shows reduced filaggrin
    expression with barrier dysfunction.
  notes: >-
    Barrier dysfunction (establishment of skin barrier, DECREASED) is documented only
    in the homozygous Card14 C127S mouse, at about sixfold transepidermal water loss;
    it has not been measured in patients.
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  - preferred_term: outer root sheath cell
    term:
      id: CL:0002561
      label: outer root sheath cell
  biological_processes:
  - preferred_term: keratinocyte proliferation
    modifier: INCREASED
    term:
      id: GO:0043616
      label: keratinocyte proliferation
  - preferred_term: keratinization
    modifier: ABNORMAL
    term:
      id: GO:0031424
      label: keratinization
  - preferred_term: establishment of skin barrier
    modifier: DECREASED
    term:
      id: GO:0061436
      label: establishment of skin barrier
  locations:
  - preferred_term: skin epidermis
    term:
      id: UBERON:0001003
      label: skin epidermis
  - preferred_term: hair follicle
    term:
      id: UBERON:0002073
      label: hair follicle
  evidence:
  - reference: PMID:31849081
    reference_title: Histopathologic findings characteristic of CARD14-associated papulosquamous eruption.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Lesional skin biopsies from patients with CARD14-associated papulosquamous eruption consistently showed alternating checkerboard parakeratosis and orthokeratosis, acanthosis without acantholysis, and dilated vessels in the dermal papillae, with some cases also showing follicular plugging."
    explanation: >-
      The epidermal histopathology in genotyped CARD14 patients.
  - reference: DOI:10.21203/rs.3.rs-2513325/v1
    reference_title: IL-17 axis is a significant driver of skin inflammation in Card14 mutant pityriasis rubra pilaris model mice
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The Card14C127S/C127S knock-in mice recapitulate key aspects of human PRP, including hair follicle dilatation, follicular plugs, and palmoplantar hyperkeratosis, and show skin barrier dysfunction"
    explanation: >-
      Follicular plugging, palmoplantar hyperkeratosis and barrier loss in the
      PRP-allele mouse.
  - reference: PMID:29689250
    reference_title: CARD14 Gain-of-Function Mutation Alone Is Sufficient to Drive IL-23/IL-17-Mediated Psoriasiform Skin Inflammation In Vivo.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Here, we report that heterozygous mice harboring a CARD14 gain-of-function mutation (Card14ΔE138) spontaneously develop a chronic psoriatic phenotype with characteristic scaling skin lesions, epidermal thickening, keratinocyte hyperproliferation, hyperkeratosis, and immune cell infiltration."
    explanation: >-
      Epidermal thickening and keratinocyte hyperproliferation from a heterozygous
      CARD14 gain-of-function allele.
  downstream:
  - target: Follicular hyperkeratosis
    causal_link_type: DIRECT
    description: Follicular plugging by retained cornified material produces the keratotic follicular papules.
    evidence:
    - reference: PMID:31849081
      reference_title: Histopathologic findings characteristic of CARD14-associated papulosquamous eruption.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Lesional skin biopsies from patients with CARD14-associated papulosquamous eruption consistently showed alternating checkerboard parakeratosis and orthokeratosis, acanthosis without acantholysis, and dilated vessels in the dermal papillae, with some cases also showing follicular plugging."
      explanation: >-
        Follicular plugging in lesional biopsies of genotyped patients.
  - target: Palmoplantar keratoderma
    causal_link_type: DIRECT
    description: Hyperkeratosis of palmar and plantar epidermis.
    evidence:
    - reference: DOI:10.21203/rs.3.rs-2513325/v1
      reference_title: IL-17 axis is a significant driver of skin inflammation in Card14 mutant pityriasis rubra pilaris model mice
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "The Card14C127S/C127S knock-in mice recapitulate key aspects of human PRP, including hair follicle dilatation, follicular plugs, and palmoplantar hyperkeratosis"
      explanation: >-
        Palmoplantar hyperkeratosis arising from the same epidermal process in the PRP-allele mouse.
  - target: Orange-red scaling plaques
    causal_link_type: DIRECT
    description: Confluent acanthosis with checkerboard parakeratosis and dilated papillary vessels gives the erythematous scaling plaques.
  - target: Facial erythema
    causal_link_type: DIRECT
    description: The same plaque process involving the cheeks, chin and ears.
  - target: Erythroderma
    causal_link_type: DIRECT
    description: Generalisation of the plaque process over most of the body surface.
  - target: Checkerboard parakeratosis with follicular plugging
    causal_link_type: DIRECT
    description: The histological correlate of the abnormal cornification.
    evidence:
    - reference: PMID:31849081
      reference_title: Histopathologic findings characteristic of CARD14-associated papulosquamous eruption.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Lesional skin biopsies from patients with CARD14-associated papulosquamous eruption consistently showed alternating checkerboard parakeratosis and orthokeratosis, acanthosis without acantholysis, and dilated vessels in the dermal papillae, with some cases also showing follicular plugging."
      explanation: >-
        The checkerboard pattern and follicular plugging in genotyped patients.
- name: Replication Stress-Driven Revertant Mosaicism
  biological_scale: CELLULAR
  description: >-
    In some patients, clinically normal skin patches arise in which the epidermis has
    lost the germline CARD14 mutation, mostly through copy-neutral loss of
    heterozygosity of 17q. Mutant CARD14 increases double-strand breaks under
    replication stress and suppresses new origin firing, favouring break-induced
    replication; this is a somatic compensatory branch, not part of the pathogenic
    chain, and is observed rather than therapeutically exploitable.
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  biological_processes:
  - preferred_term: double-strand break repair via homologous recombination
    modifier: INCREASED
    term:
      id: GO:0000724
      label: double-strand break repair via homologous recombination
  evidence:
  - reference: PMID:34004138
    reference_title: Altered replication stress response due to CARD14 mutations promotes recombination-induced revertant mosaicism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we show that heterozygous pathogenic CARD14 mutations causing autoinflammatory skin diseases, including psoriasis and pityriasis rubra pilaris, are repaired mainly via homologous recombination."
    explanation: >-
      Revertant patches in CARD14-mutant patients, including PRP, arise by homologous
      recombination.
  - reference: PMID:34004138
    reference_title: Altered replication stress response due to CARD14 mutations promotes recombination-induced revertant mosaicism.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Rather than altering the DNA damage response to exogenous stimuli, such as X-irradiation or etoposide treatment, mutant CARD14 increased DNA double-strand breaks under conditions of replication stress."
    explanation: >-
      The cellular mechanism proposed for the reversion events, from cultured cells.
phenotypes:
- name: Follicular hyperkeratosis
  category: Dermatologic
  frequency: FREQUENT
  description: >-
    Keratotic follicular papules, the defining PRP lesion, were present in 6 of 15
    CARD14 index cases and 45% of 31 reviewed paediatric cases; they are less
    constant in CARD14-related disease than in classic adult PRP.
  phenotype_term:
    preferred_term: Keratotic follicular papules
    term:
      id: HP:0007502
      label: Follicular hyperkeratosis
  evidence:
  - reference: PMID:34448248
    reference_title: "CARD14-associated papulosquamous eruption (CAPE) in pediatric patients: Three additional cases and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the 31 previously reported cases, clinical features typical of PRP such as follicular papules were observed in 45%, islands of sparing in 42%, palmoplantar keratoderma in 68%, and sclerodermatous changes of the hands in 6%."
    explanation: >-
      Frequency of follicular papules across reported paediatric CARD14 cases.
  - reference: PMID:42561834
    reference_title: Ixekizumab for genetically confirmed type 5 pityriasis rubra pilaris with a CARD14 p.Met119Thr variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Physical examination revealed generalized erythematous, hyperkeratotic, follicular papules and plaques involving the trunk and extremities, with prominent palmoplantar keratoderma"
    explanation: >-
      Follicular papules in a genotyped type V patient.
- name: Palmoplantar keratoderma
  category: Dermatologic
  frequency: VERY_FREQUENT
  description: >-
    Waxy orange-red or yellowish thickening of palms and soles, often with painful
    fissuring; present in 12 of 15 CARD14 index cases and 68% of reviewed paediatric
    cases.
  phenotype_term:
    preferred_term: Palmoplantar keratoderma
    term:
      id: HP:0000982
      label: Palmoplantar keratoderma
  evidence:
  - reference: PMID:29477734
    reference_title: "CARD14-associated papulosquamous eruption: A spectrum including features of psoriasis and pityriasis rubra pilaris."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most (12/15) subjects had some degree of palmoplantar keratoderma, and two had scleroderma-like changes of the hands."
    explanation: >-
      Frequency in the 15-kindred series.
  - reference: PMID:34448248
    reference_title: "CARD14-associated papulosquamous eruption (CAPE) in pediatric patients: Three additional cases and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the 31 previously reported cases, clinical features typical of PRP such as follicular papules were observed in 45%, islands of sparing in 42%, palmoplantar keratoderma in 68%, and sclerodermatous changes of the hands in 6%."
    explanation: >-
      Frequency across 31 reviewed paediatric cases.
  - reference: PMID:39104646
    reference_title: Severe atypical juvenile pityriasis rubra pilaris diagnosed in adulthood with a dramatic improvement with ustekinumab.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "From aged six weeks and throughout childhood she had scaly erythroderma, sparing the flexural surfaces and parts of the back, and yellowish hyperkeratotic palms and soles."
    explanation: >-
      Palmoplantar hyperkeratosis from infancy in a genotyped type V patient.
- name: Orange-red scaling plaques
  category: Dermatologic
  frequency: VERY_FREQUENT
  description: >-
    Well-demarcated, confluent, orange-red to pink-red scaly plaques, characteristically
    leaving islands of unaffected skin (seen in 42% of reviewed paediatric cases);
    scalp involvement with thick scale is common.
  phenotype_term:
    preferred_term: Orange-red scaly plaques with islands of sparing
    term:
      id: HP:0040189
      label: Scaling skin
  notes: >-
    HPO has no term for islands of sparing or for the orange-red plaque of PRP; the
    binding is to the scaling itself and the specificity is carried in preferred_term.
  evidence:
  - reference: PMID:40766060
    reference_title: "Case Report: Successful treatment of a novel variant of CARD14-mutated juvenile Pityriasis rubra pilaris with ixekizumab."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The further physical examination revealed prominent facial involvement of cheeks and ears with erythematosquamous plaques, palmar and plantar waxy orange-red keratoderma, bilateral ectropion and extensive thick scaly plaques on the scalp (Figure 1A)."
    explanation: >-
      Scaly plaques, scalp scale and keratoderma in a 3-year-old with a novel CARD14
      variant.
  - reference: PMID:28301045
    reference_title: Beneficial effect of ustekinumab in familial pityriasis rubra pilaris with a new missense mutation in CARD14.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A 49-year-old woman and her 20-year-old son had lifelong, generalized, patchy erythematous scale with a few islands of sparing, as well as minor nail ridging and mild palmoplantar keratoderma, features consistent with generalized PRP."
    explanation: >-
      Generalized erythematous scale with islands of sparing in a p.Met119Arg family.
  - reference: PMID:34448248
    reference_title: "CARD14-associated papulosquamous eruption (CAPE) in pediatric patients: Three additional cases and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the 31 previously reported cases, clinical features typical of PRP such as follicular papules were observed in 45%, islands of sparing in 42%, palmoplantar keratoderma in 68%, and sclerodermatous changes of the hands in 6%."
    explanation: >-
      Frequency of islands of sparing across reviewed paediatric cases.
- name: Facial erythema
  category: Dermatologic
  frequency: VERY_FREQUENT
  description: >-
    Early, symmetric, well-demarcated pink-red patches or thin plaques of the cheeks,
    chin and ears with sparing of the infralabial region; present in 14 of 15 index
    cases and 93% of reviewed paediatric cases, and the feature that most distinguishes
    CARD14-related disease from sporadic PRP and psoriasis.
  phenotype_term:
    preferred_term: Facial erythema involving cheeks, chin and ears
    term:
      id: HP:0001041
      label: Facial erythema
  evidence:
  - reference: PMID:29477734
    reference_title: "CARD14-associated papulosquamous eruption: A spectrum including features of psoriasis and pityriasis rubra pilaris."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most notable characteristic among the group is prominent facial involvement, which was displayed by all but 1 subject and in most cases presented early in the disease course as symmetric, well-demarcated pink-red patches or thin plaques involving the bilateral cheeks and chin with sparing of the infralabial region (Figure 1)."
    explanation: >-
      Facial involvement in 14 of 15 index cases.
  - reference: PMID:34448248
    reference_title: "CARD14-associated papulosquamous eruption (CAPE) in pediatric patients: Three additional cases and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "As described in 93% of the 31 previously described patients, all of our patients had facial involvement that occurred early as symmetric, well-demarcated pink-red plaques involving the cheeks, chin, and ears with sparing of the infralabial region."
    explanation: >-
      Facial involvement in 93% of reviewed paediatric cases.
- name: Erythroderma
  category: Dermatologic
  frequency: OCCASIONAL
  description: >-
    Generalisation to erythroderma occurs in a minority, sometimes from infancy and
    sometimes as a flare during intercurrent infection.
  phenotype_term:
    preferred_term: Erythroderma
    term:
      id: HP:0001019
      label: Erythroderma
  evidence:
  - reference: PMID:29477734
    reference_title: "CARD14-associated papulosquamous eruption: A spectrum including features of psoriasis and pityriasis rubra pilaris."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The skin phenotype ranged from predominantly psoriasis-like to predominantly PRP-like, with several patients showing features typical of both diseases. Two patients were erythrodermic."
    explanation: >-
      Two of 15 index cases were erythrodermic.
  - reference: PMID:39104646
    reference_title: Severe atypical juvenile pityriasis rubra pilaris diagnosed in adulthood with a dramatic improvement with ustekinumab.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "From aged six weeks and throughout childhood she had scaly erythroderma, sparing the flexural surfaces and parts of the back, and yellowish hyperkeratotic palms and soles."
    explanation: >-
      Infantile-onset erythroderma in a genotyped type V patient.
- name: Ectropion
  category: Ophthalmologic
  frequency: OCCASIONAL
  description: >-
    Bilateral ectropion accompanies severe facial and periorbital involvement in some
    children; reported in 6% of reviewed paediatric cases.
  phenotype_term:
    preferred_term: Ectropion
    term:
      id: HP:0000656
      label: Ectropion
  evidence:
  - reference: PMID:40766060
    reference_title: "Case Report: Successful treatment of a novel variant of CARD14-mutated juvenile Pityriasis rubra pilaris with ixekizumab."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "palmar and plantar waxy orange-red keratoderma, bilateral ectropion and extensive thick scaly plaques on the scalp"
    explanation: >-
      Bilateral ectropion in a 3-year-old with a novel CARD14 variant.
  - reference: PMID:34448248
    reference_title: "CARD14-associated papulosquamous eruption (CAPE) in pediatric patients: Three additional cases and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bilateral ectropion, palmoplantar keratoderma, and scleroderma-like changes in the hands were also noted."
    explanation: >-
      Ectropion in one of the three new paediatric cases.
- name: Patchy macular hyperpigmentation
  category: Dermatologic
  frequency: OCCASIONAL
  description: >-
    Patchy macular brown hyperpigmentation was present in all three CARD14-positive
    type V patients of the Japanese series and proposed as a clue to the genotype; it
    is not reported as a constant feature in other series, and its mechanism is not
    established, so it is left unconnected in the pathograph.
  phenotype_term:
    preferred_term: Patchy macular brown hyperpigmentation
    term:
      id: HP:0000953
      label: Hyperpigmentation of the skin
  evidence:
  - reference: PMID:27760266
    reference_title: Pityriasis Rubra Pilaris Type V as an Autoinflammatory Disease by CARD14 Mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All 3 patients displayed unique patchy macular brown hyperpigmentation additionally to other typical features of PRP."
    explanation: >-
      The pigmentary feature in all three genotyped type V patients.
- name: Pruritus
  category: Dermatologic
  frequency: FREQUENT
  description: >-
    Itch accompanies the plaques in most children and improves with IL-17A blockade.
  phenotype_term:
    preferred_term: Pruritus
    term:
      id: HP:0000989
      label: Pruritus
  notes: >-
    Itch is a feature of the inflamed plaque rather than a separately mechanised
    phenotype; it is left unconnected rather than wired to a node that does not explain
    it.
  evidence:
  - reference: PMID:40433052
    reference_title: Clinical Characteristics of CARD14-Associated Papulosquamous Eruption and Evaluation of Therapeutic Efficacy of Secukinumab.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Eight of these patients reported pruritus."
    explanation: >-
      Pruritus in all eight genotyped paediatric CAPE patients.
- name: Checkerboard parakeratosis with follicular plugging
  category: Histopathologic
  frequency: VERY_FREQUENT
  description: >-
    Alternating vertical and horizontal orthokeratosis and parakeratosis, acanthosis
    without acantholysis, dilated papillary vessels and, in some biopsies, follicular
    plugging; the pattern favours PRP over psoriasis and was found consistently in
    biopsies from genotyped patients.
  phenotype_term:
    preferred_term: Checkerboard parakeratosis
    term:
      id: HP:0001036
      label: Parakeratosis
  evidence:
  - reference: PMID:31849081
    reference_title: Histopathologic findings characteristic of CARD14-associated papulosquamous eruption.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Lesional skin biopsies from patients with CARD14-associated papulosquamous eruption consistently showed alternating checkerboard parakeratosis and orthokeratosis, acanthosis without acantholysis, and dilated vessels in the dermal papillae, with some cases also showing follicular plugging."
    explanation: >-
      The defining histopathology in genotyped patients.
  - reference: PMID:31849081
    reference_title: Histopathologic findings characteristic of CARD14-associated papulosquamous eruption.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CARD14-associated papulosquamous eruption has a range of findings, with a predominance of features typically associated with pityriasis rubra pilaris."
    explanation: >-
      The histology favours PRP over psoriasis.
progression:
- phase: Infantile onset
  age_range: Birth to 3 years (4 to 36 months in the gene-discovery kindreds; before 1 year in most CARD14 index cases)
  notes: >-
    Facial erythema and scale usually precede truncal and palmoplantar disease.
  evidence:
  - reference: PMID:29477734
    reference_title: "CARD14-associated papulosquamous eruption: A spectrum including features of psoriasis and pityriasis rubra pilaris."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "With the exception of 2 subjects, all had onset of their disease at or before one year of age."
    explanation: >-
      Onset timing in the 15-kindred series.
  - reference: PMID:34448248
    reference_title: "CARD14-associated papulosquamous eruption (CAPE) in pediatric patients: Three additional cases and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Patients with CARD14 mutations can be distinguished from more common forms of psoriasis and acquired PRP by the early age of onset (primarily before 1 year of age), prominent facial involvement (cheeks, chin and ears), frequent family history of psoriasis or PRP, and limited response to conventional topical and systemic therapies for psoriasis or PRP."
    explanation: >-
      Early onset as a distinguishing feature of CARD14-related disease.
- phase: Chronic persistent course
  age_range: Childhood through adult life
  notes: >-
    Unlike classic adult (type I) PRP, which usually remits within a few years, the
    familial form persists lifelong without treatment, with flares during intercurrent
    infection; somatic revertant patches can appear but do not generalise.
  evidence:
  - reference: PMID:29477734
    reference_title: "CARD14-associated papulosquamous eruption: A spectrum including features of psoriasis and pityriasis rubra pilaris."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "None has experienced remission of disease without treatment."
    explanation: >-
      No spontaneous remission in 15 kindreds.
  - reference: PMID:33431438
    reference_title: "Identification of a pathogenic CARD14 mutation in a 70-year-old woman with pityriasis rubra pilaris: when genetic diagnosis influences choice of treatment strategy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We present a case of lifelong PRP in a 70-year-old woman, where genetic testing revealed a heterozygote missense variant c.412G>A, p.(Glu138Lys) in CARD14."
    explanation: >-
      Lifelong persistence into the eighth decade.
diagnosis:
- name: CARD14 sequencing
  description: >-
    Sequencing of CARD14 coding exons and splice junctions (single-gene, keratinization
    panel or exome) in a child with early-onset papulosquamous disease, prominent facial
    involvement, a family history of PRP or psoriasis, and poor response to conventional
    therapy; deep sequencing of lesional skin can detect mosaic alleles missed in blood.
  diagnosis_term:
    preferred_term: CARD14 gene sequencing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:29477734
    reference_title: "CARD14-associated papulosquamous eruption: A spectrum including features of psoriasis and pityriasis rubra pilaris."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Subjects with clinical features suggestive of CAPE should undergo CARD14 sequencing and may benefit from treatment with ustekinumab."
    explanation: >-
      Recommendation for CARD14 sequencing from the largest genotyped series.
  - reference: PMID:40433052
    reference_title: Clinical Characteristics of CARD14-Associated Papulosquamous Eruption and Evaluation of Therapeutic Efficacy of Secukinumab.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole-exome sequencing (WES) was performed in all patients to identify the mutation type."
    explanation: >-
      Exome sequencing as the diagnostic route in a paediatric series.
- name: Lesional skin biopsy
  description: >-
    Histopathology showing checkerboard parakeratosis and orthokeratosis, acanthosis
    without acantholysis and follicular plugging supports PRP over psoriasis, but the
    overlap with psoriasis means biopsy cannot replace genotyping.
  diagnosis_term:
    preferred_term: Skin biopsy
    term:
      id: NCIT:C51692
      label: Skin Biopsy
  evidence:
  - reference: PMID:31849081
    reference_title: Histopathologic findings characteristic of CARD14-associated papulosquamous eruption.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CARD14-associated papulosquamous eruption has a range of findings, with a predominance of features typically associated with pityriasis rubra pilaris."
    explanation: >-
      Biopsy findings in genotyped patients.
treatments:
- name: Ustekinumab (IL-12/IL-23 p40 blockade)
  description: >-
    The best-documented therapy: near-complete clearance in 5 of 6 treated subjects in
    the 15-kindred series and in several familial PRP families, often after failure of
    retinoids, methotrexate and TNF inhibitors. Weight-based or more frequent dosing
    than the psoriasis label has been needed to maintain response.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: ustekinumab
      term:
        id: NCIT:C84237
        label: Ustekinumab
  target_mechanisms:
  - target: IL-23/IL-17 Axis Amplification
    treatment_effect: INHIBITS
    description: Binds the shared p40 subunit of IL-12 and IL-23, removing the IL-23 signal that maintains the type 17 response.
    evidence:
    - reference: PMID:29477734
      reference_title: "CARD14-associated papulosquamous eruption: A spectrum including features of psoriasis and pityriasis rubra pilaris."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "Notable is the near complete response to ustekinumab in 5 of 6 subjects treated and partial response in the sixth (subject 5), who had the most severe phenotype and was also notably the heaviest and thus may have required a higher dosage."
      explanation: >-
        Clinical response to p40 blockade as evidence that the axis drives the disease.
  evidence:
  - reference: PMID:29477734
    reference_title: "CARD14-associated papulosquamous eruption: A spectrum including features of psoriasis and pityriasis rubra pilaris."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Notable is the near complete response to ustekinumab in 5 of 6 subjects treated and partial response in the sixth (subject 5), who had the most severe phenotype and was also notably the heaviest and thus may have required a higher dosage."
    explanation: >-
      Response in six genotyped subjects.
  - reference: PMID:28301045
    reference_title: Beneficial effect of ustekinumab in familial pityriasis rubra pilaris with a new missense mutation in CARD14.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ustekinumab, at a dose of 45 mg every 12 weeks, brought about a significant physical and emotional improvement in both the mother and son within a few days of the initial dose, which was sustained on maintenance dosing."
    explanation: >-
      Sustained response in a p.Met119Arg family.
  - reference: PMID:33431438
    reference_title: "Identification of a pathogenic CARD14 mutation in a 70-year-old woman with pityriasis rubra pilaris: when genetic diagnosis influences choice of treatment strategy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Therapy with ustekinumab was initiated with remarkable effect, which improved the patient's quality of life significantly."
    explanation: >-
      Response in a p.Glu138Lys patient after a lifetime of disease.
  - reference: PMID:36529810
    reference_title: Treatment Options for Juvenile Pityriasis Rubra Pilaris.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Ustekinumab, in particular, is emerging as a first-line agent for patients with pityriasis rubra pilaris with CARD14 gene variations."
    explanation: >-
      Review consensus on ustekinumab for CARD14-related PRP.
- name: IL-17 blockade (secukinumab, ixekizumab, bimekizumab)
  description: >-
    Secukinumab gave 84.6%, 76.9% and 68.8% PASI improvement at 52 weeks in three
    genotyped children, and ixekizumab produced rapid clearance in genotyped type V
    patients, although one subject in the 15-kindred series had only a partial
    response to ixekizumab. Three adult CAPE patients reported in the literature
    improved on the IL-17A/F inhibitor bimekizumab. In the Card14 C127S mouse
    anti-IL-17A reduced inflammation without restoring barrier function.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: secukinumab
      term:
        id: NCIT:C152315
        label: Secukinumab
    - preferred_term: ixekizumab
      term:
        id: NCIT:C174646
        label: Ixekizumab
    - preferred_term: bimekizumab
      term:
        id: NCIT:C171829
        label: Bimekizumab
  target_mechanisms:
  - target: IL-23/IL-17 Axis Amplification
    treatment_effect: INHIBITS
    description: Neutralises IL-17A, the effector cytokine of the axis and the ligand of the CARD14-dependent keratinocyte IL-17 receptor pathway.
    evidence:
    - reference: DOI:10.21203/rs.3.rs-2513325/v1
      reference_title: IL-17 axis is a significant driver of skin inflammation in Card14 mutant pityriasis rubra pilaris model mice
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Administering anti-IL-17A neutralizing antibody significantly attenuates the skin symptoms in mutant mice."
      explanation: >-
        Preclinical IL-17A dependence of the PRP-allele mouse disease.
  evidence:
  - reference: PMID:40433052
    reference_title: Clinical Characteristics of CARD14-Associated Papulosquamous Eruption and Evaluation of Therapeutic Efficacy of Secukinumab.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "They achieved 84.6%, 76.9%, and 68.8% improvement in PASI score, respectively."
    explanation: >-
      52-week PASI responses to secukinumab in three genotyped children.
  - reference: PMID:40433052
    reference_title: Clinical Characteristics of CARD14-Associated Papulosquamous Eruption and Evaluation of Therapeutic Efficacy of Secukinumab.
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Following the treatment with IL-17A inhibitors (five pediatric patients receiving secukinumab, two adult patients receiving ixekizumab and three adult patients receiving bimekizumab, an IL-17A/F inhibitor), there was significant improvement in skin lesions, and pruritus was alleviated or resolved."
    explanation: >-
      The authors' pooled summary of their own cases and the reported literature,
      including the three adults treated with bimekizumab.
  - reference: PMID:40766060
    reference_title: "Case Report: Successful treatment of a novel variant of CARD14-mutated juvenile Pityriasis rubra pilaris with ixekizumab."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we present a case of successful treatment with ixekizumab, a humanized monoclonal anti-IL-17A antibody, in an atypical juvenile PRP (type V) patient with a novel variant of CARD14 mutation."
    explanation: >-
      Ixekizumab response in a genotyped type V child.
  - reference: PMID:42561834
    reference_title: Ixekizumab for genetically confirmed type 5 pityriasis rubra pilaris with a CARD14 p.Met119Thr variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At 24-weeks, clinical remission persisted (PGA 0–1) without adverse events."
    explanation: >-
      Sustained remission on ixekizumab in a p.Met119Thr patient.
  - reference: PMID:41798160
    reference_title: Familial CARD14-associated papulosquamous eruption with a novel mutation successfully treated with secukinumab.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we describe an infrequent familial presentation involving a father and daughter with severe disease who carried a previously unreported CARD14 variant (c.356T>A; p.Met119Lys)"
    explanation: >-
      A father-daughter p.Met119Lys family treated with secukinumab.
  - reference: DOI:10.21203/rs.3.rs-2513325/v1
    reference_title: IL-17 axis is a significant driver of skin inflammation in Card14 mutant pityriasis rubra pilaris model mice
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Administering anti-IL-17A neutralizing antibody significantly attenuates the skin symptoms in mutant mice."
    explanation: >-
      Preclinical IL-17A dependence in the PRP-allele mouse.
- name: Systemic retinoids (acitretin, isotretinoin)
  description: >-
    Oral retinoids are the conventional first-line systemic therapy for juvenile PRP
    and control some CARD14 patients, but responses in genotyped series are variable
    and often partial, and several families failed retinoids before responding to
    biologics.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: acitretin
      term:
        id: CHEBI:50172
        label: acitretin
    - preferred_term: isotretinoin
      term:
        id: CHEBI:6067
        label: isotretinoin
  target_mechanisms:
  - target: Epidermal Hyperproliferation and Abnormal Cornification
    treatment_effect: MODULATES
    description: Retinoids normalise keratinocyte differentiation and cornification without acting on the upstream CARD14 signal.
  evidence:
  - reference: PMID:34075616
    reference_title: CARD14-associated papulosquamous eruption (CAPE) in a toddler responding to treatment with acitretin.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She was refractory to treatment with topical emollients and topical corticosteroids, but responsive to oral acitretin."
    explanation: >-
      Acitretin response in a genotyped toddler.
  - reference: PMID:39104646
    reference_title: Severe atypical juvenile pityriasis rubra pilaris diagnosed in adulthood with a dramatic improvement with ustekinumab.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Her skin was very well controlled on acitretin 20 mg daily for many years."
    explanation: >-
      Long-term acitretin control before a switch for pregnancy planning.
  - reference: PMID:28301045
    reference_title: Beneficial effect of ustekinumab in familial pityriasis rubra pilaris with a new missense mutation in CARD14.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Topical steroids, phototherapy and oral retinoids proved ineffective."
    explanation: >-
      Retinoid failure in a p.Met119Arg family.
  - reference: PMID:36529810
    reference_title: Treatment Options for Juvenile Pityriasis Rubra Pilaris.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Despite concerns over their side-effect profiles, oral retinoids are generally accepted as a first-line systemic therapy."
    explanation: >-
      Retinoids as conventional first-line systemic therapy for juvenile PRP.
- name: TNF inhibition (etanercept)
  description: >-
    TNF inhibitors, like topical therapy and methotrexate, give little benefit in most
    CARD14 patients: of eight subjects treated with etanercept monotherapy in the
    15-kindred series, one had a partial response, six minimal response and one
    worsened. Recorded here as a documented poor response rather than a recommended
    treatment.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: etanercept
      term:
        id: NCIT:C2381
        label: Etanercept
  notes: >-
    Etanercept is a TNF receptor-Fc fusion protein, not a monoclonal antibody; no
    therapeutic_modality value names a receptor-fusion biologic, so PROTEIN_REPLACEMENT
    is used as the nearest recombinant-protein platform value, not as a claim that it
    replaces a deficient protein.
  evidence:
  - reference: PMID:29477734
    reference_title: "CARD14-associated papulosquamous eruption: A spectrum including features of psoriasis and pityriasis rubra pilaris."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Among the eight subjects who had been treated with etanercept as monotherapy, only one subject demonstrated partial response, six had minimal response, and one had worsening."
    explanation: >-
      Poor response to etanercept in genotyped subjects.
- name: Topical therapy (corticosteroids, calcineurin inhibitors, vitamin D analogues)
  description: >-
    Topical corticosteroids, calcineurin inhibitors, vitamin D analogues, topical
    retinoids and tar preparations gave universally minimal responses across the
    15-kindred series. Recorded as a documented poor response, not a recommended
    treatment.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: topical pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: topical corticosteroid
      term:
        id: CHEBI:50858
        label: corticosteroid
  evidence:
  - reference: PMID:29477734
    reference_title: "CARD14-associated papulosquamous eruption: A spectrum including features of psoriasis and pityriasis rubra pilaris."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Response to topical medications, including corticosteroids, calcineurin inhibitors, Vitamin D analogues, topical retinoids, and tar preparations had been universally minimal among the group."
    explanation: >-
      Minimal response to every class of topical therapy in the genotyped series.
- name: Methotrexate
  description: >-
    Methotrexate has been used in CARD14 patients as a conventional psoriasis agent
    with variable and generally inadequate response in the 15-kindred series, where
    failure of methotrexate, acitretin or TNF inhibition is treated as part of the
    picture suggesting CAPE. Recorded as a documented poor response, not a
    recommended treatment.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: methotrexate
      term:
        id: CHEBI:44185
        label: methotrexate
  evidence:
  - reference: PMID:29477734
    reference_title: "CARD14-associated papulosquamous eruption: A spectrum including features of psoriasis and pityriasis rubra pilaris."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Responses to other treatments, including phototherapy, oral retinoids, methotrexate, cyclosporine and biological therapies had been variable and are detailed in the Table."
    explanation: >-
      Methotrexate was among the conventional agents used in the series, with variable
      response.
  - reference: PMID:29477734
    reference_title: "CARD14-associated papulosquamous eruption: A spectrum including features of psoriasis and pityriasis rubra pilaris."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the constellation of findings are highly suggestive of CAPE, particularly when coupled with inadequate response to conventional psoriasis therapies such as methotrexate, acitretin or TNF-α inhibitors."
    explanation: >-
      The authors treat inadequate response to methotrexate as characteristic of the
      genotyped disease.
- name: MALT1 protease inhibition (preclinical)
  description: >-
    Genetic deletion or oral pharmacological inhibition of MALT1 protease in
    keratinocytes suppresses CARD14 E138A-driven skin disease in mice. This is a
    mechanism-directed rationale established in psoriasis-allele models; no MALT1
    inhibitor has been given to a patient with familial PRP.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: Constitutive CARD14-BCL10-MALT1 Complex Assembly
    treatment_effect: INHIBITS
    description: Blocks the paracaspase activity of MALT1 within the mutant CARD14 signalosome.
  evidence:
  - reference: PMID:32343482
    reference_title: MALT1 targeting suppresses CARD14-induced psoriatic dermatitis in mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Keratinocyte-specific MALT1 deletion as well as oral treatment of mice with a specific MALT1 protease inhibitor strongly reduces psoriatic skin disease in CARD14E138A mice."
    explanation: >-
      In vivo proof of concept for MALT1 inhibition against mutant CARD14 signalling.
  - reference: PMID:27113748
    reference_title: The paracaspase MALT1 mediates CARD14-induced signaling in keratinocytes.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Moreover, we show that MALT1 deficiency or pharmacological inhibition of MALT1 catalytic activity inhibits pathogenic mutant CARD14-induced cytokine and chemokine expression in human primary keratinocytes."
    explanation: >-
      MALT1 inhibition blunts mutant CARD14 output in human keratinocytes.
animal_models:
- name: Card14 C127S knock-in mouse (PRP allele)
  species: Mouse
  genotype: Card14 c.380G>C (p.Cys127Ser) knock-in, homozygous (heterozygotes show milder, transient disease)
  publication: PMID:39159782
  description: >-
    The first mouse carrying a PRP-causing human allele. Homozygotes develop generalized
    scaling, hair-follicle dilatation and plugging, palmoplantar hyperkeratosis,
    markedly increased transepidermal water loss, IL-36/inflammasome and IL-17-axis
    activation in the outer root sheath and interfollicular epidermis, and high neonatal
    mortality; anti-IL-17A improves inflammation but not barrier function. Heterozygotes,
    the genotype that matches patients, have mild transient disease.
  notes: >-
    The peer-reviewed report is PMID:39159782 (J Invest Dermatol 2025). The quoted
    sentences are from the authors' 2023 Research Square preprint of the same study
    (DOI:10.21203/rs.3.rs-2513325/v1), which reports the same allele, genotype and
    anti-IL-17A result.
  evidence:
  - reference: DOI:10.21203/rs.3.rs-2513325/v1
    reference_title: IL-17 axis is a significant driver of skin inflammation in Card14 mutant pityriasis rubra pilaris model mice
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We report the first mouse model of PRP to carry a homozygous knock-in mutation, c.380G>C (p.Cys127Ser) corresponding to a PRP-causative human mutation, in CARD14."
    explanation: >-
      Establishes the model: a knock-in of a human PRP-causing CARD14 allele.
  modeled_mechanisms:
  - target: Epidermal Hyperproliferation and Abnormal Cornification
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      Follicular plugging, follicle dilatation and palmoplantar hyperkeratosis, the
      histological core of the human disease.
    limitations: >-
      The full phenotype requires homozygosity, whereas patients are heterozygous;
      heterozygous mice have only mild, self-resolving disease.
    evidence:
    - reference: DOI:10.21203/rs.3.rs-2513325/v1
      reference_title: IL-17 axis is a significant driver of skin inflammation in Card14 mutant pityriasis rubra pilaris model mice
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The Card14C127S/C127S knock-in mice recapitulate key aspects of human PRP, including hair follicle dilatation, follicular plugs, and palmoplantar hyperkeratosis"
      explanation: >-
        The follicular and palmoplantar phenotype of the homozygous knock-in.
  - target: IL-23/IL-17 Axis Amplification
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      IL-17 axis activation in follicular and interfollicular epidermis, and clinical
      improvement with anti-IL-17A antibody.
    limitations: >-
      Anti-IL-17A improved inflammation but not transepidermal water loss, so
      inflammation and barrier dysfunction are separable in this model.
    evidence:
    - reference: DOI:10.21203/rs.3.rs-2513325/v1
      reference_title: IL-17 axis is a significant driver of skin inflammation in Card14 mutant pityriasis rubra pilaris model mice
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Administering anti-IL-17A neutralizing antibody significantly attenuates the skin symptoms in mutant mice."
      explanation: >-
        IL-17A dependence of the model's skin disease.
- name: Card14 delta-E138 knock-in mouse (psoriasis allele)
  species: Mouse
  genotype: Card14 p.Glu138del knock-in, heterozygous
  publication: PMID:29689250
  description: >-
    Heterozygous knock-in of a psoriasis-associated gain-of-function allele from the
    same coiled-coil region. Mice spontaneously develop chronic psoriasiform scaling,
    epidermal thickening, keratinocyte hyperproliferation and a neutrophil- and
    T-cell-rich infiltrate driven by the IL-23/IL-17 axis; IL-23p19 neutralisation
    reduces disease. Related Card14 E138A knock-ins show that the disease is
    keratinocyte-intrinsic and depends on the CBM complex.
  evidence:
  - reference: PMID:29689250
    reference_title: CARD14 Gain-of-Function Mutation Alone Is Sufficient to Drive IL-23/IL-17-Mediated Psoriasiform Skin Inflammation In Vivo.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Here, we report that heterozygous mice harboring a CARD14 gain-of-function mutation (Card14ΔE138) spontaneously develop a chronic psoriatic phenotype with characteristic scaling skin lesions, epidermal thickening, keratinocyte hyperproliferation, hyperkeratosis, and immune cell infiltration."
    explanation: >-
      Establishes the model: a heterozygous knock-in of a psoriasis-associated
      CARD14 gain-of-function allele with spontaneous skin disease.
  modeled_mechanisms:
  - target: IL-23/IL-17 Axis Amplification
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      The IL-23/IL-17-dependent inflammation downstream of a CARD14 gain-of-function
      allele, in a heterozygous animal.
    limitations: >-
      The allele is a psoriasis allele and the readout is psoriasiform rather than
      PRP-like dermatitis, without follicular plugging or palmoplantar keratoderma.
    evidence:
    - reference: PMID:29689250
      reference_title: CARD14 Gain-of-Function Mutation Alone Is Sufficient to Drive IL-23/IL-17-Mediated Psoriasiform Skin Inflammation In Vivo.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Disease pathogenesis was driven by the IL-23/IL-17 axis, and neutralization of IL-23p19, the key cytokine in maintaining T helper type 17 cell polarization, significantly reduced skin lesions and the expression of antimicrobial peptides and proinflammatory cytokines."
      explanation: >-
        IL-23 dependence of the model.
  - target: Constitutive CARD14-BCL10-MALT1 Complex Assembly
    relationship: PERTURBS
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Keratinocyte-specific deletion of MALT1 or BCL10 in the related Card14 E138A/+
      knock-in abolishes skin and systemic inflammation, placing the keratinocyte CBM
      complex upstream of the whole cascade.
    limitations: >-
      Shown for the E138A psoriasis allele; the PRP alleles have not been tested this
      way in vivo.
    evidence:
    - reference: PMID:33419765
      reference_title: Intrinsic Abnormalities of Keratinocytes Initiate Skin Inflammation through the IL-23/T17 Axis in a MALT1-Dependent Manner.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Targeting CBM complex by conditional deletion of MALT1 or BCL10 in keratinocytes abrogated both the cutaneous and systemic inflammation of heterozygous Card14 E138A/+ mice."
      explanation: >-
        Genetic epistasis placing the CBM complex upstream in vivo.
    - reference: PMID:32597759
      reference_title: CARD14(E138A) signalling in keratinocytes induces TNF-dependent skin and systemic inflammation.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "CARD14E138A-induced skin inflammation and systemic disease were independent of adaptive immune cells, ameliorated by blocking TNF and induced by CARD14E138A signalling only in keratinocytes."
      explanation: >-
        The keratinocyte-intrinsic origin of CARD14 gain-of-function disease.
discussions:
- discussion_id: fprp_hom_mouse_vs_het_human
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Why does the Card14 C127S knock-in mouse need homozygosity to show PRP-like
    disease, when every reported patient with the same allele is heterozygous, and
    does the heterozygous mouse's transient disease mean mouse skin buffers CARD14
    gain of function more effectively than human skin?
  rationale: >-
    The only PRP-allele model recapitulates follicular plugging and palmoplantar
    hyperkeratosis in homozygotes, with early mortality and barrier failure that have
    no human counterpart, while heterozygous mice resolve by 6-7 weeks. Mechanism
    claims drawn from the model (IL-36/inflammasome activation, barrier loss) may
    reflect the doubled allele dose rather than the human disease state.
  attaches_to:
  - pathophysiology#Epidermal Hyperproliferation and Abnormal Cornification
  - pathophysiology#IL-23/IL-17 Axis Amplification
  evidence:
  - reference: DOI:10.21203/rs.3.rs-2513325/v1
    reference_title: IL-17 axis is a significant driver of skin inflammation in Card14 mutant pityriasis rubra pilaris model mice
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We report the first mouse model of PRP to carry a homozygous knock-in mutation, c.380G>C (p.Cys127Ser) corresponding to a PRP-causative human mutation, in CARD14."
    explanation: >-
      The model that recapitulates PRP is homozygous for an allele that is
      heterozygous in every reported patient.
  - reference: PMID:27760266
    reference_title: Pityriasis Rubra Pilaris Type V as an Autoinflammatory Disease by CARD14 Mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "2 de novo novel mutations (p.Cys127Ser and p.Gln136Leu), and another previously reported mutation (p.Gly117Ser)"
    explanation: >-
      The human p.Cys127Ser case was heterozygous and de novo.
  posed_by: dismech curation
  posed_date: "2026-10-23T00:00:00Z"
- discussion_id: fprp_allele_phenotype_prp_vs_psoriasis
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    What determines whether a CARD14 gain-of-function allele produces PRP-like,
    psoriasis-like or mixed disease, given that p.Gly117Ser causes both and that
    members of one kindred can carry the same allele with different phenotypes?
  rationale: >-
    The functional studies cited in this entry compare each CARD14 allele with wild
    type, not PRP alleles with psoriasis alleles, so they cannot say whether the two
    phenotypes differ biochemically; and none of them tests a modifier locus. Until a
    study does, the familial PRP and PSORS2 entries rest on clinical rather than
    mechanistic separation.
  attaches_to:
  - pathophysiology#CARD14 Gain-of-Function Variant
  - genetic#CARD14
  evidence:
  - reference: PMID:22703878
    reference_title: Familial pityriasis rubra pilaris is caused by mutations in CARD14.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The present data demonstrate that autosomal-dominant PRP is allelic to familial psoriasis, which was recently shown to also be caused by mutations in CARD14."
    explanation: >-
      The allelism that makes the PRP-versus-psoriasis determinant an open question.
  - reference: PMID:27760266
    reference_title: Pityriasis Rubra Pilaris Type V as an Autoinflammatory Disease by CARD14 Mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "another previously reported mutation (p.Gly117Ser)"
    explanation: >-
      The PSORS2 psoriasis allele p.Gly117Ser recurring in a type V PRP patient.
  posed_by: dismech curation
  posed_date: "2026-10-23T00:00:00Z"

📚

References & Deep Research

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (2)

Review round 1: Familial Pityriasis Rubra Pilaris · 2026-10-24T00:05:53Z · View source

Answered the first automated review of PR 15418. The topical-therapy REFUTE item that sat under the etanercept treatment was moved to its own Topical therapy treatment record bound to CHEBI:50858 corticosteroid. A Methotrexate treatment record was added, citing the 15-kindred series (PMID:29477734) full text for its variable and generally inadequate response. Bimekizumab (NCIT:C171829) was added as a third therapeutic agent on the IL-17 blockade row with the pooled-literature sentence from PMID:40433052 graded REVIEW_SYNTHESIS, and the row renamed IL-17 blockade. The 9-of-10-biopsies figure, which came from the deep-research report rather than the cached abstract of PMID:31849081, was softened to the abstract's consistently. The knowledge-gap rationale was reworded to state only what the cited functional studies do and do not compare. Declined: splitting the PMID:30018619 item by evidence_source, because its single sentence cannot be divided into two substantive quotes and repeating it under two grades would trip check-snippet-grading; and replacing the p.Leu156Pro snippet, because PMID:22703878 full text is not in PMC (publisher-free access only). Validated with just validate-disorders (107 of 107 snippets), validate-terms, check-entity-refs, check-causal-targets, check-enum-values, check-duplicate-keys and check-block-scalar-comments.

Create: Familial Pityriasis Rubra Pilaris · 2026-10-23T23:16:54Z · View source

De novo curation of the CARD14-defined familial (type V) form of pityriasis rubra pilaris (MONDO:0008251, OMIM 173200), scoped to the gain-of-function CARD14 disease and mapped to the broader PRP concept (MONDO:0100017) only as skos:broadMatch; the sporadic Griffiths types are stated as out of scope. Sources: a Falcon deep-research report (research/Familial_Pityriasis_Rubra_Pilaris-deep-research-falcon.md, preflight-dr PASS on CARD14/OMIM 173200) used as a lead, with every claim re-grounded in cached PubMed abstracts: the 2012 gene-discovery paper (Fuchs-Telem, PMID:22703878), the PSORS2 allelism paper (PMID:22521418), the CAPE 15-kindred series (Craiglow, PMID:29477734) and its histopathology companion (PMID:31849081), the paediatric CAPE review (PMID:34448248), the Japanese type V series (PMID:27760266), the CBM biochemistry papers (PMID:27071417, PMID:27113748), Card14 knock-in mouse studies (PMID:29689250, PMID:29980436, PMID:32597759, PMID:33419765, PMID:32343482) and the Card14 C127S PRP-allele mouse (quoted from the 2023 Research Square preprint DOI:10.21203/rs.3.rs-2513325/v1 because the J Invest Dermatol abstract, PMID:39159782, has no cached content), the revertant-mosaicism study (PMID:34004138), and ustekinumab, secukinumab, ixekizumab and acitretin case reports or series in genotyped patients. Pathograph: CARD14 GOF variant (GO:0035591 signaling adaptor activity, GAIN_OF_FUNCTION) -> constitutive CBM complex (GO:0032449) -> keratinocyte NF-kappaB hyperactivation -> keratinocyte chemokine/cytokine production -> IL-23/IL-17 axis amplification -> epidermal hyperproliferation and abnormal cornification -> six dermatologic/histopathologic phenotypes, plus a replication-stress revertant-mosaicism side branch. Pruritus and patchy hyperpigmentation are deliberately left unconnected. Two animal models carry modeled_mechanisms with the homozygous-mouse versus heterozygous-human caveat recorded as a HUMAN_MODEL_MISMATCH discussion. Treatments: ustekinumab, IL-17A blockade, systemic retinoids, etanercept (documented poor response) and preclinical MALT1 inhibition, each with target_mechanisms. No ORPHA record exists for the familial form and ClinGen has not classified CARD14-PRP, so no structured-source rows or gene_disease_validity are recorded; check-genereviews reports no GeneReviews chapter. Validation: just validate-disorders (104/104 snippets verified, 0 issues), validate-terms passed, check-gene-activity-grounding does not list the entry, plus the offline entity-ref, causal-target, duplicate-key, qualifier-term, coarse-phenotype, enum-value and block-scalar gates. Stub stubs/Familial_Pityriasis_Rubra_Pilaris.yaml set to entry_type DISEASE and deleted.

Falcon ▸

Disease Characteristics Research Template

Edison Scientific Literature 45 citations 2026-10-13T09:12:55.414176

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: Familial Pityriasis Rubra Pilaris
MONDO ID: MONDO:0008251 (if available)
Category: Mendelian

Research Objectives

Please provide a comprehensive research report on Familial Pityriasis Rubra Pilaris 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

Present this section as an ordered causal chain first, then the detail below. Open with a numbered sequence of mechanistic steps running from the initiating lesion (mutation, exposure, infection) to the clinical manifestation, one step per line, each naming what it causes next. State the causal verb explicitly ("leads to", "results in") and say where a step is inferred rather than demonstrated. Where the mechanism branches, show the branch. The categories below are a checklist of what to cover within those steps, not the organizing structure — a step may draw on several of them, and a category may contribute to several steps.

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

Familial pityriasis rubra pilaris: disease-characteristics research report

Scope and evidence convention. Familial pityriasis rubra pilaris (PRP) is principally an early-onset, often autosomal-dominant inflammatory keratinization disorder associated with activating CARD14 variants and the atypical juvenile, or type V, PRP phenotype. Type V can also arise de novo; conversely, the wider category of CARD14-associated papulosquamous eruption (CAPE) includes psoriasis-like disease and is not synonymous with familial PRP. Findings from unselected or adult-onset PRP are identified separately below. This entry synthesizes published families, case series, experiments, reviews and trial registrations—not individual electronic health records. (fuchstelem2012familialpityriasisrubra pages 1-2, takeichi2017pityriasisrubrapilaris pages 1-2, frare2021card14‐associatedpapulosquamouseruption pages 1-3)

The following evidence map makes those distinctions explicit. (fuchstelem2012familialpityriasisrubra pages 1-2, takeichi2017pityriasisrubrapilaris pages 1-2, frare2021card14‐associatedpapulosquamouseruption pages 3-4, yoshikawa2023il17axisis pages 4-6, zhou2024updatesonpityriasis pages 3-4, zhao2025clinicalcharacteristicsof pages 3-6)

Study date / setting	Exact observation	Evidence grade	Applicability / limitation
2012 — Four unrelated autosomal-dominant familial-PRP kindreds	Linkage mapped disease to 17q25.3; three heterozygous CARD14 variants segregated: c.467T>C (p.Leu156Pro) in families A/B, c.412_414delGAG (p.Glu138del) in family C, and c.349+1G>A in family D, the latter producing a 66-bp intronic insertion. Variants were absent from 200 matched-control alleles and >8,200 reference sequences. Onset was 4–36 months; two asymptomatic obligatory carriers demonstrated incomplete penetrance. PRP skin showed increased CARD14, activated p65, and NF-κB target expression. (fuchstelem2012familialpityriasisrubra pages 1-2, fuchstelem2012familialpityriasisrubra pages 2-4, fuchstelem2012familialpityriasisrubra pages 4-6, fuchstelem2012familialpityriasisrubra pages 6-7)	Strong disease-specific human genetic evidence	Foundational causal evidence for familial PRP. The 90% penetrance used in linkage analysis was a modeling assumption, not an observed penetrance estimate; functional work examined affected skin rather than variant-specific reporter activity.
2017 — Case series of 22 patients across five PRP subtypes	All 3/3 type V patients carried CARD14 variants: p.Cys127Ser and p.Gln136Leu were de novo, and p.Gly117Ser was previously reported. All three had patchy macular brown hyperpigmentation. (takeichi2017pityriasisrubrapilaris pages 1-2)	Moderate-to-strong subtype-specific human evidence	Supports a close CARD14–type V association, but the denominator was only three type V cases; pathogenicity relied partly on in-silico prediction, and rare variants also occurred in one type I and one type IV case.
2021 — Three new pediatric CAPE cases plus 31 previously reported pediatric cases	Among the 31 prior cases, facial involvement occurred in 93%, palmoplantar keratoderma in 68%, follicular papules in 45%, islands of sparing in 42%, truncal disease in 64%, ectropion in 6%, and sclerodermatous hand change in 6%. Mean onset was 12.4 months overall. (frare2021card14‐associatedpapulosquamouseruption pages 3-4)	Moderate phenotypic-spectrum evidence	CAPE spans psoriasis-like and PRP-like disease and is broader than strictly diagnosed familial/type V PRP. Percentages describe the previous 31 pediatric CAPE cases, not all familial PRP patients.
2023 preprint; subsequently published in revised form — CRISPR Card14 p.Cys127Ser knock-in mice	Homozygous Card14C127S/C127S mice developed generalized scaling, follicular plugs, palmoplantar hyperkeratosis, approximately sixfold higher TEWL, IL-17/IL-36 and inflammasome activation, and high neonatal mortality; anti-IL-17A improved inflammation but not TEWL. Heterozygotes had milder, transient disease. (yoshikawa2023il17axisis pages 1-4, yoshikawa2023il17axisis pages 6-9, yoshikawa2023il17axisis media dc3c37bf, yoshikawa2023il17axisis pages 4-6)	Strong mechanistic animal evidence	PRP-specific mutation and morphology strengthen relevance, but severe disease required homozygosity whereas human disease is usually heterozygous. Single-cell RNA sequencing compared only one 12-month-old mutant with one wild-type mouse, limiting inference.
2024 — Scoping review of PRP literature through October 2022	Treatment reports covered 192 individuals, but only 5 had type V PRP; 55 were untyped. CARD14 evidence was concentrated in familial/type V disease, and no validated PRP severity score existed. (zhou2024updatesonpityriasis pages 2-3, zhou2024updatesonpityriasis pages 3-4, zhou2024updatesonpityriasis pages 4-6, zhou2024updatesonpityriasis pages 6-7)	Moderate aggregated PRP evidence; weak familial-specific treatment evidence	Apparent response rates combine heterogeneous case reports, case series, nonvalidated PASI/BSA measures, combination therapies, and multiple PRP subtypes; they should not be interpreted as familial-PRP efficacy estimates.
2024 — Guselkumab nonrandomized adult-PRP trial, NCT03975153	Open-label phase 2 study enrolled 15 adults and evaluated IL-23p19 blockade over 20 weeks; linked publication: JAMA Dermatology, June 1, 2024, DOI 10.1001/jamadermatol.2024.0257, PMID 38598229. (NCT03975153 chunk 1, NCT03975153 chunk 2)	Prospective interventional evidence for PRP generally	Not familial/type V-specific; the registry does not establish that participants carried pathogenic CARD14 variants. Familial-PRP-specific response cannot be inferred.
Adult PRP trials — Ixekizumab NCT03485976 and secukinumab NCT03342573	Ixekizumab enrolled 12 adults for 24 weeks; secukinumab enrolled 12 adults for 28 weeks, both single-arm and open-label. (NCT03485976 chunk 1, NCT03342573 chunk 1)	Prospective but uncontrolled PRP evidence	Not familial-specific and largely adult/acquired PRP. Small enrollment, no randomized comparator, PASI is not validated for PRP, and outcomes cannot be assigned to CARD14-associated type V disease without genotype-stratified data.
2025 — Eight pediatric CAPE patients; three treated with secukinumab	Seven patients had germline CARD14 variants; one had mosaic p.Glu138Lys with variant allele fractions of 24% in lesional skin and 4% in blood. Three secukinumab-treated patients had PASI changes 5.2→0.8, 35.5→8.2, and 25.3→7.9 over 52 weeks, corresponding to 84.6%, 76.9%, and 68.8% improvement. (zhao2025clinicalcharacteristicsof pages 1-2, zhao2025clinicalcharacteristicsof pages 2-3, zhao2025clinicalcharacteristicsof pages 3-6)	Moderate, recent genotype-defined clinical evidence	Retrospective, uncontrolled pediatric CAPE series; only three treated patients, heterogeneous genotypes/phenotypes and dosing, and residual disease was substantial in two. CAPE is relevant to but not synonymous with familial/type V PRP.

Table: Evidence-grading summary separating familial/type V PRP and CARD14-associated CAPE findings from studies of unselected adult PRP. It highlights exact denominators, genotype-specific observations, and major limitations affecting clinical interpretation.

1. Disease information and identifiers

Familial PRP causes persistent erythematous, scaly plaques, keratotic follicular papules and palmoplantar keratoderma, often with sharply bounded islands of unaffected skin. The foundational four-family study described onset at 4–36 months and characteristic alternating orthokeratosis and parakeratosis on biopsy. Its abstract states: “We ascertained four unrelated families affected by autosomal-dominant PRP” and “identified three different heterozygous mutations in CARD14.” Primary human genetic evidence: Fuchs-Telem et al., published 13 July 2012, DOI 10.1016/j.ajhg.2012.05.010. (fuchstelem2012familialpityriasisrubra pages 1-2, fuchstelem2012familialpityriasisrubra pages 2-4)

Verified identifiers: familial PRP MONDO:0008251; broader PRP MONDO:0100017, OMIM/MIM 173200, and MeSH D010916; causal-gene record CARD14 OMIM/MIM 607211, Ensembl ENSG00000141527. The general PRP clinical code is ICD-10 L44.0; it does not uniquely designate the familial genotype. A familial-specific Orphanet identifier or ICD-11 code was not independently verified and should not be populated by inference. Synonyms or related search terms include familial PRP, atypical juvenile PRP, type V PRP, Devergie disease (for PRP broadly), and, for the broader genotype-associated spectrum, CAPE. (OpenTargets Search: pityriasis rubra pilaris-CARD14, miyauchi2021alteredreplicationstress pages 1-2, NCT03485976 chunk 2, zhou2024updatesonpityriasis pages 1-2, frare2021card14‐associatedpapulosquamouseruption pages 1-3)

2. Etiology: causal, risk and protective factors

The established cause in the original kindreds is a heterozygous germline CARD14 alteration. Familial clustering is therefore an important risk indicator. In linkage analysis, the kindreds mapped to chromosome 17q25.3, overlapping psoriasis susceptibility locus PSORS2; two obligate variant/haplotype carriers had no symptoms, showing incomplete penetrance. The study’s 90% penetrance was an assumption used to calculate linkage, not a measured population estimate. CARD14 variants can also arise de novo, so a negative family history does not exclude genotype-associated type V disease. (fuchstelem2012familialpityriasisrubra pages 1-2, fuchstelem2012familialpityriasisrubra pages 2-4, takeichi2017pityriasisrubrapilaris pages 1-2)

Environment and gene–environment interaction. Sun exposure aggravated scaling in one CARD14-associated type V case; one CAPE child worsened to erythroderma during a viral illness despite methotrexate, and another flared during an upper-respiratory infection while receiving secukinumab. These are individual observations, not established causal risk factors. A 2024 review found reports of COVID-19 infection/vaccination and malignancy preceding PRP generally; these observations must not be transferred to inherited familial PRP or interpreted as proof of causation. Host–microbiome interactions and unidentified genetic or environmental modifiers were explicitly proposed, rather than demonstrated, in the original families. No reproducible protective allele, diet, toxin, occupational exposure or proven preventive lifestyle intervention was established. (takeichi2017pityriasisrubrapilaris pages 1-2, frare2021card14‐associatedpapulosquamouseruption pages 1-3, zhao2025clinicalcharacteristicsof pages 3-6, zhou2024updatesonpityriasis pages 2-3, fuchstelem2012familialpityriasisrubra pages 6-7)

A potentially protective somatic process has been observed after disease begins: two people with type V PRP had clinically normalized skin patches in which the germline CARD14 mutation was absent from the epidermis. All 6/6 examined patches showed reversion; 4/6 had chromosome-17q copy-neutral loss of heterozygosity. This is revertant mosaicism, not an inherited protective allele or a validated therapy. Primary human-plus-cell study: Miyauchi et al., 3 June 2021, DOI 10.1016/j.ajhg.2021.04.021. (miyauchi2021alteredreplicationstress pages 5-7, miyauchi2021alteredreplicationstress pages 1-2)

3. Phenotypes and quality of life

Phenotype and type	Onset, course and severity	Frequency and ontology suggestion
Follicular keratotic papules/plugging—physical sign	Usually early childhood; variable and often chronic. Follicular plugging can be seen histologically.	Present in the four foundational kindreds; follicular papules in 45% of 31 previously reported pediatric CAPE cases, not a familial-PRP prevalence. Suggested HPO label: follicular hyperkeratosis. (fuchstelem2012familialpityriasisrubra pages 1-2, frare2021card14‐associatedpapulosquamouseruption pages 3-4)
Orange-red or pink-red scaly plaques, erythema—physical signs	May become widespread or erythrodermic; extent fluctuates.	Found in founding families; 6/8 children in a 2025 CAPE series had scaly plaques, 1/8 erythroderma. Suggested HPO labels: erythema, scaling skin, erythroderma. (fuchstelem2012familialpityriasisrubra pages 1-2, zhao2025clinicalcharacteristicsof pages 1-2)
Palmoplantar keratoderma—physical sign	Persistent thickening and sometimes painful fissuring, affecting hand/foot function; severity variable.	68% of the 31 earlier CAPE cases; 5/8 in the 2025 CAPE series. Suggested HPO label: palmoplantar keratoderma. (frare2021card14‐associatedpapulosquamouseruption pages 3-4, zhao2025clinicalcharacteristicsof pages 1-2, NCT03975153 chunk 1)
Islands of spared skin—distributional sign	Appears amid confluent plaques; not universal across CAPE.	42% of the earlier 31 CAPE cases. Suggested HPO label: islands of spared skin, subject to ontology verification. (fuchstelem2012familialpityriasisrubra pages 1-2, frare2021card14‐associatedpapulosquamouseruption pages 3-4)
Facial/scalp involvement—site-specific signs	Facial involvement can be early, symmetric and pronounced; may interfere with appearance and comfort.	93% facial involvement among the earlier 31 CAPE cases; scalp involvement varied in the four founding families. Suggested HPO labels: facial erythema, scalp scaling. (frare2021card14‐associatedpapulosquamouseruption pages 3-4, fuchstelem2012familialpityriasisrubra pages 2-4)
Pruritus, burning or painful fissures—symptoms	Variable, potentially disruptive to sleep and activities.	Pruritus in 6/8 children with CAPE in 2025; familial-specific rates unavailable. Suggested HPO label: pruritus. (zhao2025clinicalcharacteristicsof pages 1-2, NCT03975153 chunk 1)
Ectropion, nail/hair changes and pigmentation—less-consistent physical signs	Ectropion occurs with severe facial disease; brown macules described in one type V series.	Ectropion 6% in 31 earlier CAPE cases but 3/8 in a differently ascertained 2025 series; all 3/3 CARD14-positive type V patients in a 2017 series had patchy brown hyperpigmentation. Suggested HPO labels: ectropion, hyperpigmentation of the skin; neither percentage is a population estimate. (frare2021card14‐associatedpapulosquamouseruption pages 3-4, zhao2025clinicalcharacteristicsof pages 1-2, takeichi2017pityriasisrubrapilaris pages 1-2)

These HPO labels are suggested mappings, not verified HP accession numbers. There is no established familial-PRP behavioral or laboratory-abnormality phenotype, and no validated phenotype-by-phenotype severity scale. In PRP-wide surveys, impairment of dermatology-specific quality of life and psychological distress were reported, but those results cannot be assigned to familial/type V cases; DLQI, Skindex and PASI have been used in research although no PRP-specific severity instrument is validated. (zhou2024updatesonpityriasis pages 4-6, zhou2024updatesonpityriasis pages 6-7, NCT06444399 chunk 1)

4. Genetic and molecular information

CARD14 encodes the epithelial scaffold CARD14/CARMA2, rather than an enzyme whose deficiency explains the usual familial disease. In the founding study, NM_024110.4:c.467T>C (p.Leu156Pro) occurred in families A and B on different haplotypes, arguing against a single founder; c.412_414delGAG (p.Glu138del) occurred in C; and c.349+1G>A, a splice-donor alteration yielding a 66-base intronic insertion, occurred in D. These variants were absent from 200 ancestry-matched control alleles and from the historical reference sequences examined in 2012. Those historical absences are not contemporary gnomAD allele frequencies. The original authors demonstrated variant cosegregation and enhanced NF-κB activity in affected tissue, not variant-specific biochemical activity for every allele. Figure 3 documents the three alleles and their splice effect. (fuchstelem2012familialpityriasisrubra pages 2-4, fuchstelem2012familialpityriasisrubra pages 4-6, fuchstelem2012familialpityriasisrubra media 6dfcbce5, fuchstelem2012familialpityriasisrubra media 59870192)

Other reported type V-associated changes include p.Cys127Ser, p.Gln136Leu and p.Gly117Ser; two of three type V cases in Takeichi et al. were de novo. That study sequenced 22 PRP patients but contained only three type V cases: 3/3 carried these variants, an ascertainment-limited observation, not evidence that 100% of all type V patients have pathogenic CARD14 changes. A specific variant’s ClinVar/ACMG classification, current frequency and molecular effect must be checked individually before clinical reporting. (takeichi2017pityriasisrubrapilaris pages 1-2)

A 2025 pediatric CAPE, not familial-PRP-only, series found seven germline-positive children and one somatic mosaic p.Glu138Lys child; measured variant fractions in that child were 24% in lesional skin and 4% in blood. Three newly described sequence changes were c.392_397del, c.391_392delinsTT and c.-280C>T; novelty or author-described activation is not, by itself, a laboratory-specific pathogenic classification. No established familial-PRP chromosomal aneuploidy, recurrent structural rearrangement, validated severity-modifier gene or characteristic DNA-methylation signature was identified. The observed chromosome-17q loss of heterozygosity occurs somatically in revertant patches, not as the usual inherited initiating lesion. (zhao2025clinicalcharacteristicsof pages 1-2, zhao2025clinicalcharacteristicsof pages 2-3, miyauchi2021alteredreplicationstress pages 5-7)

5. Environmental and infectious information

No environmental exposure or pathogen is established as the primary cause of CARD14-related familial PRP. Published infection, vaccination, UV-exacerbation and malignancy observations pertain to individual cases or mixed-etiology PRP; they do not establish transmissibility, a vaccine contraindication or a preventive exposure threshold for mutation carriers. HIV-associated type VI PRP is a distinct clinical subtype, not a demonstration that familial/type V PRP is caused by HIV. Consequently, assigning an infectious-agent taxon, lifestyle risk factor or CHEBI-coded toxin to the Mendelian entry would currently overstate the evidence. (fuchstelem2012familialpityriasisrubra pages 1-2, takeichi2017pityriasisrubrapilaris pages 1-2, zhou2024updatesonpityriasis pages 2-3, zhou2024updatesonpityriasis pages 6-7)

6. Mechanism and pathophysiology

Ordered causal chain—observed links versus inference:

Germline activating CARD14 variation leads to altered CARD14 signaling in epidermal keratinocytes. Human cosegregation is demonstrated; gain of function is supported by related cellular and animal experiments, but should not be presumed for every reported allele. (fuchstelem2012familialpityriasisrubra pages 1-2, fuchstelem2012familialpityriasisrubra pages 4-6, mellett2018card14gainoffunctionmutation pages 4-6)
Altered CARD14–BCL10–MALT1 complex activity leads to greater NF-κB signaling and inflammatory transcription. CARD14/p65 and downstream CCL20, IL1B, NOS2 were elevated in familial-PRP skin; keratinocyte-specific Malt1 deletion suppressed disease in a psoriasis-associated E138A mouse, so extension of that intervention to human type V PRP remains inferred. (fuchstelem2012familialpityriasisrubra pages 4-6, fuchstelem2012familialpityriasisrubra pages 6-7, nuffel2020malt1targetingsuppresses pages 1-2)
Epidermal inflammatory transcription leads to chemokine production, immune-cell recruitment and an amplifying IL-23/IL-17 response. This branch is experimentally supported in C127S PRP-model mice; exact initiating cytokine sequence in humans is inferred. A parallel IL-1/IL-36/inflammasome branch accompanies IL-17 signaling in mutant mouse epidermis and follicular outer-root-sheath cells. (yoshikawa2023il17axisis pages 4-6, yoshikawa2023il17axisis pages 6-9)
IL-17-driven signaling and epithelial differentiation changes lead to epidermal hyperplasia, scale and follicular plugging; down-regulated filaggrin/FLG2 contributes to a barrier-dysfunction branch. The expression and lesion changes are observed in mice; a direct causal route from an individual cytokine to human follicular plugs is inferred. (yoshikawa2023il17axisis pages 4-6, yoshikawa2023il17axisis pages 6-9, yoshikawa2023il17axisis media dc3c37bf)
Epidermal thickening, follicular obstruction, inflammation and barrier disruption result in papules, red scaly plaques, palmoplantar keratoderma and sometimes erythroderma; clinical manifestations are documented in human families and reproduced incompletely by the model. (fuchstelem2012familialpityriasisrubra pages 1-2, yoshikawa2023il17axisis pages 1-4, yoshikawa2023il17axisis media dc3c37bf)
Separate compensatory branch: in some carriers, replication-stress-associated somatic recombination leads to loss of the mutant allele in epidermal clones, resulting in clinically spared revertant patches. Somatic reversion is observed; break-induced replication as the precise repair route remains a mechanistic interpretation. (miyauchi2021alteredreplicationstress pages 1-2, miyauchi2021alteredreplicationstress pages 5-7, miyauchi2021alteredreplicationstress pages 9-10)

Profiling and cellular resolution. In the 2023 PRP-model preprint, mouse skin at postnatal day 5 had 760 upregulated and 459 downregulated genes at a twofold threshold; enriched pathways included IL-17, cytokine–receptor, NOD-like receptor and TNF signaling. Il17a/f, Il23a, Il1b, Il6, S100a8/a9, Krt16 and phospholipase-A2 genes increased, whereas Flg/Flg2 decreased. Single-cell analysis of 8,364 cells implicated granular keratinocytes, follicular outer-root-sheath keratinocytes and fibroblasts; increased Il17ra and Pla2g2f in outer-root-sheath cells support, but do not prove, their role in follicular plugging. Crucially, this single-cell comparison used one mutant and one control adult mouse. Anti-IL-17A reduced inflammation and ear thickness without an apparent improvement in measured ear transepidermal water loss: inflammation and barrier dysfunction must not be represented as identical processes. The 2023 text is a preprint DOI 10.21203/rs.3.rs-2513325/v1; a subsequent journal article is listed with DOI 10.1016/j.jid.2024.04.036, but the detailed numbers here were checked against the accessible preprint. (yoshikawa2023il17axisis pages 4-6, yoshikawa2023il17axisis pages 14-17, yoshikawa2023il17axisis pages 6-9)

Candidate annotations—not verified accession mappings: biological processes GO: NF-κB signaling, GO: inflammatory response, GO: epidermis development, GO: keratinocyte differentiation, GO: response to interleukin-17, and GO: DNA repair by homologous recombination; cell types CL: keratinocyte, CL: dermal fibroblast, CL: dendritic cell, CL: CD4-positive T cell and CL: lymphocyte. Candidate components are GO: cytoplasm/CARD14 signalosome and GO: nucleus/NF-κB transcriptional activity. MAPK/AP-1 involvement has experimental support in related CARD14 psoriasis models; Wnt, PI3K–AKT, mTOR, disease-specific metabolomics, lipidomics, spatial transcriptomics, human PRP CRISPR screens and a validated epigenetic mechanism were not established by the familial-specific evidence reviewed. Phospholipase expression alone is not a measured lipidomic signature. (mellett2018card14gainoffunctionmutation pages 4-6, nuffel2020malt1targetingsuppresses pages 1-2, fuchstelem2012familialpityriasisrubra pages 4-6, yoshikawa2023il17axisis pages 4-6)

7. Anatomical structures affected

The primary organ is skin, especially interfollicular epidermis, hair-follicle epithelium/outer root sheath, palms and soles, and often the face and scalp. The superficial dermis shows inflammatory-cell infiltration; widespread severe disease can impair skin barrier function and cause fissuring, but a distinct, routinely affected internal organ has not been established for familial type V PRP. The mouse model directly demonstrates follicular plugging and barrier injury, with human biopsies supporting epidermal and follicular involvement. Candidate ontology labels requiring UBERON/CL identifier validation are skin of face, scalp, skin of palm, skin of sole, epidermis, dermis, hair follicle, keratinocyte and fibroblast. Clinical distribution is often symmetric or widespread rather than consistently unilateral; Blaschko-linear lesions in one CAPE patient reflected somatic mosaicism, not the standard familial distribution. (fuchstelem2012familialpityriasisrubra pages 1-2, fuchstelem2012familialpityriasisrubra pages 2-4, yoshikawa2023il17axisis media dc3c37bf, yoshikawa2023il17axisis pages 4-6, zhao2025clinicalcharacteristicsof pages 1-2)

8. Temporal development

Founding-kindred onset occurred at 4, 8, 9 and 36 months, respectively; other CARD14-positive cases arose de novo. Familial/type V disease tends to persist or recur, rather than following the relatively favorable spontaneous-remission course described for classical adult/type I PRP. Disease extent and itching may fluctuate during infections or treatment. There is no validated sequence of early/intermediate/end stages, progression rate, critical intervention window, or lifetime remission percentage for genetically confirmed familial PRP. In one individual, somatic reversion produced unaffected skin islands, but this does not establish generalized spontaneous cure. (fuchstelem2012familialpityriasisrubra pages 2-4, zhou2024updatesonpityriasis pages 1-2, miyauchi2021alteredreplicationstress pages 5-7, zhao2025clinicalcharacteristicsof pages 3-6)

9. Inheritance, epidemiology and population

Autosomal dominant with incomplete penetrance and variable expressivity best describes the original pedigrees. Across reported families, de novo type V variants and mosaic CAPE further broaden the presentation; there is no reliable numerical penetrance, carrier frequency, genetic anticipation, consanguinity effect, germline-mosaicism rate or established population founder variant. The same p.Leu156Pro variant arose on different family haplotypes, arguing against one founder in those kindreds. (fuchstelem2012familialpityriasisrubra pages 1-2, fuchstelem2012familialpityriasisrubra pages 2-4, fuchstelem2012familialpityriasisrubra pages 4-6, takeichi2017pityriasisrubrapilaris pages 1-2, zhao2025clinicalcharacteristicsof pages 1-2)

Historical figures of approximately 1 PRP case per 5,000 dermatology patients, up to 6.5% of PRP cases reporting family history, and approximately 5% classified as type V have different denominators and are not incidence or prevalence per 100,000 residents. No trustworthy familial/type V population incidence, prevalence, geographic enrichment or sex ratio was identified. The 2017 mixed-subtype cohort included 12 men and 10 women, which should not be recast as a familial-case sex ratio. (fuchstelem2012familialpityriasisrubra pages 1-2, takeichi2017pityriasisrubrapilaris pages 1-2)

10. Diagnosis and screening

Clinical approach: identify early-onset persistent papulosquamous disease, follicular papules, orange-red plaques, facial involvement, palmoplantar keratoderma, islands of sparing and a compatible family history; document body-surface involvement and symptoms. Biopsy may reveal checkerboard alternating orthokeratosis/parakeratosis, hypergranulosis, broad rete ridges, follicular plugs and superficial lymphocytic inflammation. In a CAPE pathology study, 9/10 biopsies showed alternating parakeratosis and orthokeratosis, although the series was seven CAPE patients, not seven confirmed familial type V cases. Diagnostic appearances overlap psoriasis and may change over time; repeat clinicopathological assessment may be necessary. (fuchstelem2012familialpityriasisrubra pages 1-2, ring2020histopathologicfindingscharacteristic pages 1-3, zhou2024updatesonpityriasis pages 6-7)

Genetic approach: for strongly suggestive disease, sequence CARD14, including coding exons and relevant splice junctions, with copy-number analysis if the assay design supports it. A genodermatosis/inflammatory-keratinization multigene panel or WES/WGS is reasonable when presentation is atypical, the single-gene test is negative or another disorder is possible. Trio testing and segregation studies help establish de novo status and interpretation; deep sequencing of affected skin plus blood can detect mosaicism that ordinary blood-based sequencing may miss. The original families required linkage, exome and targeted Sanger sequencing; a 2025 pediatric series used WES and found different lesional-skin versus blood variant fractions in a mosaic child. Testing must use contemporary variant classification and laboratory validation rather than treating every rare CARD14 change as pathogenic. Routine karyotype, CMA, FISH, mitochondrial DNA or repeat-expansion assays have no established role in otherwise typical familial PRP. (fuchstelem2012familialpityriasisrubra pages 2-4, fuchstelem2012familialpityriasisrubra pages 4-6, zhao2025clinicalcharacteristicsof pages 1-2, zhao2025clinicalcharacteristicsof pages 2-3)

Differential diagnosis: psoriasis—particularly infantile or familial CARD14-related psoriasis—eczema/atopic dermatitis, other inherited keratinization disorders, acquired adult PRP, HIV-associated type VI PRP, erythrodermic drug reactions and inflammatory follicular dermatoses. Some cases genuinely lie on a CAPE spectrum rather than being separable by a single biopsy. Neither diagnostic blood chemistry nor imaging, ECG, EEG, electrophysiology, liquid biopsy, RNA-seq or proteomics is a validated routine test for familial PRP. Population newborn screening is not established; targeted cascade testing can be considered after a familial causal variant has been established. (frare2021card14‐associatedpapulosquamouseruption pages 1-3, ring2020histopathologicfindingscharacteristic pages 1-3, zhou2024updatesonpityriasis pages 6-7, fuchstelem2012familialpityriasisrubra pages 2-4)

11. Outcomes and prognosis

The principal burden is chronic skin inflammation, discomfort, pruritus, visible lesions, palmoplantar fissuring and functional/psychosocial impairment. Extensive disease can become erythrodermic; serious secondary infection has been documented in severe PRP generally, but its incidence in familial/type V disease is unknown. In homozygous mouse mutants, most pups died by postnatal day 11 with severe barrier dysfunction; that animal result must not be presented as human mortality or life expectancy. No familial-PRP-specific survival probability, mortality rate, standardized disability distribution, validated prognostic model or prognostic biomarker was identified. Variable expression and incomplete penetrance complicate individual prediction. (frare2021card14‐associatedpapulosquamouseruption pages 1-3, zhou2024updatesonpityriasis pages 3-4, yoshikawa2023il17axisis pages 1-4, fuchstelem2012familialpityriasisrubra pages 1-2)

12. Treatment and real-world implementation

Strategy: specialist-directed emollients and topical anti-inflammatory treatment for limited symptoms; for extensive or refractory disease, consider systemic retinoids, methotrexate or immunomodulation with safety monitoring; for severe genotype-defined CAPE/type V-like disease, discuss off-label cytokine-directed biologics. No treatment is established as curative or specifically approved for familial PRP; PASI and DLQI may track responses but PASI is not validated for PRP. Suggested NCIT intervention labels—topical corticosteroid therapy, systemic retinoid therapy, methotrexate therapy, phototherapy, anti-IL-12/23 therapy, anti-IL-17 therapy, anti-IL-23 therapy and genetic counseling—are label suggestions, not verified NCIT codes. (frare2021card14‐associatedpapulosquamouseruption pages 1-3, zhou2024updatesonpityriasis pages 3-4, NCT03342573 chunk 1)

Supportive/topical treatments and retinoids. Emollients and topical corticosteroids may ease scaling and inflammation; a familial/type V-like child responded only partially to isotretinoin, then methotrexate, before improving with ustekinumab. In a 2025 CAPE series, acitretin improved one patient’s PASI 22.2→10.5 at 16 weeks but plateaued; in another, palms/soles remained affected. Systemic retinoids entail pregnancy-prevention and hepatic/lipid monitoring according to the drug used; the 2024 PRP review reported a liver-injury case, not a familial-specific adverse-event rate. (frare2021card14‐associatedpapulosquamouseruption pages 1-3, zhao2025clinicalcharacteristicsof pages 2-3, zhou2024updatesonpityriasis pages 4-6)
Ustekinumab, targeting IL-12/23 p40. A pediatric CAPE literature synthesis reported 7/8 near-complete/complete responses, a highly selected and uncontrolled observation. One reported child’s affected body surface fell from 80% to 20% initially and 11% after interval adjustment. This cannot be interpreted as a familial-PRP trial response probability; infections and other biologic risks require individualized monitoring. (frare2021card14‐associatedpapulosquamouseruption pages 6-6, frare2021card14‐associatedpapulosquamouseruption pages 1-3)
IL-17A blockade. A 2025 retrospective series of eight genotype-defined pediatric CAPE patients, three receiving secukinumab, reported respective 52-week PASI improvements of 84.6%, 76.9% and 68.8%; two still had considerable residual affected surface area. This is the most directly relevant recent treatment series but is CAPE-wide, n=3 treated, uncontrolled, with heterogeneous phenotypes and dosing. In PRP-model mice, anti-IL-17A improved skin inflammation but did not restore measured ear barrier function. (zhao2025clinicalcharacteristicsof pages 1-2, zhao2025clinicalcharacteristicsof pages 3-6, yoshikawa2023il17axisis pages 6-9)
Adults with PRP of mixed or different subtypes: phase-2 single-arm ixekizumab, NCT03485976, enrolled 12; guselkumab, NCT03975153, enrolled 15 and has a 2024 report, DOI 10.1001/jamadermatol.2024.0257, PMID 38598229; adult-onset secukinumab, NCT03342573, enrolled 12. The ixekizumab report is PMID 32293641; the adult secukinumab report is PMID 35701384. These trials do not supply genotype-stratified efficacy for inherited type V PRP in the material examined. A more recent TYK2-inhibitor study, NCT06444399, began in 2024 and enrolled seven adults with types I/II, explicitly excluding atypical presentations: it cannot be cited as a familial/type V treatment trial, despite its proposed single-cell biomarker analysis. (NCT03485976 chunk 1, NCT03975153 chunk 2, NCT03342573 chunk 1, NCT06444399 chunk 1)
Experimental mechanism-directed treatment: genetic or oral pharmacological MALT1 inhibition suppresses CARD14-E138A-driven mouse psoriasis-like dermatitis. It is a preclinical rationale, not demonstrated treatment for people with familial PRP. No established familial-PRP gene replacement/editing, RNA therapeutic, stem-cell intervention, surgical correction or validated pharmacogenomic dosing rule was identified. (nuffel2020malt1targetingsuppresses pages 1-2, nuffel2020malt1targetingsuppresses pages 6-8)

The 2024 scoping review assembled treatment reports for 192 PRP patients but only five identified type V cases. Reported pooled biologic responses combine case reports, nonvalidated outcomes, different subtypes and sometimes other systemic drugs; their percentages should not be imported as familial-PRP-specific efficacy or adverse-event estimates. Expert appraisal accordingly favors separating mechanistically plausible therapies from proven disease-specific outcomes. (zhou2024updatesonpityriasis pages 3-4, zhou2024updatesonpityriasis pages 4-6, zhou2024updatesonpityriasis pages 6-7)

13. Prevention and counseling

Primary prevention of a germline CARD14 allele is not available. After molecular confirmation, genetic counseling can explain autosomal-dominant transmission—a 1-in-2 probability of passing a heterozygous allele to each offspring, distinct from the child’s uncertain probability of clinical disease—and discuss variant-specific cascade, prenatal or preimplantation testing according to family preferences. Secondary prevention means prompt assessment of symptomatic at-risk relatives and early care of inflammatory/barrier complications, not universal screening. Tertiary prevention includes skin care, assessment of fissures/infection, and therapy-specific safety monitoring. No familial-PRP-specific vaccine, antimicrobial prophylaxis, exposure-avoidance regimen or public-health prevention program is established. (fuchstelem2012familialpityriasisrubra pages 1-2, fuchstelem2012familialpityriasisrubra pages 2-4, frare2021card14‐associatedpapulosquamouseruption pages 1-3)

14. Other species and natural disease

The naturally described familial disorder is human (Homo sapiens, NCBI Taxonomy 9606). Orthologous mouse Card14 underlies an engineered model discussed below; an ortholog does not establish naturally occurring veterinary PRP. The material reviewed establishes no naturally occurring CARD14-related familial PRP in a named nonhuman species or breed, no verified VBO breed or animal-ortholog NCBI Gene identifier, and no zoonotic or cross-species infectious transmission. Conservation of the mutated region was examined in the founding genetics paper, but model and human phenotypes differ. (fuchstelem2012familialpityriasisrubra pages 4-6, yoshikawa2023il17axisis pages 1-4, yoshikawa2023il17axisis media dc3c37bf)

15. Model organisms and model limitations

The most disease-directed model is laboratory mouse (Mus musculus, NCBI Taxonomy 10090) carrying a CRISPR-generated Card14 c.380G>C/p.Cys127Ser knock-in, homologous to a human type V-associated allele. Homozygous mice develop early generalized scaling, follicular dilation/plugging, palmoplantar hyperkeratosis, roughly sixfold greater transepidermal water loss, inflammatory gene expression and substantial early mortality; only 8/42 homozygotes in the described cohort survived comparably to controls. Heterozygous mice—genetically more analogous to affected people—develop milder, transient changes that resolved by approximately 6–7 weeks. Thus the model captures follicular pathology and pathway activation but its severe homozygote phenotype overstates typical heterozygous human disease. Anti-IL-17A intervention and one-animal-per-genotype adult single-cell profiling make it valuable for hypothesis testing, not a validated predictor of patient response. Mouse Figure 1 visually corroborates the genotype contrast, plugging and barrier measurement. (yoshikawa2023il17axisis pages 1-4, yoshikawa2023il17axisis pages 4-6, yoshikawa2023il17axisis pages 14-17, yoshikawa2023il17axisis media dc3c37bf)

Other Card14 E138A/ΔE138 mouse lines and primary keratinocyte or engineered cell systems interrogate CARD14–BCL10–MALT1, NF-κB and IL-23/IL-17 signaling, but their primary readout is commonly psoriasis-like inflammation. Human affected/revertant skin plus cultured-cell replication-stress assays separately illuminate somatic correction. No independently established PRP-specific organoid, zebrafish, fly or naturally affected animal breed was found in the reviewed evidence. (mellett2018card14gainoffunctionmutation pages 4-6, nuffel2020malt1targetingsuppresses pages 1-2, miyauchi2021alteredreplicationstress pages 5-7)

Source-quality and annotation note

The strongest familial-specific evidence is the four-kindred human linkage/segregation study, supplemented by type V cases and human revertant patches. 2023–2024 developments add a PRP-allele knock-in with transcriptomic and single-cell analyses, a comprehensive 2024 PRP evidence review, and a 2024 adult-PRP guselkumab study; the 2025 genotype-defined pediatric CAPE series adds treatment and somatic-mosaic observations. Exact PMIDs are given only where verified in the retrieved records; DOI links identify other primary studies without inventing PubMed identifiers. Suggested HPO/GO/CL/UBERON/NCIT labels require ontology lookup before automated ID assignment, and unsupported gene-frequency, prevalence, prognosis or treatment-response fields should remain unpopulated rather than inherit values from all-PRP or psoriasis cohorts. (fuchstelem2012familialpityriasisrubra pages 1-2, takeichi2017pityriasisrubrapilaris pages 1-2, miyauchi2021alteredreplicationstress pages 5-7, yoshikawa2023il17axisis pages 4-6, zhou2024updatesonpityriasis pages 1-2, NCT03975153 chunk 2, zhao2025clinicalcharacteristicsof pages 1-2, zhou2024updatesonpityriasis pages 3-4)

References

(fuchstelem2012familialpityriasisrubra pages 1-2): Dana Fuchs-Telem, Ofer Sarig, Maurice A.M. van Steensel, Ofer Isakov, Shirli Israeli, Janna Nousbeck, Katharina Richard, Veronique Winnepenninckx, Marigje Vernooij, Noam Shomron, Jouni Uitto, Philip Fleckman, Gabriele Richard, and Eli Sprecher. Familial pityriasis rubra pilaris is caused by mutations in card14. American journal of human genetics, 91 1:163-70, Jul 2012. URL: https://doi.org/10.1016/j.ajhg.2012.05.010, doi:10.1016/j.ajhg.2012.05.010. This article has 206 citations and is from a highest quality peer-reviewed journal.
(takeichi2017pityriasisrubrapilaris pages 1-2): Takuya Takeichi, Kazumitsu Sugiura, Toshifumi Nomura, Taiko Sakamoto, Yasushi Ogawa, Naoki Oiso, Yuko Futei, Aki Fujisaki, Akiko Koizumi, Yumi Aoyama, Kimiko Nakajima, Yutaka Hatano, Kei Hayashi, Akemi Ishida-Yamamoto, Sakuhei Fujiwara, Shigetoshi Sano, Keiji Iwatsuki, Akira Kawada, Yasushi Suga, Hiroshi Shimizu, John A. McGrath, and Masashi Akiyama. Pityriasis rubra pilaris type v as an autoinflammatory disease by card14 mutations. JAMA Dermatology, 153:66–70, Jan 2017. URL: https://doi.org/10.1001/jamadermatol.2016.3601, doi:10.1001/jamadermatol.2016.3601. This article has 97 citations and is from a domain leading peer-reviewed journal.
(frare2021card14‐associatedpapulosquamouseruption pages 1-3): Cindy P. Frare, Alli J. Blumstein, Amy S. Paller, Lia Pieretti, Keith A. Choate, Anne M. Bowcock, and Margarita Larralde. Card14‐associated papulosquamous eruption (cape) in pediatric patients: three additional cases and review of the literature. Pediatric Dermatology, 38:1237-1242, Aug 2021. URL: https://doi.org/10.1111/pde.14779, doi:10.1111/pde.14779. This article has 24 citations and is from a peer-reviewed journal.
(frare2021card14‐associatedpapulosquamouseruption pages 3-4): Cindy P. Frare, Alli J. Blumstein, Amy S. Paller, Lia Pieretti, Keith A. Choate, Anne M. Bowcock, and Margarita Larralde. Card14‐associated papulosquamous eruption (cape) in pediatric patients: three additional cases and review of the literature. Pediatric Dermatology, 38:1237-1242, Aug 2021. URL: https://doi.org/10.1111/pde.14779, doi:10.1111/pde.14779. This article has 24 citations and is from a peer-reviewed journal.
(yoshikawa2023il17axisis pages 4-6): Takenori Yoshikawa, Takuya Takeichi, Tetsuya Hirabayashi, Yoshinao Muro, Yuki Miyasaka, Tamio Ohno, and Masashi Akiyama. Il-17 axis is a significant driver of skin inflammation in card14 mutant pityriasis rubra pilaris model mice. Feb 2023. URL: https://doi.org/10.21203/rs.3.rs-2513325/v1, doi:10.21203/rs.3.rs-2513325/v1.
(zhou2024updatesonpityriasis pages 3-4): Ted Zhou, Abdullah Al Muqrin, and Mohannad Abu-Hilal. Updates on pityriasis rubra pilaris: a scoping review. Journal of Cutaneous Medicine and Surgery, 28:158-166, Jan 2024. URL: https://doi.org/10.1177/12034754231223159, doi:10.1177/12034754231223159. This article has 31 citations and is from a peer-reviewed journal.
(zhao2025clinicalcharacteristicsof pages 3-6): Xinrong Zhao, Zhaoyang Wang, Yunliu Chen, Xin Xiang, Yuanxiang Liu, Chaoyang Miao, and Zigang Xu. Clinical characteristics of card14-associated papulosquamous eruption and evaluation of therapeutic efficacy of secukinumab. Journal of Inflammation Research, 18:6597-6605, May 2025. URL: https://doi.org/10.2147/jir.s519554, doi:10.2147/jir.s519554. This article has 2 citations and is from a peer-reviewed journal.
(fuchstelem2012familialpityriasisrubra pages 2-4): Dana Fuchs-Telem, Ofer Sarig, Maurice A.M. van Steensel, Ofer Isakov, Shirli Israeli, Janna Nousbeck, Katharina Richard, Veronique Winnepenninckx, Marigje Vernooij, Noam Shomron, Jouni Uitto, Philip Fleckman, Gabriele Richard, and Eli Sprecher. Familial pityriasis rubra pilaris is caused by mutations in card14. American journal of human genetics, 91 1:163-70, Jul 2012. URL: https://doi.org/10.1016/j.ajhg.2012.05.010, doi:10.1016/j.ajhg.2012.05.010. This article has 206 citations and is from a highest quality peer-reviewed journal.
(fuchstelem2012familialpityriasisrubra pages 4-6): Dana Fuchs-Telem, Ofer Sarig, Maurice A.M. van Steensel, Ofer Isakov, Shirli Israeli, Janna Nousbeck, Katharina Richard, Veronique Winnepenninckx, Marigje Vernooij, Noam Shomron, Jouni Uitto, Philip Fleckman, Gabriele Richard, and Eli Sprecher. Familial pityriasis rubra pilaris is caused by mutations in card14. American journal of human genetics, 91 1:163-70, Jul 2012. URL: https://doi.org/10.1016/j.ajhg.2012.05.010, doi:10.1016/j.ajhg.2012.05.010. This article has 206 citations and is from a highest quality peer-reviewed journal.
(fuchstelem2012familialpityriasisrubra pages 6-7): Dana Fuchs-Telem, Ofer Sarig, Maurice A.M. van Steensel, Ofer Isakov, Shirli Israeli, Janna Nousbeck, Katharina Richard, Veronique Winnepenninckx, Marigje Vernooij, Noam Shomron, Jouni Uitto, Philip Fleckman, Gabriele Richard, and Eli Sprecher. Familial pityriasis rubra pilaris is caused by mutations in card14. American journal of human genetics, 91 1:163-70, Jul 2012. URL: https://doi.org/10.1016/j.ajhg.2012.05.010, doi:10.1016/j.ajhg.2012.05.010. This article has 206 citations and is from a highest quality peer-reviewed journal.
(yoshikawa2023il17axisis pages 1-4): Takenori Yoshikawa, Takuya Takeichi, Tetsuya Hirabayashi, Yoshinao Muro, Yuki Miyasaka, Tamio Ohno, and Masashi Akiyama. Il-17 axis is a significant driver of skin inflammation in card14 mutant pityriasis rubra pilaris model mice. Feb 2023. URL: https://doi.org/10.21203/rs.3.rs-2513325/v1, doi:10.21203/rs.3.rs-2513325/v1.
(yoshikawa2023il17axisis pages 6-9): Takenori Yoshikawa, Takuya Takeichi, Tetsuya Hirabayashi, Yoshinao Muro, Yuki Miyasaka, Tamio Ohno, and Masashi Akiyama. Il-17 axis is a significant driver of skin inflammation in card14 mutant pityriasis rubra pilaris model mice. Feb 2023. URL: https://doi.org/10.21203/rs.3.rs-2513325/v1, doi:10.21203/rs.3.rs-2513325/v1.
(yoshikawa2023il17axisis media dc3c37bf): Takenori Yoshikawa, Takuya Takeichi, Tetsuya Hirabayashi, Yoshinao Muro, Yuki Miyasaka, Tamio Ohno, and Masashi Akiyama. Il-17 axis is a significant driver of skin inflammation in card14 mutant pityriasis rubra pilaris model mice. Feb 2023. URL: https://doi.org/10.21203/rs.3.rs-2513325/v1, doi:10.21203/rs.3.rs-2513325/v1.
(zhou2024updatesonpityriasis pages 2-3): Ted Zhou, Abdullah Al Muqrin, and Mohannad Abu-Hilal. Updates on pityriasis rubra pilaris: a scoping review. Journal of Cutaneous Medicine and Surgery, 28:158-166, Jan 2024. URL: https://doi.org/10.1177/12034754231223159, doi:10.1177/12034754231223159. This article has 31 citations and is from a peer-reviewed journal.
(zhou2024updatesonpityriasis pages 4-6): Ted Zhou, Abdullah Al Muqrin, and Mohannad Abu-Hilal. Updates on pityriasis rubra pilaris: a scoping review. Journal of Cutaneous Medicine and Surgery, 28:158-166, Jan 2024. URL: https://doi.org/10.1177/12034754231223159, doi:10.1177/12034754231223159. This article has 31 citations and is from a peer-reviewed journal.
(zhou2024updatesonpityriasis pages 6-7): Ted Zhou, Abdullah Al Muqrin, and Mohannad Abu-Hilal. Updates on pityriasis rubra pilaris: a scoping review. Journal of Cutaneous Medicine and Surgery, 28:158-166, Jan 2024. URL: https://doi.org/10.1177/12034754231223159, doi:10.1177/12034754231223159. This article has 31 citations and is from a peer-reviewed journal.
(NCT03975153 chunk 1): Teri Greiling. Guselkumab in the Treatment of Pityriasis Rubra Pilaris (PRP). Oregon Health and Science University. 2019. ClinicalTrials.gov Identifier: NCT03975153
(NCT03975153 chunk 2): Teri Greiling. Guselkumab in the Treatment of Pityriasis Rubra Pilaris (PRP). Oregon Health and Science University. 2019. ClinicalTrials.gov Identifier: NCT03975153
(NCT03485976 chunk 1): Teri Greiling. Ixekizumab in the Treatment of Pityriasis Rubra Pilaris (PRP). Oregon Health and Science University. 2018. ClinicalTrials.gov Identifier: NCT03485976
(NCT03342573 chunk 1): Jason Sluzevich MD. Cosentyx (Secukinumab) for the Treatment of Adult Onset Pityriasis Rubra Pilaris. Mayo Clinic. 2018. ClinicalTrials.gov Identifier: NCT03342573
(zhao2025clinicalcharacteristicsof pages 1-2): Xinrong Zhao, Zhaoyang Wang, Yunliu Chen, Xin Xiang, Yuanxiang Liu, Chaoyang Miao, and Zigang Xu. Clinical characteristics of card14-associated papulosquamous eruption and evaluation of therapeutic efficacy of secukinumab. Journal of Inflammation Research, 18:6597-6605, May 2025. URL: https://doi.org/10.2147/jir.s519554, doi:10.2147/jir.s519554. This article has 2 citations and is from a peer-reviewed journal.
(zhao2025clinicalcharacteristicsof pages 2-3): Xinrong Zhao, Zhaoyang Wang, Yunliu Chen, Xin Xiang, Yuanxiang Liu, Chaoyang Miao, and Zigang Xu. Clinical characteristics of card14-associated papulosquamous eruption and evaluation of therapeutic efficacy of secukinumab. Journal of Inflammation Research, 18:6597-6605, May 2025. URL: https://doi.org/10.2147/jir.s519554, doi:10.2147/jir.s519554. This article has 2 citations and is from a peer-reviewed journal.
(OpenTargets Search: pityriasis rubra pilaris-CARD14): Open Targets Query (pityriasis rubra pilaris-CARD14, 2 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(miyauchi2021alteredreplicationstress pages 1-2): Toshinari Miyauchi, Shotaro Suzuki, Masae Takeda, Jin Teng Peh, Masayuki Aiba, Ken Natsuga, Yasuyuki Fujita, Takuya Takeichi, Taiko Sakamoto, Masashi Akiyama, Hiroshi Shimizu, and Toshifumi Nomura. Altered replication stress response due to card14 mutations promotes recombination-induced revertant mosaicism. The American Journal of Human Genetics, 108:1026-1039, Jun 2021. URL: https://doi.org/10.1016/j.ajhg.2021.04.021, doi:10.1016/j.ajhg.2021.04.021. This article has 9 citations.
(NCT03485976 chunk 2): Teri Greiling. Ixekizumab in the Treatment of Pityriasis Rubra Pilaris (PRP). Oregon Health and Science University. 2018. ClinicalTrials.gov Identifier: NCT03485976
(zhou2024updatesonpityriasis pages 1-2): Ted Zhou, Abdullah Al Muqrin, and Mohannad Abu-Hilal. Updates on pityriasis rubra pilaris: a scoping review. Journal of Cutaneous Medicine and Surgery, 28:158-166, Jan 2024. URL: https://doi.org/10.1177/12034754231223159, doi:10.1177/12034754231223159. This article has 31 citations and is from a peer-reviewed journal.
(miyauchi2021alteredreplicationstress pages 5-7): Toshinari Miyauchi, Shotaro Suzuki, Masae Takeda, Jin Teng Peh, Masayuki Aiba, Ken Natsuga, Yasuyuki Fujita, Takuya Takeichi, Taiko Sakamoto, Masashi Akiyama, Hiroshi Shimizu, and Toshifumi Nomura. Altered replication stress response due to card14 mutations promotes recombination-induced revertant mosaicism. The American Journal of Human Genetics, 108:1026-1039, Jun 2021. URL: https://doi.org/10.1016/j.ajhg.2021.04.021, doi:10.1016/j.ajhg.2021.04.021. This article has 9 citations.
(NCT06444399 chunk 1): Aaron R. Mangold. Deucravacitinib (BMS-986165) for Pityriasis Rubra Pilaris. Mayo Clinic. 2024. ClinicalTrials.gov Identifier: NCT06444399
(fuchstelem2012familialpityriasisrubra media 6dfcbce5): Dana Fuchs-Telem, Ofer Sarig, Maurice A.M. van Steensel, Ofer Isakov, Shirli Israeli, Janna Nousbeck, Katharina Richard, Veronique Winnepenninckx, Marigje Vernooij, Noam Shomron, Jouni Uitto, Philip Fleckman, Gabriele Richard, and Eli Sprecher. Familial pityriasis rubra pilaris is caused by mutations in card14. American journal of human genetics, 91 1:163-70, Jul 2012. URL: https://doi.org/10.1016/j.ajhg.2012.05.010, doi:10.1016/j.ajhg.2012.05.010. This article has 206 citations and is from a highest quality peer-reviewed journal.
(fuchstelem2012familialpityriasisrubra media 59870192): Dana Fuchs-Telem, Ofer Sarig, Maurice A.M. van Steensel, Ofer Isakov, Shirli Israeli, Janna Nousbeck, Katharina Richard, Veronique Winnepenninckx, Marigje Vernooij, Noam Shomron, Jouni Uitto, Philip Fleckman, Gabriele Richard, and Eli Sprecher. Familial pityriasis rubra pilaris is caused by mutations in card14. American journal of human genetics, 91 1:163-70, Jul 2012. URL: https://doi.org/10.1016/j.ajhg.2012.05.010, doi:10.1016/j.ajhg.2012.05.010. This article has 206 citations and is from a highest quality peer-reviewed journal.
(mellett2018card14gainoffunctionmutation pages 4-6): Mark Mellett, Barbara Meier, Deepa Mohanan, Rebekka Schairer, Phil Cheng, Takashi K. Satoh, Betina Kiefer, Caroline Ospelt, Stephan Nobbe, Margot Thome, Emmanuel Contassot, and Lars E. French. Card14 gain-of-function mutation alone is sufficient to drive il-23/il-17-mediated psoriasiform skin inflammation in vivo. The Journal of investigative dermatology, 138 9:2010-2023, Sep 2018. URL: https://doi.org/10.1016/j.jid.2018.03.1525, doi:10.1016/j.jid.2018.03.1525. This article has 90 citations.
(nuffel2020malt1targetingsuppresses pages 1-2): Elien Van Nuffel, Jens Staal, Griet Baudelet, Mira Haegman, Yasmine Driege, Tino Hochepied, Inna S Afonina, and Rudi Beyaert. Malt1 targeting suppresses card14‐induced psoriatic dermatitis in mice. EMBO reports, Apr 2020. URL: https://doi.org/10.15252/embr.201949237, doi:10.15252/embr.201949237. This article has 32 citations and is from a highest quality peer-reviewed journal.
(miyauchi2021alteredreplicationstress pages 9-10): Toshinari Miyauchi, Shotaro Suzuki, Masae Takeda, Jin Teng Peh, Masayuki Aiba, Ken Natsuga, Yasuyuki Fujita, Takuya Takeichi, Taiko Sakamoto, Masashi Akiyama, Hiroshi Shimizu, and Toshifumi Nomura. Altered replication stress response due to card14 mutations promotes recombination-induced revertant mosaicism. The American Journal of Human Genetics, 108:1026-1039, Jun 2021. URL: https://doi.org/10.1016/j.ajhg.2021.04.021, doi:10.1016/j.ajhg.2021.04.021. This article has 9 citations.
(yoshikawa2023il17axisis pages 14-17): Takenori Yoshikawa, Takuya Takeichi, Tetsuya Hirabayashi, Yoshinao Muro, Yuki Miyasaka, Tamio Ohno, and Masashi Akiyama. Il-17 axis is a significant driver of skin inflammation in card14 mutant pityriasis rubra pilaris model mice. Feb 2023. URL: https://doi.org/10.21203/rs.3.rs-2513325/v1, doi:10.21203/rs.3.rs-2513325/v1.
(ring2020histopathologicfindingscharacteristic pages 1-3): Nan G. Ring, Brittany G. Craiglow, Gauri Panse, Richard J. Antaya, Kurt Ashack, Richard Ashack, Esteban F. Faith, Amy S. Paller, Jennifer M. McNiff, Keith A. Choate, and Christine J. Ko. Histopathologic findings characteristic of card14‐associated papulosquamous eruption. Journal of Cutaneous Pathology, 47:425-430, Dec 2020. URL: https://doi.org/10.1111/cup.13633, doi:10.1111/cup.13633. This article has 23 citations and is from a peer-reviewed journal.
(frare2021card14‐associatedpapulosquamouseruption pages 6-6): Cindy P. Frare, Alli J. Blumstein, Amy S. Paller, Lia Pieretti, Keith A. Choate, Anne M. Bowcock, and Margarita Larralde. Card14‐associated papulosquamous eruption (cape) in pediatric patients: three additional cases and review of the literature. Pediatric Dermatology, 38:1237-1242, Aug 2021. URL: https://doi.org/10.1111/pde.14779, doi:10.1111/pde.14779. This article has 24 citations and is from a peer-reviewed journal.
(nuffel2020malt1targetingsuppresses pages 6-8): Elien Van Nuffel, Jens Staal, Griet Baudelet, Mira Haegman, Yasmine Driege, Tino Hochepied, Inna S Afonina, and Rudi Beyaert. Malt1 targeting suppresses card14‐induced psoriatic dermatitis in mice. EMBO reports, Apr 2020. URL: https://doi.org/10.15252/embr.201949237, doi:10.15252/embr.201949237. This article has 32 citations and is from a highest quality peer-reviewed journal.

Artifacts

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Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome	Count
References checked	15
Resolved	15
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	15
On topic	7
Off topic	0

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Term Validation

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Outcome	Count
Terms checked	2
Resolved	2
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	0
Terms whose name was checked	1
Terms named correctly	0
Terms named as a different term	1

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MONDO:0008251 (2 mentions) - the report calls it "if available"; MONDO calls it familial pityriasis rubra pilaris

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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

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12. Treatment

13. Prevention

14. Other Species / Natural Disease

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Familial pityriasis rubra pilaris: disease-characteristics research report

1. Disease information and identifiers

2. Etiology: causal, risk and protective factors

3. Phenotypes and quality of life

4. Genetic and molecular information

5. Environmental and infectious information

6. Mechanism and pathophysiology

7. Anatomical structures affected

8. Temporal development

9. Inheritance, epidemiology and population

10. Diagnosis and screening

11. Outcomes and prognosis

12. Treatment and real-world implementation

13. Prevention and counseling

14. Other species and natural disease

15. Model organisms and model limitations

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