| 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. (pqac-00000041, pqac-00000042, pqac-00000043, pqac-00000044) | **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. (pqac-00000012, pqac-00000014) | **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. (pqac-00000002, pqac-00000051) | **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. (pqac-00000011, pqac-00000036, pqac-00000057, pqac-00000064) | **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. (pqac-00000037, pqac-00000038, pqac-00000052, pqac-00000053) | **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**. (pqac-00000010, pqac-00000029, pqac-00000047) | **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. (pqac-00000028, pqac-00000030, pqac-00000046) | **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. (pqac-00000033, pqac-00000050, pqac-00000063) | **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.*