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Are you at risk for pityriasis rubra type V? It’s in the cards!

DII small banner By Warren R. Heymann, MD
Feb. 1, 2017

Characteristic facial involvement in caspase recruitment domain family member 14 gene (CARD14)-associated papulosquamous eruption. Symmetric and geometric pink, scaly patches or plaques involving the cheeks, upper cutaneous lip, and chin with sparing of the infralabial region is highly characteristic of CARD14-associated papulosquamous eruption.
Credit: JAAD
In a recent post advising to tread lightly before prescribing secukinumab for pityriasis rubra pilaris (PRP), I suggested that the Griffiths classification of PRP be expanded from types I –VI to include type VII (paraneoplastic) and type VIII (Sézary syndrome presenting as PRP). In my opinion, of all the types, type V (atypical juvenile) is the hardest to diagnose clinically — paradoxically, it may be the easiest to diagnose molecularly.

Takeichi et al sequenced the entire coding regions of CARD14 in genomic DNA from 22 patients (12 men, 10 women, average age 26 years) with PRP encompassing 5 clinical subtypes of PRP (types I – V; type VI, HIV-associated PRP was not included). The pathogenicity of each mutation was evaluated by several computational predictions. PRP was classified into 6 subgroups, types I to VI, based on clinical criteria. The prevalence of CARD14 mutations in each subtype of PRP was evaluated. Among 3 patients with PRP type V, all were found to have CARD14 mutations, including 2 de novo novel mutations, and another previously reported mutation. All were close to the reported pathogenic domains. In silico analysis of all 3 mutations suggested that they are functionally relevant to pathogenesis. Three patients displayed unique patchy macular brown hyperpigmentation in addition to other typical features of PRP. Patients with PRP type I and type IV, 1 patient each, had rare variants of CARD14. The authors concluded that PRP type V is a distinct variant of PRP caused by CARD14 mutations. Additionally, a rare variant of CARD14 might also be implicated in the pathophysiology of other forms of PRP (1).
According to the OMIM database (accessed January 12, 2017), The caspase recruitment domain (CARD) is a protein module that consists of 6 or 7 antiparallel alpha helices. It participates in apoptosis signaling through highly specific protein-protein homophilic interactions. CARDs induce nuclear factor kappa-B (NFkB) activity through the IKK complex.

From my perspective, the most important clinical pearl from this study was the finding of macular hyperpigmentation, presenting as macules and patches in the context of other characteristic features of PRP, to suggest the diagnosis of the type V variant. There was no mention of macular hyperpigmentation in type V PRP (familial or sporadic) in the fifth edition of Hurwitz Clinical Pediatric Dermatology. Jordan et al determined that mutations in CARD14 account for PSORS2 (the psoriasis susceptibility locus 2 in familial psoriasis). They described fifteen additional rare missense variants in CARD14, their distribution in seven psoriasis cohorts (> 6,000 cases and > 4,000 controls), and their effects on NFkB activation and the transcriptome of keratinocytes. There were more rare CARD14 variants in cases than in controls (2). I did not find any mention of hyperpigmentation describing the psoriatic patients in this manuscript. I searched PubMed for hyperpigmentation and PRP and only found an article detailing a woman with type VI PRP (HIV-associated), manifested by severe generalized disease complicated by secondary infection (3); this pigmentation was different from the distinctive macules and patches described in the type V patients of the featured manuscript. It is difficult to reach any conclusions about the hyperpigmentation in type V PRP – is it postinflammatory or part of the disease process related to the CARD14 mutation itself? The answer awaits us.
I still view PRP as a reaction pattern, not a specific disease. Type V may be the exception as the CARD14 mutation may be specific in this variant. Understanding the precise inflammatory pathway should allow specific therapies to be targeted, leading to a potential cure, as opposed to the broader therapeutic strokes currently available for PRP (retinoids, phototherapy, methotrexate, biologics, etc.). For these patients, who currently have to live with the deck they have been dealt, will hopefully have a more optimistic future that is in their cards.

1. Takeichi T, et al. Pityriasis rubra pilaris type V as an autoinflammatory disease by CARD14 JAMA Dermatol 2017; 153: 66-70.
2. Jordan CT, et al. Rare and common variants in CARD14, encoding an epidermal regulator of NF-kappaB, in psoriasis. Am J Hum Genet 2012; 90: 796-808.
3. Lerebours-Nadal L, et al. Severe, disfiguring, pityriasis rubra pilaris in a woman in the Dominican Republic: Histopathologic diagnosis and response to antiretroviral therapy. J Int Assoc Provid AIDS Care 2016; 15: 11-4.

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