Keratosis Lichenoides Chronica Research Articles

Diseases categorized as autoinflammatory keratinization diseases (AiKDs), and their pathologies and treatments.

Whole-exome and whole-genome sequencing have become widespread in approximately the last 15 years, and the predisposing factors and pathomechanisms of inflammatory keratinization diseases, which have been unknown for a long time, have gradually been revealed. Hence, various inflammatory keratinization diseases are recognized to cause innate immunity hyperactivation. Therefore, we have been advocating for the clinical entity, "autoinflammatory keratinization diseases (AiKDs)" since 2017. AiKDs are inflammatory keratinization diseases caused by autoinflammatory-related pathomechanisms in the skin. The aberrant activation of innate immunity and the resultant autoinflammation in the epidermis and the superficial dermis in AiKDs cause hyperkeratosis in the epidermis. Our initially proposed concept of AiKDs included generalized pustular psoriasis and related conditions, pityriasis rubra pilaris type V, and familial keratosis lichenoides chronica. Since then, the number of diseases known to be AiKDs has increased as previously unknown disease-causing factors and pathogenetic mechanisms of inflammatory keratinization diseases have been clarified one by one. To date, porokeratosis, hidradenitis suppurative, keratosis linearis with ichthyosis congenita and sclerosing keratoderma (KLICK) syndrome, and AiKDs associated with epidermal growth factor receptor (EGFR) deficiency or with hepatitis and autism have been recognized as AiKDs. The concept of AiKDs is considered extremely useful in our precise understanding of the pathogeneses behind inflammatory keratinization diseases and our appropriate treatment method selection. The number of AiKDs is expected to grow with the clarification of the pathomechanisms of further inflammatory keratinization diseases.

Keratosis lichenoides chronica: a diagnosis to remember

Keratosis lichenoides chronica: a diagnosis to remember

Role of the NLRP1 inflammasome in skin cancer and inflammatory skin diseases.

Inflammasomes are cytoplasmic protein complexes that play a crucial role in protecting the host against pathogenic and sterile stressors by initiating inflammation. Upon activation, these complexes directly regulate the proteolytic processing and activation of proinflammatory cytokines interleukin (IL)-1β and IL-18 to induce a potent inflammatory response, and induce a programmed form of cell death called pyroptosis to expose intracellular pathogens to the surveillance of the immune system, thus perpetuating inflammation. There are various types of inflammasome complexes, with the NLRP1 (nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-1) inflammasome being the first one identified and currently recognized as the predominant inflammasome sensor protein in human keratinocytes. Human NLRP1 exhibits a unique domain structure, containing both an N-terminal pyrin (PYD) domain and an effector C-terminal caspase recruitment domain (CARD). It can be activated by diverse stimuli, such as viruses, ultraviolet B radiation and ribotoxic stress responses. Specific mutations in NLRP1 or related genes have been associated with rare monogenic skin disorders, such as multiple self-healing palmoplantar carcinoma; familial keratosis lichenoides chronica; autoinflammation with arthritis and dyskeratosis; and dipeptidyl peptidase 9 deficiency. Recent research breakthroughs have also highlighted the involvement of dysfunctions in the NLRP1 pathway in a handful of seemingly unrelated dermatological conditions. These range from monogenic autoinflammatory diseases to polygenic autoimmune diseases such as vitiligo, psoriasis, atopic dermatitis and skin cancer, including squamous cell carcinoma, melanoma and Kaposi sarcoma. Additionally, emerging evidence implicates NLRP1 in systemic lupus erythematosus, pemphigus vulgaris, Addison disease, Papillon-Lefèvre syndrome and leprosy. The aim of this review is to shed light on the implications of pathological dysregulation of the NLRP1 inflammasome in skin diseases and investigate the potential rationale for targeting this pathway as a future therapeutic approach.

A homozygous p.Leu813Pro gain-of-function NLRP1 variant causes phenotypes of different severity in two siblings.

A trio exome sequencing study identified a previously unreported NLRP1 gene variant resulting in a p.Leu813Pro substitution of the LRR (leucine-rich repeats) domain of the NLRP1 protein (NACHT, LRR and PYD domains-containing protein 1). This homozygous mutation was shared by two sisters with different clinical presentation: the younger sister had generalized inflammatory nodules with keratotic plugs, clinically resembling multiple keratoacanthomas, while the older had manifestations of familial keratosis lichenoides chronica. To analyse the consequences of this NLRP1 variant in two siblings with a different clinical spectrum of severity. To demonstrate the pathogenicity, p.Leu813Pro was recombinantly expressed, and its effect on inflammasome assembly was assessed. Exome sequencing and RNA-Seq were performed to identify factors with potentially modifying effects on the severity of the skin manifestation between each sibling. The variant p.Leu813Pro triggered activation of the NLRP1 inflammasome leading to ASC (apoptosis-associated speck-like protein containing a CARD) speck formation and interleukin (IL)-1β release. The more severely affected sister had several additional genomic variants associated with atopy and psoriasis that were not present in her sibling. IL-5 and IL-17 emerged as dominant cytokines driving prominent inflammation in the skin of the severely affected sibling. To the best of our knowledge, this is the first report of a NLRP1 variant that leads to a different clinical spectrum of severity within the same sibship. IL-5 and IL-17 were the main cytokines expressed in the inflammatory lesions of the severely affected patient and might be regarded as disease modifying factors, and therefore may be considered as therapeutic targets.

Autoinflammatory keratinization diseases

As predisposing factors and pathogenic mechanisms of inflammatory keratinization disorders of the skin have become increasingly elucidated in recent years, a number of inflammatory keratinization disorders are now known to have the excessive activation of innate immunity as their pathogenesis. Autoinflammation-associated pathogeneses have been clarified in patients with generalized pustular psoriasis (GPP), pityriasis rubra pilaris (PRP) type V, and familial keratosis lichenoides chronica (KLC). Thus, based on these findings, in 2017, we proposed the clinical entity “autoinflammatory keratinization disease (AiKD),” which comprehensively includes inflammatory keratinization disorders with pathogenic mechanisms related to autoinflammation (the excessive activation of innate immunity). In 2017, GPP and associated diseases, PRP type V, and familial KLC came to be considered as AiKDs. In addition to these diseases, hidradenitis suppurative, porokeratosis, keratosis linearis with ichthyosis congenita and sclerosing keratoderma syndrome, and AiKDs with hepatitis and autism have been newly recognized as AiKDs. The concept of AiKD may contribute to the selection of novel treatment methods. For example, recognizing hidradenitis suppurativa precisely as an AiKD has resulted in the application of adalimumab, an anti-tumor necrosis factor alpha antibody, as a treatment. The concept of AiKD is thought to be useful toward our accurate understanding of the pathogeneses of inflammatory keratinization disorders and our choice of appropriate treatment methods. As the pathogenic mechanisms of inflammatory keratinization disorders are further elucidated, it is presumed that the number of keratinization diseases whose pathogeneses are associated with autoinflammation will increase and that the number of diseases recognized as AiKDs will grow more and more.

UVB-Induced Skin Autoinflammation Due to Nlrp1b Mutation and Its Inhibition by Anti-IL-1β Antibody.

NLRP1 (NACHT and leucine-rich repeat-containing protein family, pyrin domain-containing protein 1) is an innate immune sensor that is involved in the formation of inflammasome complexes. NLRP1 hyperactivity has been reported to cause inherited autoinflammatory diseases including familial keratosis lichenoides chronica and NLRP1-associated autoinflammation with arthritis and dyskeratosis. We generated Nlrp1b (the mouse homologue of human NLRP1) gain-of-function knock-in (Nlrp1b KI) mice with UVB irradiation-induced autoinflammatory skin lesions. We demonstrated that UVB irradiation induces IL-1β upregulation and IL-1β-dependent inflammation via caspase-1 activation in these Nlrp1b KI mice. RNA sequencing revealed the upregulation of inflammasome pathway-related genes, keratinocyte stress marker genes, and keratinocyte differentiation marker genes in the Nlrp1b KI mice after UVB irradiation. The skin inflammation and hyperkeratosis from UVB irradiation in the Nlrp1b KI mice were inhibited by both intraperitoneal and subcutaneous administration of anti-IL-1β antibodies before UVB irradiation. UVB irradiation and the IL-1β pathway are important in the pathogenesis of NLRP1-associated autoinflammatory skin lesions.

Childhood Keratosis Lichenoides Chronica: Treated Successfully with Acitretin and NBUVB.

Childhood Keratosis Lichenoides Chronica: Treated Successfully with Acitretin and NBUVB.

Keratosis lichenoides chronica: A case report and focused overview of the literature

Keratosis lichenoides chronica: A case report and focused overview of the literature

Erythema ab igne with features resembling keratosis lichenoides chronica

Erythema ab igne (EAI) is an asymptomatic dermatosis that develops in response to chronic exposure to low-grade heat. Characteristic findings on histopathology include epidermal atrophy, dermal elastosis, atypical histiocytes, and melanin and hemosiderin deposition. Reactive endothelial changes and prominent vascular proliferation are variable. Keratosis lichenoides chronica (KLC) is a rare lichenoid hyperkeratotic dermatosis. Acanthosis with parakeratosis and a lichenoid interface dermatitis with lymphocytes, histiocytes, and plasma cells are characteristic findings of KLC. Although its etiology remains unclear, KLC has been reported to occur in response to heat. Herein, we report a case of EAI with features resembling KLC.

Two Cases of Pediatric Keratosis Lichenoides Chronica with Review of the Clinical and Hitopathological Features of Pediatric versus Adult Presentation and Treatment with Acitretin

Keratosis Lichenoides Chronica (KLC) is a rare and chronic disorder of keratinization of unknown etiology. It is a progressive disease characterized by the linear and reticulate appearance of erythematous-to-violaceous keratotic and lichenoid papules over the trunk and limbs. KLC is uncommon in the pediatric population is uncommon and its clinical and histopathological presentation differs from the adult form. We report two cases in pediatric population, one of which has been treated successfully by acitretin. We also review the clinical and histopathologic features of the pediatric versus the adult form.

Keratosis lichenoides chronica: First case reported in Chile

We present a woman with a history of years of evolution of confluent hyperkeratotic papules and plaques with a generalized linear and reticulate pattern. Histopathological characteristics concordant with keratosis lichenoides chronica were finally evidenced after several non-specific biopsies. The cutaneous manifestations, chronicity. histopathology findings, and refractoriness to therapies are typical of this rare dermatosis.

Germline NLRP1 Mutations Cause Skin Inflammatory and Cancer Susceptibility Syndromes via Inflammasome Activation

Inflammasome complexes function as key innate immune effectors that trigger inflammation in response to pathogen- and danger-associated signals. Here, we report that germline mutations in the inflammasome sensor NLRP1 cause two overlapping skin disorders: multiple self-healing palmoplantar carcinoma (MSPC) and familial keratosis lichenoides chronica (FKLC). We find that NLRP1 is the most prominent inflammasome sensor in human skin, and all pathogenic NLRP1 mutations are gain-of-function alleles thatpredispose to inflammasome activation. Mechanistically, NLRP1 mutations lead to increased self-oligomerization by disrupting the PYD and LRR domains, which are essential in maintaining NLRP1 as an inactive monomer. Primary keratinocytes from patients experience spontaneous inflammasome activation and paracrine IL-1 signaling, which is sufficient to cause skin inflammation and epidermal hyperplasia. Our findings establish a group of non-fever inflammasome disorders, uncover an unexpected auto-inhibitory function for the pyrin domain, and provide the first genetic evidence linking NLRP1 toskin inflammatory syndromes and skin cancer predisposition.

Lichen planus and other lichenoid dermatoses: Kids are not just little people

Lichenoid dermatoses, a group of inflammatory skin conditions with characteristic clinical and histopathologic findings, range from common to rare. Classic lichen planus typically presents as pruritic, polygonal, violaceous flat-topped papules and plaques; many variants in morphology and location also exist. Other lichenoid dermatoses share similar clinical presentations and histopathologic findings. These include lichenoid drug eruption, lichen planus-like keratosis, lichen striatus, lichen nitidus, and keratosis lichenoides chronica. Epidemiologic characteristics vary among each lichenoid disorder. While classic lichen planus is considered a disease of adults, other lichenoid dermatoses may be more common in younger populations. The literature contains an array of reports on the variations in presentation and successful management of lichen planus and lichenoid dermatoses among diverse populations. Familiarity with the characteristics of each lichenoid dermatosis, rare or common within each patient population, is key to accomplishing timely recognition and effective management.

Keratosis Lichenoides Chronica – a Case Report and Literature Review

Abstract Keratosis lichenoides chronica represents a distinct entity, a rare disease of unknown etiology and pathogenesis, with clinical manifestations which, although typical, require extensive differential diagnosis. The course of the disease is chronic, progressive, and it is resistant to various treatment options, so despite variations in the clinical picture it is really easier to diagnose than to treat. This is a case report of a male patient in whom the diagnosis of keratosis lichenoides chronica was based on typical clinical picture, repeated biopsies and histopathological findings, course of the disease and poor response to any therapy.

Generalized Keratosis Lichenoides Chronica Induced By Antituberculosis Therapy: A Case Report

Generalized Keratosis Lichenoides Chronica Induced By Antituberculosis Therapy: A Case Report

Keratosis lichenoides chronica masquerading as discoid lupus erythematosus

Clinical and Experimental DermatologyVolume 38, Issue 3 p. 327-329 CPD • A memorable patient Keratosis lichenoides chronica masquerading as discoid lupus erythematosus J. S. Wee, J. S. Wee Department of Dermatology, Kingston Hospital, Kingston upon Thames, Surrey, UKSearch for more papers by this authorA. Viros, A. Viros Department of Dermatology, Kingston Hospital, Kingston upon Thames, Surrey, UKSearch for more papers by this authorL. Ffolkes, L. Ffolkes Department of Pathology, St George’s Hospital, London, UKSearch for more papers by this authorK. Misch, K. Misch Department of Dermatology, Kingston Hospital, Kingston upon Thames, Surrey, UKSearch for more papers by this authorJ. Natkunarajah, J. Natkunarajah Department of Dermatology, Kingston Hospital, Kingston upon Thames, Surrey, UKSearch for more papers by this author J. S. Wee, J. S. Wee Department of Dermatology, Kingston Hospital, Kingston upon Thames, Surrey, UKSearch for more papers by this authorA. Viros, A. Viros Department of Dermatology, Kingston Hospital, Kingston upon Thames, Surrey, UKSearch for more papers by this authorL. Ffolkes, L. Ffolkes Department of Pathology, St George’s Hospital, London, UKSearch for more papers by this authorK. Misch, K. Misch Department of Dermatology, Kingston Hospital, Kingston upon Thames, Surrey, UKSearch for more papers by this authorJ. Natkunarajah, J. Natkunarajah Department of Dermatology, Kingston Hospital, Kingston upon Thames, Surrey, UKSearch for more papers by this author First published: 21 March 2013 https://doi.org/10.1111/j.1365-2230.2012.04477.xCitations: 3 Dr Jamie S. Wee, Department of Dermatology, Kingston Hospital, Surrey, KT2 7QB, UK E-mail: drjamie.wee@gmail.com Conflict of interest: none declared. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume38, Issue3April 2013Pages 327-329 RelatedInformation

Keratosis lichenoides chronica in association with primary cutaneous anaplastic large cell lymphoma

Keratosis lichenoides chronica in association with primary cutaneous anaplastic large cell lymphoma

Keratosis lichenoides chronica responding to narrow band UVB phototherapy

Keratosis lichenoides chronica responding to narrow band UVB phototherapy

Pediatric Onset Keratosis Lichenoides Chronica: A Case Report

Keratosis lichenoides chronica (KLC) is an acquired keratinization disorder that is rare in childhood. We report a case of sporadic pediatric-onset KLC with seborrheic dermatitis-like lesions on the forehead, papules in a retiform pattern in the axillae and mons pubis, and eye and oral mucosal involvement,with additional features of premature canities and a transient photosensitive eruption.

Queratose liquenoide crônica: relato de caso

Keratosis lichenoides chronica or Nekam's disease is a rare mucocutaneous dermatosis characterized by keratinization. It is chronic and progressive usually affecting individuals aged 20-40 years. Around 70 cases have been reported in the literature. Due to the rarity of this condition and the lack of effective treatment, it is a difficult disease to manage. In the case described below we present a 42-year old patient with violaceous and hyperkeratotic papules in linear, reticular or plaque form, located on the trunk and limbs for five years. Aphthous lesions in the oral cavity and shallow ulcers on the genitalia also formed part of the clinical manifestation. Pathologic examination was suggestive of keratosis lichenoides chronica. Acitretin and dapsone was introduced and the lesions partially improved.