Recent advances in understanding ichthyosis pathogenesis

Abstract

The ichthyoses, also known as disorders of keratinization (DOK), encompass a heterogeneous group of skin diseases linked by the common finding of abnormal barrier function, which initiates a default compensatory pathway of hyperproliferation, resulting in the characteristic clinical manifestation of localized and/or generalized scaling. Additional cutaneous findings frequently seen in ichthyoses include generalized xerosis, erythroderma, palmoplantar keratoderma, hypohydrosis, and recurrent infections. In 2009, the Ichthyosis Consensus Conference established a classification consensus for DOK based on pathophysiology, clinical manifestations, and mode of inheritance. This nomenclature system divides DOK into two main groups: nonsyndromic forms, with clinical findings limited to the skin, and syndromic forms, with involvement of additional organ systems. Advances in next-generation sequencing technology have allowed for more rapid and cost-effective genetic analysis, leading to the identification of novel, rare mutations that cause DOK, many of which represent phenotypic expansion. This review focuses on new findings in syndromic and nonsyndromic ichthyoses, with emphasis on novel genetic discoveries that provide insight into disease pathogenesis.

Ichthyosis molecular fingerprinting shows profound TH17 skewing and a unique barrier genomic signature

“…Disrupted terminal differentiation, lipid homeostasis, increased TEWL, and associations with atopy have historically linked ichthyoses to AD. 2,3,18,[27][28][29][30][31][32][33][34][35][36][37][38][39][40][41]43,[50][51][52][83][84][85][86] However, our recent profiling of ichthyotic skin using a limited geneexpression approach demonstrated enhanced T H 17/IL-23 response with marginal T H 2 skewing and lack of abnormalities in 3 differentiation proteins (FLG, LOR, and PPL), aligning it more closely to the psoriasis profile. 53 The present study is the first comprehensive genomic skin fingerprinting of the most common orphan ichthyosis subtypes to J ALLERGY CLIN IMMUNOL VOLUME 143, NUMBER 2 FIG 5.…”

“…Ichthyoses have barrier defects, 2,5,53,102 as reflected by increased TEWL, 2,3,5,18,28,30,31,53,102 and many forms have defective lamellar body transport and lipid homeostasis. Hence we comprehensively analyzed epidermal barrier genes, including those contributing to terminal differentiation, tight junctions (TJs), and lipid metabolism to dissect contributions of each component to impaired barrier function.…”

“…The ichthyoses are a heterogeneous group of rare genetic, debilitating cutaneous disorders 1-4 that share defective keratinization, a compromised epidermal barrier, and increased transepidermal water loss (TEWL). 2,3,5 Patients present with xerosis, hyperkeratosis, often severe erythema, and reduced quality of life. [6][7][8][9][10] Current treatments lack specificity and efficacy and are largely limited to topical emollients, keratolytics, and oral retinoids, [8][9][10][11] all with potential toxicity.…”

Angeborene Ichthyosen: Warum Lipide in der obersten Hautschicht lebenswichtig sind

“…Ichthyosen sind zumeist genetisch bedingt. Einer allgemein akzeptierten Theorie zufolge wird das Krankheitsbild durch kompensatorische Reaktionen auf eine Störung der epidermalen Permeabilitätsbarriere hervorgerufen [3]. Träger dieser Barrierefunktion ist die Hornschicht der Haut (Stratum corneum), die vor allem aus abgestorbenen, abgeflachten Keratinozyten (Korneozyten) besteht (▶Abb.…”

Genodermatozy – patogeneza i diagnostyka molekularna

“…Ponadto u chorych występować mogą: erytrodermia (zapalenie skóry), zaburzenia potliwości, tendencja do nawracających zakażeń, a także zaburzenia funkcjonowania szeregu innych narządów i układów (np. szkieletowego, nerwowego, krwionośnego) [36].…”