Inherited Nonsyndromic Ichthyoses: An Update on Pathophysiology, Diagnosis and Treatment

Abstract

Hereditary ichthyoses are due to mutations on one or both alleles of more than 30 different genes, mainly expressed in the upper epidermis. Syndromic as well as nonsyndromic forms of ichthyosis exist. Irrespective of etiology, virtually all types of ichthyosis exhibit a defective epidermal barrier that constitutes the driving force for hyperkeratosis, skin scaling, and inflammation. In nonsyndromic forms, these features are most evident in severe autosomal recessive congenital ichthyosis (ARCI) and epidermolytic ichthyosis, but to some extent also occur in the common type of non-congenital ichthyosis. A correct diagnosis of ichthyosis-essential not only for genetic counseling but also for adequate patient information about prognosis and therapeutic options-is becoming increasingly feasible thanks to recent progress in genetic knowledge and DNA sequencing methods. This paper reviews the most important aspects of nonsyndromic ichthyoses, focusing on new knowledge about the pathophysiology of the disorders, which will hopefully lead to novel ideas about therapy.

Fig. 1

Examples of ichthyosis subtypes discussed in the text. a Ichthyosis vulgaris on the lower extremity associated with FLG mutations. b Generalized autosomal recessive congenital ichthyosis (ARCI); lamellar ichthyosis due to truncating mutations in TGM1. c Pleomorphic ARCI; focal ichthyosis on the trunk due to point mutations in TGM1 rendering the enzyme inactive only in areas with higher skin surface temperature (so-called bathing suit ichthyosis). d Epidermolytic ichthyosis due to a dominant negative KRT10 mutation (pictures from the files of AV)

Fig. 2

Diagram of ARCI pathophysiology. For protein/enzyme abbreviations see Table 1. ARCI autosomal recessive congenital ichthyosis, CE cornified envelope, CLE corneocyte lipid envelope, ECM extracellular matrix, FFA free fatty acids, LB lamellar bodies, ULC-FA ultra-long-chain fatty acids. Asterisk indicates proteins defective in syndromic ichthyosis

Fig. 3

The relationship between ichthyosis and erythema severity post-infancy in the four subtypes of autosomal recessive congenital ichthyosis (ARCI): Lamellar ichthyosis (LI), congenital ichthyosiform erythroderma (CIE), pleomorphic ichthyosis (PI), and harlequin ichthyosis (HI). The ARCI genes most commonly mutated are indicated for each subgroup in order of the frequency observed in a Scandinavian cohort [17]. The position, shape, and size of the circles (or ellipses) reflect the mean score ranges and relative number of patients (from [17]). Except in the case of HI with truncating ABCA12 mutations, some overlapping does occur, both clinically and genetically, between the other groups. (Modified from [17] by permission from the publisher)