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.

Dominant ELOVL1 mutation causes neurological disorder with ichthyotic keratoderma, spasticity, hypomyelination and dysmorphic features

“…Inherited ichthyosis occurs in a group of Mendelian disorders caused by mutations of relatively large number of genes affecting epidermal function 1. Ichthyosis may be syndromic; that is, it coexists with extracutaneous involvement, for example, neurological symptoms (Sjogren-Larsson syndrome (SLS; MIM: 270200), myopathy (Chanarin-Dorfman syndrome (CDS; MIM: 275630) or sensorineural hearing impairment (diseases caused by dominant GJB2 mutations MIM: 148210).…”

Patients with congenital ichthyosis and TGM1 mutations overexpress other ARCI genes in the skin: Part of a barrier repair response?

“…Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of rare monogenic skin disorders with a prevalence of 1:100 000 . ARCI is characterized by a defective epidermal barrier reflected in an increased trans‐epidermal water loss (TEWL) and a presumed compensatory hyperkeratosis.…”

“…At birth, many of these patients present as collodion babies. Subsequently the skin phenotype transforms into either of four major clinical subtypes of ARCI, the most common of which is lamellar ichthyosis . Severe forms of ARCI often cause a reduced quality of life and usually require chronic treatment with systemic retinoids.…”

Quantitative image analysis of protein expression and colocalisation in skin sections

“…Figure 1 shows an example of IF staining of transglutaminase-1 (TGm-1) ( Figure 1A) and short-chain dehydrogenase/reductase family 9C member 7 (SDR9C7) ( Figure 1D), 2 genes causing autosomal recessive congenital ichthyosis. [7] ROIs were manually outlined with Pipeline II ( Figure 1B,E) and subsequently automatically divided into up to 20 layers by Pipeline F I G U R E 1 Quantification of immunofluorescence (IF) staining in normal skin using customised CellProfiler pipelines. Microphotographs of IF of TGm-1 (green) (A) and SDR9C7 (red) (D) with nuclear counterstaining (blue) were obtained and exported as lossless .tif images.…”