High rate of self‐improving phenotypes in children with non‐syndromic congenital ichthyosis: case series from south‐western Germany

Abstract

Background Non-syndromic congenital ichthyosis describes a heterogeneous group of hereditary skin disorders associated with erythroderma and scaling at birth. Although both severe and mild courses are known, the prediction of the natural history in clinical practice may be challenging.Objectives To determine clinical course and genotype-phenotype correlations in children affected by non-syndromic congenital ichthyosis in a case series from south-western Germany.Methods We performed a retrospective observational study of 32 children affected by non-syndromic congenital ichthyoses seen in our genodermatosis clinic between 2011 and 2020. Follow-ups included assessment of weight and severity of skin involvement utilizing a modified Ichthyosis Area Severity Index (mIASI). mIASI was calculated as a sum comprising the previously published IASI score and an additional novel score to evaluate palmoplantar involvement. Linear regression was assessed using Pearson correlation, and statistical analysis was performed using the Wilcoxon-Mann-Whitney test. ResultsThis study included 23 patients with autosomal recessive congenital ichthyosis, seven with keratinopathic ichthyosis and two with harlequin ichthyosis. Cutaneous manifestations improved in more than 70% of the children during the follow-up. Especially in patients with mutations in ALOXE3 and ALOX12B, mIASI scores dropped significantly. The most common phenotype observed in this study was designated 0 mild fine scaling ichthyosis 0 . Severe palmoplantar involvement occurred in patients with KRT1 and ABCA12 mutations; most patients demonstrated hyperlinearity as a sign of dryness and scaling. Weight was mainly in the normal range and negatively correlated with the severity of skin involvement.Conclusions Congenital ichthyosis that self-improves and evolves with mild fine scaling ichthyosis was the most common phenotype observed in our patients. This type might be underdiagnosed if the genetic diagnosis is not performed in the first year of life. mIASI is an easy and fast instrument for scoring disease severity and adding additional points for palmoplantar involvement might be valuable.

A case of self-improving collodion ichthyosis associated with a rare variant of the ALOX12B gene

“…For example, cases of SICI due to splicing modulation have been reported [3,5]. In our case, two missense variants were identified, c.1294C> known to be pathogenic, and c.1405C>T, reported as causative of ARCI in only two unrelated individuals, one homozygous and another compound heterozygous [4,5]. Although this suggests a pathogenic role for this variant, the data available is not conclusive.…”

“…However, identical mutations can result in very different phenotypes, suggesting that other factors, genetic, epigenetic, or environmental, can affect mutation expression. For example, cases of SICI due to splicing modulation have been reported [3,5]. In our case, two missense variants were identified, c.1294C> known to be pathogenic, and c.1405C>T, reported as causative of ARCI in only two unrelated individuals, one homozygous and another compound heterozygous [4,5].…”

“…In two TGM1 variants, the mutated protein was found to be inactivated by high uterine pressures, regaining part of its function after birth [1,4]. Genetic variants in which the mutated protein retains residual activity are also described [4,5]. However, identical mutations can result in very different phenotypes, suggesting that other factors, genetic, epigenetic, or environmental, can affect mutation expression.…”

Identification of the first congenital ichthyosis case caused by a homozygous deletion in the ALOX12B gene due to chromosome 17 mixed uniparental disomy

“…The search terms included the combination of the following groups of keywords: 1) “ ALOX12B gene,” or “Arachidonate 12-Lipoxygenase”; 2) “variant” or “mutation”; and 3) “recessive congenital ichthyosis” or “self-improving collodion ichthyosis.” The initial electronic search identified 90 articles in PubMed, 46 in Scopus, 92 in Embase, and 77 in Web of Science. After removing the duplicates and screening the articles by title and abstract, we discarded 281 articles, and 24 remained ( Jobard et al, 2002 ; Eckl et al, 2005 ; Ashoor et al, 2006 ; Lesueur et al, 2007 ; Harting et al, 2008 ; Eckl et al, 2009 ; Akiyama et al, 2010 ; Kurban et al, 2010 ; Vahlquist et al, 2010 ; Li et al, 2012 ; Chaitidis et al, 2013 ; Israeli et al, 2013 ; Osorio et al, 2013 ; Numata et al, 2015 ; Lolas et al, 2016 ; Bastaki et al, 2017 ; Alavi et al, 2020 ; Fioretti et al, 2020 ; Anker et al, 2021 ; Frommherz et al, 2021 ; Hotz et al, 2021 ; Mohamad et al, 2021 ; Srinivas et al, 2021 ). Mutations in the ALOX12B gene were described according to the Human Genome Variation Society, using the NCBI reference sequence NM_001139.3.…”

Congenital Ichthyosis: Clinical and Genetic Characteristics of the Disease

“…Тяжелые ладонно-подошвенные поражения были у пациентов с дефектами в генах KRT1, ABCA12 и TGM1. У всех больных с ладонно-подошвенными поражениями отмечено выраженное снижение качества жизни, обусловленное трудностями при ходьбе и ограничениями повседневной деятельности [40].…”