Genetic analysis of seven patients with inherited ichthyosis and Nagashima­type palmoplantar keratoderma.

Inherited ichthyosis comprises a series of heterogeneous dermal conditions; it mainly manifests as widespread hyperkeratosis, xerosis and scaling of the skin. At times, overlapping symptoms require differential diagnosis between ichthyosis and several other similar disorders. The present study reports seven patients with confirmed or suspected to be associated with ichthyosis by conducting a thorough clinical and genetic investigation. Genetic testing was conducted using whole­exome sequencing, with Sanger sequencing as the validation method. The MEGA7 program was used to analyze the conservation of amino acid residues affected by the detected missense variants. The enrolled patients exhibited ichthyosis­like but distinct clinical manifestations. Genetic analysis identified diagnostic variations in the FLG, STS, KRT10 and SERPINB7 genes and clarified the carrying status of each variant in the respective family members. The two residues affected by the detected missense variants remained conserved across multiple species. Of note, the two variants, namely STS: c.452C>T(p.P151L) and c.647_650del(p.L216fs) are novel. In conclusion, a clear genetic differential diagnosis was made for the enrolled ichthyosis­associated patients; the study findings also extended the mutation spectrum of ichthyosis and provided solid evidence for the counseling of the affected families.

OSBPL2 compound heterozygous variants cause dyschromatosis, ichthyosis, deafness and atopic disease syndrome.

PURPOSE: In this study, we identified and diagnosed a novel inherited condition called Dyschromatosis, Ichthyosis, Deafness, and Atopic Disease (DIDA) syndrome. We present a series of studies to clarify the pathogenic variants and specific mechanism. METHODS: Exome sequencing and Sanger sequencing was conducted in affected and unaffected family members. A variety of human and cell studies were performed to explore the pathogenic process of keratosis. RESULTS: Our finding indicated that DIDA syndrome was caused by compound heterozygous variants in the oxysterol-binding protein-related protein 2 (OSBPL2) gene. Furthermore, our findings revealed a direct interaction between OSBPL2 and Phosphoinositide phospholipase C-beta-3 (PLCB3), a key player in hyperkeratosis. OSBPL2 effectively inhibits the ubiquitylation of PLCB3, thereby stabilizing PLCB3. Conversely, OSBPL2 variants lead to enhanced ubiquitination and subsequent degradation of PLCB3, leading to epidermal hyperkeratosis, characterized by aberrant proliferation and delayed terminal differentiation of keratinocytes. CONCLUSIONS: Our study not only unveiled the association between OSBPL2 variants and the newly identified DIDA syndrome but also shed light on the underlying mechanism.

Altered skin microbiome, inflammation, and JAK/STAT signaling in Southeast Asian ichthyosis patients.

BACKGROUND: Congenital ichthyosis (CI) is a collective group of rare hereditary skin disorders. Patients present with epidermal scaling, fissuring, chronic inflammation, and increased susceptibility to infections. Recently, there is increased interest in the skin microbiome; therefore, we hypothesized that CI patients likely exhibit an abnormal profile of epidermal microbes because of their various underlying skin barrier defects. Among recruited individuals of Southeast Asian ethnicity, we performed skin meta-genomics (i.e., whole-exome sequencing to capture the entire multi-kingdom profile, including fungi, protists, archaea, bacteria, and viruses), comparing 36 CI patients (representing seven subtypes) with that of 15 CI age-and gender-matched controls who had no family history of CI. RESULTS: This case-control study revealed 20 novel and 31 recurrent pathogenic variants. Microbiome meta-analysis showed distinct microbial populations, decreases in commensal microbiota, and higher colonization by pathogenic species associated with CI; these were correlated with increased production of inflammatory cytokines and Th17- and JAK/STAT-signaling pathways in peripheral blood mononuclear cells. In the wounds of CI patients, we identified specific changes in microbiota and alterations in inflammatory pathways, which are likely responsible for impaired wound healing. CONCLUSIONS: Together, this research enhances our understanding of the microbiological, immunological, and molecular properties of CI and should provide critical information for improving therapeutic management of CI patients.

Updated mutational spectrum and genotype-phenotype correlations in ichthyosis patients with ABCA12 pathogenic variants.

Autosomal recessive congenital ichthyoses (ARCI) is a genetically heterogeneous condition that can be caused by pathogenic variants in at least 12 genes, including ABCA12. ARCI mainly consists of congenital ichthyosiform erythroderma (CIE), lamellar ichthyosis (LI) and harlequin ichthyosis (HI). The objective was to determine previously unreported pathogenic variants in ABCA12 and to update genotype-phenotype correlations for patients with pathogenic ABCA12 variants. Pathogenic variants in ABCA12 were detected using Sanger sequencing or a combination of Sanger sequencing and whole-exome sequencing. To verify the pathogenicity of a previously unreported large deletion and intron variant, cDNA analysis was performed using total RNA extracted from hair roots. Genetic analyses were performed on the patients with CIE, LI, HI and non-congenital ichthyosis with unusual phenotypes (NIUP), and 11 previously unreported ABCA12 variants were identified. Sequencing of cDNA confirmed the aberrant splicing of the variant ABCA12 in the patients with the previously unreported large deletion and intron variant. Our findings expand the phenotype spectrum of ichthyosis patients with ABCA12 pathogenic variants. The present missense variants in ABCA12 are considered to be heterogenous in pathogenicity, and they lead to varying disease severities in patients with ARCI and non-congenital ichthyosis with unusual phenotypes (NIUP).

French national protocol for the management of congenital ichthyosis.

Congenital ichthyoses (CI) comprise a heterogeneous group of monogenic genetic skin diseases characterized by diffuse scaling, often associated with skin inflammation. Diagnosis of the individual form of ichthyosis is complex and is guided by clinical expertise. CI usually has a major impact on quality of life (QOL) and thus requires lifelong treatment. To date, there are no curative therapies, although various symptomatic treatment options exist. The present protocol for the management of CI has been drawn up in accordance with the recommendations published in 2012 by the French National Authority for Health, based on a literature review, with the help and validation of members of the French network for rare skin diseases (FIMARAD). It provides a summary of evidence and expert-based recommendations and is intended to help clinicians with the management of these rare and often complex diseases.

Congenital Ichthyosis: Current Approaches to Prenatal Diagnoses.

INTRODUCTION: Congenital ichthyosis represents a wide spectrum of diseases. This article reviews prenatal testing for ichthyosis. METHODS: We used pubmed.ncbi.nlm.nih.gov to search for 38 types of congenital ichthyosis combined with 17 words related to prenatal testing. RESULTS: Search resulted in 408 publications covering 13 types of ichthyoses and four types of tests. DISCUSSION: Biochemical testing is diagnostic in trichothiodystrophy, but nonspecific in X-linked ichthyosis and Refsum syndrome. Except in X-linked ichthyosis, biochemical testing requires invasive procedures to obtain fetal skin biopsy, amniocytes, or chorionic villus samples. It is superior to histological and cytological examination of fetal skin biopsy or amniocytes because keratinization occurs later in pregnancy and microscopy cannot differentiate between ichthyosis types. Imaging is more acceptable due to noninvasiveness and routine use, although ultrasonography is operator-dependent, nonspecific, and captures abnormalities at late stage. Molecular tests are described in at-risk pregnancies but testing of free fetal DNA was not described.

Unraveling the molecular mechanisms of cell migration impairment and apoptosis associated with steroid sulfatase deficiency: Implications for X-linked ichthyosis.

Steroid sulfatase (STS) deficiency is responsible for X-linked ichthyosis (XLI), a genetic disorder characterized by rough and dry skin caused by excessive keratinization. The impaired keratinization process leads to reduced cell mobility and increased apoptosis, which can cause an excessive buildup of the stratum corneum. In this study, we investigated the mechanisms underlying XLI and found that STS deficiency reduces cell mobility and increases apoptosis in human keratinocyte HaCaT cells. To explore these mechanisms further, RNA-sequencing was conducted on skin tissues from STS transgenic and knockout mice. Our RNA-seq results revealed that STS deficiency plays a critical role in regulating multiple signaling pathways associated with cell mobility and apoptosis, such as Wnt/ß signaling and the Hippo signaling pathway. Knockdown of the STS gene using shRNA in HaCaT cells led to an upregulation of E-cadherin expression and suppression of key factors involved in epithelial-mesenchymal transition (EMT), such as N-cadherin and vimentin. Inhibition of EMT involved the Hippo signaling pathway and reduction of HIF-1α. Interestingly, inhibiting STS with shRNA increased mitochondrial respiration levels, as demonstrated by the extracellular flux oxygen consumption rate. Additionally, we observed a significant increase in ROS production in partial STS knockout cells compared to control cells. Our study demonstrated that the excessive generation of ROS caused by STS deficiency induces the expression of Bax and Bak, leading to the release of cytochrome c and subsequent cell death. Consequently, STS deficiency impairs cell mobility and promotes apoptosis, offering insights into the pathophysiological processes and potential therapeutic targets for XLI.

Two novel heterozygous exonic deletions lead to Chanarin-Dorfman syndrome in a patient with congenital ichthyosis, sensorineural hearing loss, and liver dysfunction.

Chanarin-Dorfman syndrome is an autosomal recessively inherited disorder characterized by ichthyosis, sensorineural hearing loss, and hepatic dysfunction. We report on a 60-year-old female of Venezuelan descent who presented with congenital ichthyosis, progressive sensorineural hearing loss, and liver cirrhosis. We identify a heterozygous copy number deletion involving exon 1 and another heterozygous deletion involving exon 3 of the ABHD5 gene. Exon 2 is preserved. Both deletions were confirmed with RT-PCR. RNAseq from peripheral blood shows a reduction of ABHD5 expression overall and an absence of exon 3 expression, confirming the deleterious effects of the identified deletions. We present exonic deletions as a potentially common type of ABHD5 variation.

Ocular phenotype and therapeutic interventions in keratitis-ichthyosis-deafness (KID) syndrome.

BACKGROUND: To report ocular manifestations, clinical course, and therapeutic management of patients with molecular genetically confirmed keratitis-ichthyosis-deafness syndrome. METHODS: Four patients, aged 19 to 46, with keratitis-ichthyosis-deafness syndrome from across the UK were recruited for a general and ocular examination and GJB2 (Cx26) mutational analysis. The ocular examination included best-corrected visual acuity, slit-lamp bio-microscopy, and ocular surface assessment. Mutational analysis of the coding region of GJB2 (Cx26) was performed by bidirectional Sanger sequencing. RESULTS: All four individuals had the characteristic systemic features of keratitis-ichthyosis-deafness syndrome. Each patient was found to have a missense mutation, resulting in the substitution of aspartic acid with asparagine at codon 50 (p.D50N). Main ophthalmic features were vascularizing keratopathy, ocular surface disease, hyperkeratotic lid lesions, recurrent epithelial defects, and corneal stromal scarring. One patient had multiple surgical procedures, including superficial keratectomies and lamellar keratoplasty, which failed to prevent severe visual loss. In contrast, oral therapy with ketoconazole stabilized the corneal and skin disease in two other patients with keratitis-ichthyosis-deafness syndrome. The patient who underwent intracorneal bevacizumab injection showed a marked reduction in corneal vascularization following a single application. CONCLUSIONS: Keratitis-ichthyosis-deafness syndrome is a rare ectodermal dysplasia caused by heterozygous mutations in GJB2 (Cx26) with a severe, progressive vascularizing keratopathy. Oral ketoconazole therapy may offer benefit in stabilizing the corneal and skin disease.

CLDN1 Arg81His founder variant causes ichthyosis, leukocyte vacuoles, alopecia, and sclerosing cholangitis (ILVASC) syndrome in Moroccan Jews.

Neonatal ichthyosis and sclerosing cholangitis syndrome (NISCH), also known as ichthyosis, leukocyte vacuoles, alopecia, and sclerosing cholangitis (ILVASC), is an extremely rare disease of autosomal recessive inheritance, resulting from loss of function of the tight junction protein claudin-1. Its clinical presentation is highly variable, and is characterized by liver and ectodermal involvement. Although most ILVASC cases described to date were attributed to homozygous truncating variants in CLDN1, a single missense variant CLDN1 p.Arg81His, associated with isolated skin ichthyosis phenotype, has been recently reported in a family of Moroccan Jewish descent. We now describe seven patients with ILVASC, originating from four non consanguineous families of North African Jewish ancestry (including one previously reported family), harboring CLDN1 p.Arg81His variant, and broaden the phenotypic spectrum attributed to this variant to include teeth, hair, and liver/bile duct involvement, characteristic of ILVASC. Furthermore, we provide additional evidence for pathogenicity of the CLDN1 p.Arg81His variant by transmission electron microscopy of the affected skin, revealing distorted tight junction architecture, and show through haplotype analysis in the vicinity of the CLDN1 gene, that this variant represents a founder variant in Jews of Moroccan descent with an estimated carrier frequency of 1:220.

Neu Laxova syndrome and megacystis in the first trimester: Broadening the fetal phenotype.

Neu Laxova syndrome (NLS) is a rare and lethal congenital disorder characterized by severe intra-uterine growth retardation (IUGR), ichthyosis, abnormal facial features, limb abnormalities with arthrogryposis and a wide spectrum of severe malformations of the central nervous system (CNS). NLS is due to biallelic variants in three genes previously involved in serine-deficiency disorders (PHGDH, PSAT1 and PSPH), extending the phenotypic spectrum of these disorders.

X-linked genodermatoses from diagnosis to tailored therapy.

Background: Genodermatoses are rare heterogeneous genetic skin diseases with multiorgan involvement. They severely impair an individual's well-being and can also lead to early death. Methods: During the progress of this review, we have implemented a targeted research approach, diligently choosing the most relevant and exemplary articles within the subject matter. Our method entailed a systematic exploration of the scientific literature to ensure a compre-hensive and accurate compilation of the available sources. Results: Among genodermatoses, X-linked ones are of particular importance and should always be considered when pediatric males are affected. Regardless of other syndromic forms without prevalence of skin symptoms, X-linked genodermatoses can be classified in three main groups: keratinization defects, pigmentation defects, and inflammatory skin diseases. Typical examples are dyskeratosis congenita, keratosis follicularis spinulosa decalvans, hypohidrotic ectodermal dysplasia, chondrodysplasia punctata, hypohidrotic ectodermal dysplasia, incontinentia pigmenti, chronic granulomatous disease, CHILD syndrome and ichthyosis. In this field, genetic diagnosis of the specific disease is important, also considering that numerous clinical trials of orphan drugs and genetic therapies are being proposed for these rare genetic diseases. Conclusions: Thus, this chapter starts from clinical to molecular testing and ends with a review of all clinical trials on orphan drugs and gene therapy for genodermatoses.

Case report of self-improving collodion ichthyosis in the newborn.

Self-improving collodion ichthyosis (SICI) is a relatively rare subtype of autosomal recessive congenital ichthyosis (ARCI) that is often characterized by a collodion baby (CB) phenotype at birth. A newborn girl, just 1 hour old, presented with taut, shiny, thick yellow crusts, like parchment, and scales on her trunk and upper limbs. The tightening effect had caused both upper eyelids to appear everted, and her lips and auricles were deformed. Based on whole-exome sequencing and examination of the clinical phenotype, the patient was diagnosed with ARCI. After admission, the exposed mucosa was covered with a sterile Vaseline gauze dressing, and she was placed in an incubator set to a temperature of 32°C with a humidity level of 75%. One week later, the parchment-like scales had begun to flake off, and at the age of 3 weeks, all bodily skin appeared normal. SICI was diagnosed. After discharge, the patient was followed up to 3 months of age, at which time her growth and development were comparable to those of her peers. Clinicians should consider SICI as a possible diagnosis when analyzing the prognosis of patients with CB. Reducing water loss and maintaining the electrolyte balance are particularly important for SICI treatment.

A founder DBR1 variant causes a lethal form of congenital ichthyosis.

DBR1 encodes the only known human lariat debranching enzyme and its deficiency has been found to cause an autosomal recessive inborn error of immunity characterized by pediatric brainstem viral-induced encephalitis (MIM 619441). We describe a distinct allelic disorder caused by a founder recessive DBR1 variant in four families (DBR1(NM_016216.4):c.200A > G (p.Tyr67Cys)). Consistent features include prematurity, severe intrauterine growth deficiency, congenital ichthyosis-like presentation (collodion membrane, severe skin peeling and xerosis), and death before the first year of life. Patient-derived fibroblasts displayed the characteristic accumulation of intron lariats in their RNA as revealed by targeted and untargeted analysis, in addition to a marked reduction of DBR1 on immunoblot analysis. We propose a novel DBR1-related developmental disorder that is distinct from DBR1-related encephalitis susceptibility and highlight the apparent lack of correlation with the degree of DBR1 deficiency.

Partial Loss of Function ABCA12 Mutations Generate Reduced Deposition of Glucosyl-Ceramide, Leading to Patchy Ichthyosis and Erythrodermia Resembling Erythrokeratodermia Variabilis et Progressiva (EKVP).

Ichthyoses are genetically determined cornification disorders of the epidermis characterized by the presence of different degrees of scaling, hyperkeratosis, and erythroderma often associated with palmoplantar keratoderma. Different classifications of these diseases have been proposed, often based upon the involved genes and/or the clinical presentation. The clinical features of these diseases present some overlap of phenotypes among distinct genetic entities, depending mainly on the penetrance of mutations. In this study, using a clinical, genetic, and molecular approach, we analyzed a family with two affected members who had clinical and histological features resembling erythrokeratodermia variabilis (EKV) or a type of erythrodermic hyperkeratosis with palmoplantar keratoderma. Despite of the clinical presentation, we demonstrated that the affected patients were genetically double heterozygous for two different mutations in the ABCA12 gene, known to be responsible for harlequin ichthyosis. To explain the mild phenotype of our patients, we performed a molecular characterization of the skin. In the upper layers of the epidermis, the results showed a patchy presence of the glucosyl-ceramides (GlcCer), which is the lipid transported by ABCA12, fundamental in contributing to skin impermeability. Indeed, the two mutations detected do not completely abolish ABCA12 activity, indicating that the mild phenotype is due to a partial loss of function of the enzyme, thus giving rise to an intermediate phenotype resembling EKVP, due to a partial depletion of GlcCer deposition.

Expanding the allelic spectrum of ELOVL4-related autosomal recessive neuro-ichthyosis.

BACKGROUND: Very long-chain fatty acids (VLCFAs) composed of more than 20 carbon atoms are essential in the biosynthesis of cell membranes in the brain, skin, and retina. VLCFAs are elongated beyond 28 carbon atoms by ELOVL4 enzyme. Variants in ELOVL4 are associated with three Mendelian disorders: autosomal dominant (AD) Stargardt-like macular dystrophy type 3, AD spinocerebellar ataxia, and autosomal recessive disorder congenital ichthyosis, spastic quadriplegia and impaired intellectual development (ISQMR). Only seven subjects from five unrelated families with ISQMR have been described, all of which have biallelic single-nucleotide variants. METHODS: We performed clinical exome sequencing on probands from four unrelated families with neuro-ichthyosis. RESULTS: We identified three novel homozygous ELOVL4 variants. Two of the families originated from the same Saudi tribe and had the exact homozygous exonic deletion in ELOVL4, while the third and fourth probands had two different novel homozygous missense variants. Seven out of the eight affected subjects had profound developmental delay, epilepsy, axial hypotonia, peripheral hypertonia, and ichthyosis. Delayed myelination and corpus callosum hypoplasia were seen in two of five subjects with brain magnetic rosonance imaging and cerebral atrophy in three. CONCLUSION: Our study expands the allelic spectrum of ELOVL4-related ISQMR. The detection of the same exonic deletion in two unrelated Saudi family from same tribe suggests a tribal founder mutation.