Congenital Ichthyosiform Erythroderma Research Articles

Success of Immunopathogenetic Therapy for Management of Congenital Ichthyosis, Combined Form, in a Child: Rare Clinical Case

Background. Congenital ichthyosis (CI) is relating to the group of clinical and genetically heterogeneous severe genodermatoses. SAM syndrome is included in classification of CI syndromic forms. Defects in the desmoplakin (DSP) and desmoglein 1 (DSG1) genes are the prime cause of disease. Impaired function of encoded proteins leads to desmosomal anomalies and disease symptoms. Comorbid atopic syndrome becomes the major cause of diagnostic mistakes. Patients are observed continuously with diagnosis “Atopic dermatitis (AD) torpid to standard treatment methods”. Clinical case description. This article describes a rare case of a boy with severe AD. Despite the chronic dermatosis several systemic disorders were revealed during examination: short stature, protein-energy malnutrition, adrenal insufficiency, juvenile polyarthritis, vitamin D deficiency, onychodystrophy, dysmorphic disorders. Molecular genetic study conducted via high-throughput sequencing followed by validation with Sanger sequencing has revealed two genetic variants: novel variant chr18:28934543G>T in the DSG1 gene in the heterozygous state and pathogenic variant chr5:157468728C>A in the NIPAL4 gene in the homozygous state. As a result, the final diagnosis was established: “SAM syndrome. Congenital ichthyosiform erythroderma”. Flow cytometry immunology study has shown dominant immunological profile of Th17-, and Thact-lymphocyte proliferation. The immunobiological therapy with IL-17A inhibitor, secukinumab, was initiated. Clinical efficacy was evaluated via ISS (Ichthyosis Severity Index), CDLQI (Children’s Dermatology Life Quality Index), pruritus numerical rating scale. ISS was 5.8 points, pruritus scale — 9, CDLQI — 24 at therapy initiation. Improvement in the skin condition was observed after a month of therapy. ISS was 1.2 points, pruritus scale — 2, CDLQI — 4 6 months after the therapy initiation. Conclusion. The diagnosis of a child with combined form of CI made it possible to change the management strategy, to prescribe pathogenetically justified targeted immunobiological therapy, and to achieve significant improvement in the child's health and quality of life, which does not differ from healthy peers.

Biologics in congenital ichthyosis: are they effective?

Congenital ichthyoses (CI) comprise a heterogeneous group of genetic diseases requiring lifelong treatment and having a major effect on quality of life. Conventional treatments reduce scaling and skin discomfort; however, they usually have little or no effect on erythema and pruritus. The identification of cytokine alterations in CI raised the possibility of repurposing available biologics. Several case reports in the literature report successes using different biologics. We aimed to report the effects of biologics in real life. This was a retrospective, observational, international multicenter study of patients with CI treated with at least one biologic for a minimum of 3 months. The effect of the biologics was evaluated using an Investigator Global Assessment-Change (IGA-C) scale. A comprehensive literature search was performed in parallel. A total of 98 patients were included, with a mean age of 19.7 years and both sexes equally represented. Patients with Netherton syndrome (NS) or congenital ichthyosiform erythroderma (CIE) represented the majority of patients (30% and 21.4%, respectively). Most patients (84.7%) had a severe or very severe form of CI. The most frequently used biologics were inhibitors targeting interleukin-17 (IL-17), IL-12/IL-23, or the IL-4 receptor. The mean duration of treatment was 22+20.1 months. There were 45 responders (45.9%), including 18 patients (18.3%) who were good responders; all had an erythrodermic CI subset and received one of the three main biologics. In 2 NS and CIE, IL-12/IL-23 and IL-4 receptor inhibitors tended to be most effective. Review of the literature revealed a shorter mean duration of use of biologics (11.5+8.5 months) and higher percentage of responders (85.7%), suggesting reporter bias. This series identified subsets of CI that may respond to biologics and will aid in designing future clinical trials of biologics for CI.

From Phenotype to Genotype: A Collodion Baby Case Linked to CERS3 Mutation

The term “Collodion baby” is used to describe a newborn appearing with a tight, shiny, and parchment like film covering the entire body. The collodion baby is not a distinct condition but a presentation shared by various disorders. This phenotype may evolve into a range of abnormalities, such as lamellar ichthyosis, Harlequin ichthyosis, non-bullous congenital ichthyosiform erythroderma, and intermediate phenotypes. We report a case of a collodion baby who was found to have a rare mutation in CERS3 gene. Despite the potential for numerous complications arising from impaired skin barrier function, the patient experienced a remarkable recovery following meticulous management and was subsequently discharged home.

Alopecia patterns and trichoscopic findings in patients with autosomal recessive congenital ichthyosis.

Autosomal recessive congenital ichthyosis (ARCI) is a rare genodermatosis categorized among nonsyndromic ichthyoses. While ARCI patients often manifest hair abnormalities, their impact on the quality of life remains underreported in the literature. This study aims to comprehensively characterize the clinical and trichoscopic findings of alopecia in ARCI patients. A prospective study spanning from January 2019 to December 2021 (3 years) was conducted at the Dermatology Department of Habib Thameur Hospital, Tunis, Tunisia. Clinical and trichoscopic examinations were performed on the hair of the participants, with molecular studies conducted on 15 patients. The study included 30 patients, predominantly female (male/female = 0.58), with a mean age of 20 years. Twenty-eight patients were born from consanguineous marriages. Lamellar ichthyosis was observed in 22 cases, while congenital ichthyosiform erythroderma and bathing suit ichthyosis were each present in 4 cases. The ARCI severity score, assessed using the Visual Index For Ichthyosis Severity scale, had a mean value of 15 (4-28). Alopecia emerged as a prominent finding in 11 patients, presenting as hairline recession (13%), multiple patchy alopecia (27%), and alopecia of the eyebrows (13%). Trichoscopic findings included interfollicular and perifollicular scaling, perifollicular lamellar hyperkeratosis, peripilar casts, interfollicular erythema, loss of hair openings, predominance of single hair follicles, broken hair, vellus hair, anisotrichosis, pili torti, dystrophic hair, and comma hair. Several trichoscopic findings showed statistically significant associations with the severity of ARCI. In our study, we only included 30 patients due to the rarity of this genodermatosis. Contrary to previous perceptions, alopecia is a notable finding in ARCI, particularly in patients with a severe form. This study provides a detailed characterization of alopecia in ARCI, shedding light on its prevalence and associated trichoscopic features, thereby enhancing our understanding of this dermatological condition.

Compound heterozygous ABCA12 variants identified in a Chinese patient with congenital ichthyosiform erythroderma: Advancing genotype-phenotype correlations and literature review.

Ichthyosis is a common keratotic skin disease with high clinical, etiological and genetic heterogeneity. There are four types of non-syndromic hereditary ichthyoses, among which autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of recessive Mendelian disorders. ARCI present with different phenotypes and ABCA12 pathogenic variants have been shown to cause complex ARCI phenotypes, including harlequin ichthyosis (HI), lamellar ichthyosis (LI) and congenital ichthyosiform erythroderma (CIE). A sporadic male patient, clinically diagnosed with CIE, was enrolled in this study. Exome sequencing was combined with Sanger sequencing to confirm the diagnosis and identify the pathogenic variants. In silico predictions were made using multiple software programs, and the identified variants were interpreted using the ACMG guidelines. A review of all literature reported ABCA12 variants was performed to explore genotype-phenotype correlations. Compound heterozygous ABCA12 variants [c.5381+1G>A and c.5485G>C (p.Asp1829His)] (NM_173076) were identified. The two variants were not detected in the public database. c.5381+1G>A is predicted to affect ABCA12 mRNA splicing and Asp1829 is highly conserved among various species. In silico analysis suggested that these two variants were responsible for the phenotype of the patient. Genotype-phenotype correlation analysis showed that biallelic truncation variants and/or exon/amino acid deletions in ABCA12 are the most common causes of HI. Biallelic missense variants are most common in LI and CIE. The compound heterozygous ABCA12 variants caused the CIE phenotype observed in the patient. The spectrum of ABCA12 pathogenic variants were broaden. Genotype-phenotype correlation analysis provided detailed evidence which can be used in future prenatal diagnosis and can inform the need for genetic counselling for patients with ABCA12-related ARCIs.

Cross-Sectional Study on Autosomal Recessive Congenital Ichthyoses: Association of Genotype with Disease Severity, Phenotypic, and Ultrastructural Features in 74 Italian Patients

Background: Autosomal recessive congenital ichthyoses (ARCIs) are a clinically heterogeneous group of keratinization disorders characterized by generalized skin scaling due to mutations in at least 12 genes. The aim of our study was to assess disease severity, phenotypic, and ultrastructural features and to evaluate their association with genetic findings in ARCI patients. Methods: Clinical signs and symptoms, and disease severity were scored in a single-center series of patients with a genetic diagnosis of ARCI. Skin ultrastructural findings were reviewed. Results: Seventy-four consecutive patients (mean age 11.0 years, range 0.1–48.8) affected with lamellar ichthyosis (50/74, 67.5%), congenital ichthyosiform erythroderma (18/74, 24.3%), harlequin ichthyosis (two/74, 2.7%), and other minor ARCI subtypes (four/74, 5.4%) were enrolled. Mutated genes were as follows: TGM1 in 18/74 (24.3%) patients, ALOX12B in 18/74 (24.3%), CYP4F22 in 12/74 (16.2%), ABCA12 in nine/74 (12.2%), ALOXE3 in seven/74 (9.5%), NIPAL4 in seven/74 (9.5%), and CERS3, PNPLA1, and SDR9C7 in 1 patient each (1.4%). Twenty-five previously undescribed mutations in the different ARCI causative genes, as well as two microduplications in TGM1, and two microdeletions in CYP4F22 and NIPAL4 were identified. The mean ichthyosis severity score in TGM1- and ABCA12-mutated patients was significantly higher than in all other mutated genes, while the lowest score was observed in CYP4F22-mutated patients. Alopecia, ectropion, and eclabium were significantly associated with TGM1 and ABCA12 mutations, and large, thick, and brownish scales with TGM1 mutations. Among specific phenotypic features, psoriasis-like lesions as well as a trunk reticulate scale pattern and striated keratoderma were present in NIPAL4-mutated patients. Ultrastructural data available for 56 patients showed a 100% specificity of cholesterol clefts for TGM1-mutated cases and revealed abnormal lamellar bodies in SDR9C7 and CERS3 patients. Conclusion: Our study expands the phenotypic and genetic characterization of ARCI by the description of statistically significant associations between disease severity, specific clinical signs, and different mutated genes. Finally, we highlighted the presence of psoriasis-like lesions in NIPAL4-ARCI patients as a novel phenotypic feature with diagnostic and possible therapeutic implications.

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).

Genetic inheritance in tandem: Non-syndromic autosomal recessive congenital ichthyosis with beta-thalassaemia: A rare coincidence

Ichthyosis belongs to the group of Mendelian disorders of cornification. Congenital ichthyosis is inherited as an autosomal recessive trait, so it is also known as autosomal recessive congenital ichthyosis (ARCI). ARCI is classified into two types: syndromic and non-syndromic ARCI. Non-syndromic ARCIs include lamellar ichthyosis, congenital ichthyosiform erythroderma and Harlequin ichthyosis. Syndromic-ARCI is associated with multisystemic involvement, which includes Netherton syndrome, Chanarin-Dorfman disease and others. Other systemic diseases associated with ichthyosis include Gaucher disease type II and hypothyroidism. Chanarin-Dorfman and Gaucher disease-II are additionally associated with hepatosplenomegaly (HSM) and anaemia. We describe a child of congenital ichthyosis with HSM and anaemia thought to be syndromic-ARCI, but diagnosed for beta-thalassaemia (b-thal) concurrently. An infant presented with peeling skin along with absent sweating since birth and recent onset paleness of the body. Examination revealed Ichthyosis (Lamellar-variant), severe pallor and HSM, raising the possibility of Chanarin-Dorfman syndrome and Gaucher’s disease. The investigation revealed an Erlenmeyer flask deformity of the knee, but no Gaucher’s cells were found in the bone marrow. In the absence of lipid vacuoles leaden leukocytes (Jordan’s anomaly), Chanarin-Dorfman disease was also ruled out. Haemoglobin (Hb) high-performance liquid chromatography revealed β-thal major, and both parents were traits, giving us the diagnosis, which was further confirmed by the next-generation gene sequencing for clinical exomes. This report was to highlight non-syndromic ARCI involving the CYP4F22 gene variant, which is a rare finding, and the association of such ichthyosis with β-thal major was an unexpected result. Genetic counselling was provided to the parents in light of the autosomal recessive nature of both diseases. Genes of congenital ichthyosis and β-thal were unrelated, but simultaneous expressions of two autosomal-recessive diseases together are it merely by chance or a new entity.

Photogallery. Genodermatoses. Part II

Genodermatoses are a group of hereditary diseases primarily affecting the skin. To date, there are more than two hundred genetically determined dermatoses representing about 35% of all genetic diseases and 10% of all skin diseases. Genodermatoses can be caused by mutations in a single gene or the interaction of several genes and environmental factors. Hereditary diseases are characterized by a wide variety of phenotypic manifestations and the diagnostic complexity which represents a serious problem in modern dermatology.
 We present a gallery of hereditary dermatoses.
 Unna-Tost disease is a genodermatosis inherited in an autosomal dominant manner and characterized by diffuse excessive keratinization of the skin on the palms and soles, manifesting in the first to second year of life.
 Buschke-Fischer-Brauer punctate palmoplantar keratoderma is a late-developing focal dermatosis in which painful hyperkeratotic papules can occur when traumatized.
 Ehlers-Danlos syndrome is a condition demonstrating skin hyperextensibility and a number of typical symptoms of the skeletal and cardiovascular systems.
 Progeria manifests as premature skin aging, affecting the endocrine, skeletal, cardiovascular, and other systems of the body, as well as increasing the risk of developing malignant neoplasms of internal organs and skin.
 Congenital ichthyosiform erythroderma of Brocq is a severe chronic skin disease with autosomal recessive inheritance, which follows the pattern of lamellar ichthyosis but to a milder degree.
 X-linked ichthyosis, a hereditary "darkening" condition, occurs only in males and is characterized by impaired keratinization and the presence of gray-black scales on the skin.
 Lamellar ichthyosis is an autosomal recessive dermatosis characterized by generalized skin involvement.
 Netherton syndrome is a rare condition characterized by a combination of ichthyosis with structural anomalies of the hair shaft and atopy.

Case report: Interleukin-17 targeted biological therapy in netherton syndrome

Netherton syndrome (NS) is rare and multisystemic congenital skin disorder classically distinguied as a triad of congenital ichthyosiform erythroderma, trichorrhexis invaginata (TI), and an atopic diathesis. Recent advances in pathogenesis have explored the role of IL-23/Th17 pathway in NS. Herein, we present a 17 years old girl harbouring homozygous four base pair deletion in exon 26 of the SPINK5 gene, presented with pruritus, scaling, dry skin and generalized eczematous lesions. She was administered anti IL17A (subcutaneous secukinumab) therapy. The treatment was well tolerated and resulted in a favourable clinical response, reduction of the IL17A gene expression and CD4 + Th17 cell population after 6 months which revealed an abrogation of Th17-skewing during therapy.

Congenital ichthyosis presentation and outcome - A case series.

The ichthyosis, also called disorders of keratinization or cornification, are heterogeneous group of disorders characterized by a generalized scaling of the skin of varying severity. The majority of ichthyosis is inherited but acquired forms can develop in the setting of malignancy, autoimmune or infectious disease, and nutritional deficiency. Autosomal recessive congenital ichthyosis, which include lamellar ichthyosis, congenital ichthyosiform erythroderma, and harlequin ichthyosis, are rare; their overall incidence has been estimated at approximately 1 in 300,000 births. In this article, we described four cases of congenital ichthyosis, their potential complications, causes of morbidity and mortality, and discussed the management and importance of genetic testing for diagnosis as definitive diagnosis is important for long-term management and counseling of the parents.

Patients with keratinization disorders due to ABCA12 variants showing pityriasis rubra pilaris phenotypes.

Pathogenic variants in ABCA12 are important causative genetic defects for autosomal recessive congenital ichthyoses (ARCI), which include congenital ichthyosiform erythroderma (CIE), harlequin ichthyosis, and lamellar ichthyosis. In addition, pathogenic variants in ABCA12 are known to cause a localized nevoid form of CIE due to recessive mosaicism. We previously reported siblings who carried an ABCA12 variant but did not show a "congenital" phenotype. They were considered to have pityriasis rubra pilaris (PRP). Here, we present a further patient with ABCA12 variants whose phenotype was not congenital ichthyosis, in an independent family. Notably, these three patients had geographic unaffected areas. Such areas are not usually found in patients with ARCI who have ABCA12 variants, suggesting mild phenotypes for these patients. Interestingly, the histological features of the ichthyotic lesions in these patients resembled those of PRP. All three patients had homozygous pathogenic missense variants in ABCA12. Our findings expand the phenotypic spectrum of patients with ABCA12 variants.

Mutational Spectrum of the ABCA12 Gene and Genotype–Phenotype Correlation in a Cohort of 64 Patients with Autosomal Recessive Congenital Ichthyosis

Autosomal recessive congenital ichthyosis (ARCI) is a non-syndromic congenital disorder of cornification characterized by abnormal scaling of the skin. The three major phenotypes are lamellar ichthyosis, congenital ichthyosiform erythroderma, and harlequin ichthyosis. ARCI is caused by biallelic mutations in ABCA12, ALOX12B, ALOXE3, CERS3, CYP4F22, NIPAL4, PNPLA1, SDR9C7, SULT2B1, and TGM1. The most severe form of ARCI, harlequin ichthyosis, is caused by mutations in ABCA12. Mutations in this gene can also lead to congenital ichthyosiform erythroderma or lamellar ichthyosis. We present a large cohort of 64 patients affected with ARCI carrying biallelic mutations in ABCA12. Our study comprises 34 novel mutations in ABCA12, expanding the mutational spectrum of ABCA12-associated ARCI up to 217 mutations. Within these we found the possible mutational hotspots c.4541G>A, p.(Arg1514His) and c.4139A>G, p.(Asn1380Ser). A correlation of the phenotype with the effect of the genetic mutation on protein function is demonstrated. Loss-of-function mutations on both alleles generally result in harlequin ichthyosis, whereas biallelic missense mutations mainly lead to CIE or LI.

Ихтиоздың сирек кездесетін клиникалық түрі - бір жақтық ихтиозформалы эритродермия: Клиникалық жағдай

Congenital ichthyosis is one of the hereditary dermatoses that develop due to a violation of the keratinization process. The clinical manifestation of ichthyosis is characterized by dryness of the skin during physical examination and scaling of different degrees of clarity. Congenital ichthyosis can be classified as one of the most difficult and urgent problems in the field of dermatology and pediatrics due to the fact that the pathogenesis of this pathology is not fully studied, its persistent course, and the difficulty of achieving positive treatment results.In addition, despite many common features, types of ichthyosis are distinguished based on clinical and histological appearance: simple ichthyosis, recessive X-doubled ichthyosis, classic lamellar ichthyosis, bullous and non-bullous congenital ichthyosiform erythroderma. In all these types of ichthyosis, there is a violation of cellular kinetics and their physiological exfoliation process, resulting in excessive keratinization of the skin in the primary manifestation. During ichthyosis, there is a violation of the barrier function of the skin, loss of water between the epidermis and inability of the skin to retain moisture. In this article, we have shared a patient with these symptoms who was diagnosed with unilateral ichthyosiform erythroderma, one of the rare forms of ichthyosis encountered in our practice. This article is informative for general practitioners, neonatologists, pediatricians, dermatovenerologists and geneticists.

Síndrome de Netherton: relato de caso

INTRODUCTION: Netherton Syndrome (NS), one of the most serious disorders of cornification, is an autosomal recessive disease characterized by a mutation in the SPINK5 gene on chromosome 5q32. Its incidence is estimated at 1: 100,000 to 1: 200.00 live births, with a variable phenotype among patients. The clinical picture is based on the congenital ichthyosiform erythroderma triad, invaginated trichorexis and atopic manifestations. Objectives: The purpose of this paper is to report the case of a patient with classic NS changes. METHODS: The paper in question deals with a case report of a preschooler who presented, already in the neonatal period, clinical manifestations and complications resulting from the disease, associated with mutations of the SPINK5 gene. RESULTS AND DISCUSSIONS: The case report highlights the various clinical manifestations that affected patients may present, demonstrating the criteria necessary to close the diagnosis for NS. CONCLUSIONS: NS is a rare disease. it has a highly variable phenotype among patients and has a potential risk for complications. Due to the variability of clinical presentations, the diagnosis can be difficult and take years to establish. This demonstrates the importance of early recognition of the clinical condition associated with greater access to specific diagnostic tests, which would enable an institution of early treatment adapted to the needs of patients.

213 Genetic study of the largest Tunisian cohort of 15 patients with Netherton syndrome: Two new SPINK5 mutations and founder effect

Several pathogenic mutations have been identified in the SPINK5 gene encoding kazal-type serine protease inhibitors (LEKTI) involved in the regulation of skin barrier formation resulting in Netherton syndrome NS. Our work aims to study the clinical, histological and genetic characteristics of Tunisian patients with NS. We investigated 15 patients with NS from 12 unrelated Tunisian families, referred to our department for genetic confirmation of their diagnosis. Clinical examination at birth showed non-bullous congenital ichthyosiform erythroderma (EIC) in 14 patients, bullous in only one.

Ceramide Analysis in Combination With Genetic Testing May Provide a Precise Diagnosis for Self-Healing Collodion Babies

Self-healing collodion baby (SHCB), also called “self-improving collodion baby”, is a rare mild variant of autosomal recessive congenital ichthyosis and is defined as a collodion baby who shows the nearly complete resolution of scaling within the first 3 months to 1 year of life. However, during the neonatal period, it is not easy to distinguish SHCB from other inflammatory forms of autosomal recessive congenital ichthyosis, such as congenital ichthyosiform erythroderma. Here, we report a case study of two Japanese SHCB patients with compound heterozygous mutations, c.235G>T (p.(Glu79∗))/ c.1189C>T (p.(Arg397Cys)) and c.1295A>G (p.(Tyr432Cys))/ c.1138delG (p.(Asp380Thrfs∗3)), in CYP4F22, which encodes cytochrome P450, family 4, subfamily F, polypeptide 22 (CYP4F22). Immunohistochemically, inflammation with the strong expression of IL-17C, IL-36γ, and TNF-α was seen in the skin at birth. CYP4F22 is an ultra-long-chain FA ω-hydroxylase responsible for ω-O-acylceramide (acylceramide) production. Among the epidermal ceramides, acylceramide is a key lipid in maintaining the epidermal permeability barrier function. We found that the levels of ceramides with ω-hydroxy FAs including acylceramides and the levels of protein-bound ceramides were much lower in stratum corneum samples obtained by tape stripping from SHCB patients than in those from their unaffected parents and individuals without SHCB. Additionally, our cell-based enzyme assay revealed that two mutants, p.(Glu79∗) and p.(Arg397Cys), had no enzyme activity. Our findings suggest that genetic testing coupled with noninvasive ceramide analyses using tape-stripped stratum corneum samples might be useful for the early and precise diagnosis of congenital ichthyoses, including SHCB.

Clinical and molecular characteristics of autosomal recessive congenital ichthyosis in Thailand.

Autosomal recessive congenital ichthyosis (ARCI) is a heterogenous group of rare keratinization disorders. To date, more than 13 causative genes have been identified. However, data on clinical and molecular characteristics including genotype-phenotype correlation are lacking in Thailand. We collected cases diagnosed with non-syndromic ARCI and syndromic recessive congenital ichthyosis at the Institute of Dermatology from 2011 to 2021 and performed genetic testing with next-generation sequencing and assessed clinical details. Baseline demographic data, birth history, family history, skin manifestations at birth, current cutaneous manifestations, comorbidities, and response to treatments were assessed. DNA was screened for mutations using targeted gene sequencing of 45 genes related to congenital ichthyosis. A total of 33 patients were analyzed with an average age of 23.8± 13.9 years. Congenital ichthyosiform erythroderma (CIE) was most common (60.6%), followed by lamellar ichthyosis (18.2%), self-improving congenital ichthyosis (6.1%), Netherton syndrome (6.1%), ichthyosis prematurity syndrome (3%), Sjögren-Larsson syndrome (3%) and bathing suit ichthyosis (3%). Eight genes were found with pathogenic variants in our cohort as follows: ABCA12 42.4% (14/33), NIPAL4 24.2% (8/33), TGM1 15.2% (5/33), SPINK5 6.1% (2/33), ALDH3A2 3% (1/33), SLC27A4 3% (1/33), CYP4F22 3% (1/33), and ST14 3% (1/33). Clinically, 79% of patients with ABCA12 pathogenic variants in this study had CIE, 79% of w had novel biallelic pathogenic compound heterozygous variants, whereas 21% had homozygous missense variants. This is the first study to describe clinical and molecular findings of ARCI in a cohort from Thailand. Our findings demonstrate the clinical spectrum of the diseases and expand the molecular findings in a Southeast Asian population.

Distinct skin microbiome community structures in congenital ichthyosis.

The ichthyoses are rare genetic keratinizing disorders that share the characteristics of an impaired epidermal barrier and increased risk of microbial infections. Although ichthyotic diseases share a T helper (Th) 17 cell immune signature, including increased expression of antimicrobial peptides, the skin microbiota of ichthyoses is virtually unexplored. To analyse the metagenome profile of skin microbiome for major congenital ichthyosis subtypes. Body site-matched skin surface samples were collected from the scalp, upper arm and upper buttocks of 16 healthy control participants and 22 adult patients with congenital forms of ichthyosis for whole metagenomics sequencing analysis. Taxonomic profiling showed significant shifts in bacteria and fungi abundance and sporadic viral increases across ichthyosis subtypes. Cutibacterium acnes and Malassezia were significantly reduced across body sites, consistent with skin barrier disruption and depletion of lipids. Microbial richness was reduced, with specific increases in Staphylococcus and Corynebacterium genera, as well as shifts in fungal species, including Malassezia. Malassezia globosa was reduced at all body sites, whereas M. sympodialis was reduced in the ichthyotic upper arm and upper buttocks. Malassezia slooffiae, by contrast, was strikingly increased at all body sites in participants with congenital ichthyosiform erythroderma (CIE) and lamellar ichthyosis (LI). A previously undescribed Trichophyton species was also detected as sporadically colonizing the skin of patients with CIE, LI and epidermolytic ichthyosis subtypes. The ichthyosis skin microbiome is significantly altered from healthy skin with specific changes predominating among ichthyosis subtypes. Skewing towards the Th17 pathway may represent a response to the altered microbial colonization in ichthyosis. What is already known about this topic? The skin microbiome of congenital ichthyoses is largely unexplored. Microbes play an important role in pathogenesis, as infections are common. The relative abundances of staphylococci and corynebacteria is increased in the cutaneous microbiome of patients with Netherton syndrome, but extension of these abundances to all congenital ichthyoses is unexplored. What does this study add? A common skin microbiome signature was observed across congenital ichthyoses. Distinct microbiome features were associated with ichthyosis subtypes. Changes in microbiome may contribute to T helper 17 cell immune polarization. What is the translational message? These data provide the basis for comparison of the microbiome with lipidomic and transcriptomic alterations in these forms of ichthyosis and consideration of correcting the dysbiosis as a therapeutic intervention.

397 Characterization of ABCA12 gene variant by electron microscopy in an infant with an ichthyosiform dermatitis and MALT1 deficiency

The ABCA12 gene encodes an ATP-binding cassette transporter vital to skin barrier function. In keratinocytes, ABCA12 transports ceramides into the lumen of lamellar bodies as part of the widely conserved water barrier system. Alterations in the ABCA12 gene are associated with the autosomal recessive congenital ichthyoses: harlequin ichthyosis, non-bullous congenital ichthyosiform erythroderma, and lamellar ichthyosis. We report a 4-month-old female who presented with erythroderma, diffuse fine scale, and recurrent infections.