RARE DISEASE
Autosomal recessive congenital ichthyosis
Autosomal recessive congenital ichthyosis
Autosomal recessive congenital ichthyosis
Synonyms: ARCI
Synonyms: ARCI
Synonyms: ARCI
Drug discovery
17
drugs
With orphan designations
Overview
Autosomal recessive congenital ichthyosis (ARCI) encompasses rare genetic skin disorders characterized by defective keratinization, presenting at birth with collodion membrane, generalized scaling, erythema, and varying complications like ectropion or hypohidrosis. Caused by mutations in TGM1, ALOXE3/12B, NIPAL4, CYP4F22, or ABCA12, it includes subtypes such as lamellar ichthyosis, congenital ichthyosiform erythroderma, and harlequin ichthyosis. Management focuses on symptomatic relief, with variable severity and lifelong impact [1][2][6][14].
Burden
Quality of life: Mean DLQI score 7.8; 22% report major impairment (>10 score). Key issues: pruritus, pain, social stigma, and treatment time [4][9].
Systemic: Hypohidrosis (58–100%), recurrent infections (19%), and vitamin D deficiency [9][17][18].
Economic: High care costs due to daily skincare, frequent consultations, and lost productivity [4][9][14].
Therapies
Topical: Emollients, keratolytics (urea, lactic acid), and N-acetylcysteine [5][6][16].
Systemic: Oral retinoids (acitretin, isotretinoin) for severe cases, dosed at 0.25–1 mg/kg/day depending on subtype [5][8][13].
Emerging therapies: Gene therapy (experimental TGM1 delivery), biologics (anti-IL-17 agents), and topical isotretinoin formulations (TMB-001) [3][11][16].
Categories: rare developmental anomalies during embryogenesis, rare genetic diseases, rare ophthalmic disorders, rare skin diseases
Research Papers
178 drug discovery papers about Autosomal recessive congenital ichthyosis, with 2 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
178 drug discovery papers about Autosomal recessive congenital ichthyosis, with 2 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
antibodies
2026-06-15 | Secukinumab for lamellar ichthyosis in an adolescent: a case report.
Lamellar ichthyosis (LI) is a rare hereditary disorder of keratinization, most commonly inherited in an autosomal recessive manner and frequently associated with pathogenic variants in the TGM1 gene. Patients usually present with generalized scaling, xerosis, and pruritus from birth. Current therapeutic options remain limited, and systemic retinoids are often associated with considerable adverse effects. A 14-year-old female individual presented with generalized pruritic, lamellar scale-like skin changes present since birth. The diagnosis of LI was established based on clinical findings, histopathological evaluation, and genetic testing [two pathogenic variants in the TGM1 gene, consistent with autosomal recessive congenital ichthyosis type 1, Online Mendelian Inheritance in Man (OMIM): 242300]. Oral administration of acitretin (10 mg twice daily) was initiated; however, treatment was discontinued due to elevated hepatic transaminase levels and severe xerosis with pruritus. Subcutaneous administration of secukinumab (150 mg weekly) was subsequently initiated. After five weekly doses, the dosing frequency was reduced to once monthly. Over 8 weeks, substantial clinical improvement was observed, with a satisfactory therapeutic response. The patient remained on active treatment at the time of reporting. Secukinumab appeared to be effective in this patient with LI and may warrant further investigation as a potential therapeutic option for inherited ichthyosis.
2026-04-11 | Mutation Analysis in Ten Cases With PNPLA1-Nonsyndromic Epidermal Differentiation Disorder: Evidence of a Founder Effect.
Autosomal recessive congenital ichthyosis (ARCI) belongs to a heterogeneous group of nonsyndromic epidermal differentiation disorders (nEDD). Variants in PNPLA1, which encodes a transacylase essential for the formation of epidermal lipid barrier, underlie ARCI10. This study aims to unveil the underlying genetic basis in ten Chinese cases diagnosed with ARCI, and to determine the origin of a prevalent variant. Ten cases, encompassing twelve patients with ARCI, were recruited for this study. Whole-exome sequencing combined with Sanger sequencing was used to detect the underlying variants. Haplotype analysis using flanking highly polymorphic SNPs was used to trace the origin of the c.1300delG variant in the PNPLA1 gene. All patients developed generalized fine scales and erythema shortly after birth. Marked phenotypic heterogeneity was observed among the affected individuals, leading to diagnosis of either generalized or localized nEDD. In total, we detected three recurrent variants (c.1300delG, p.A434Hfs*22; c.434 T > C, p.Ile145Thr; c.488C > T, p.Pro163Leu) and five novel variants (c.205 + 1G > A, splicing; c.74C > T, p.Ser25Phe; c.473G > A, p.Cys158Tyr; c.731A > G, p.Tyr244Cys; c.1318C > T, p.Arg440*) in PNPLA1. The c.1300delG variant, prevalent in 7 unrelated ARCI cases, was associated with a common haplotype. Furthermore, we presented the beneficial effect of secukinumab treatment in one of our patients. Our findings suggest that the c.1300delG variant is a highly prevalent variant in Chinese PNPLA1-associated nEDD patients, and indicate that the recurrent variant may originate from a common ancestor in southern China, suggesting a regional founder effect. The observed response with secukinumab in one patient suggests that it might represent a potential therapeutic option for PNPLA1-nEDD patients.
2025-12-05 | Beyond the skin: immunological profiles and infectious complications in ALOX12B-associated autosomal recessive congenital ichthyosis.
Pathogenic variants in ALOX12B, a crucial enzyme involved in epidermal lipid processing, are among the most common causes of autosomal recessive congenital ichthyosis (ARCI). Although traditionally considered a cutaneous disorder, the systemic immunological implications of ALOX12B deficiency remain poorly understood. We aimed to broaden the dermatologic and immunologic spectrum of ALOX12B-associated ARCI by characterizing the clinical, immunologic, and genetic features of six patients from three consanguineous families. This prospective study included six patients with ALOX12B-associated ARCI identified through whole-exome sequencing. Detailed dermatological evaluations, infection histories, immunoglobulin profiles, lymphocyte subset analyses, and vaccine response assessments were performed. All patients exhibited early-onset generalized ichthyosis, ranging from delayed-onset lamellar ichthyosis to collodion membrane presentations accompanied by nonbullous erythroderma. Two distinct biallelic ALOX12B variants were identified: a novel p.Thr383Lys and the known p.Cys544Arg. Several patients demonstrated recurrent bacterial or fungal infections (n = 5), markedly elevated serum IgE levels (n = 4), and isolated abnormalities in vaccine responsiveness (n = 2). Lymphocyte counts and other immunoglobulin classes were generally preserved; however, decreased IgG levels were observed in one patient (P3.1). Intravenous immunoglobulin replacement therapy reduced the frequency of infections in patients (P1.1 and P1.2). Our findings suggest that ALOX12B-related ARCI may involve secondary immune dysregulation, driven by chronic compromise of the epidermal barrier. An immunologic evaluation is warranted in selected cases, particularly those with a history of susceptibility to infections. Multidisciplinary care, encompassing dermatology, immunology, and genetics, is crucial for achieving optimal outcomes in ARCI.
2025-11-19 | Data Sheet 1_Beyond the skin: immunological profiles and infectious complications in ALOX12B-associated autosomal recessive congenital ichthyosis.docx
Background Pathogenic variants in ALOX12B, a crucial enzyme involved in epidermal lipid processing, are among the most common causes of autosomal recessive congenital ichthyosis (ARCI). Although traditionally considered a cutaneous disorder, the systemic immunological implications of ALOX12B deficiency remain poorly understood. Objectives We aimed to broaden the dermatologic and immunologic spectrum of ALOX12B-associated ARCI by characterizing the clinical, immunologic, and genetic features of six patients from three consanguineous families. Methods This prospective study included six patients with ALOX12B-associated ARCI identified through whole-exome sequencing. Detailed dermatological evaluations, infection histories, immunoglobulin profiles, lymphocyte subset analyses, and vaccine response assessments were performed. Results All patients exhibited early-onset generalized ichthyosis, ranging from delayed-onset lamellar ichthyosis to collodion membrane presentations accompanied by nonbullous erythroderma. Two distinct biallelic ALOX12B variants were identified: a novel p.Thr383Lys and the known p.Cys544Arg. Several patients demonstrated recurrent bacterial or fungal infections (n = 5), markedly elevated serum IgE levels (n = 4), and isolated abnormalities in vaccine responsiveness (n = 2). Lymphocyte counts and other immunoglobulin classes were generally preserved; however, decreased IgG levels were observed in one patient (P3.1). Intravenous immunoglobulin replacement therapy reduced the frequency of infections in patients (P1.1 and P1.2). Conclusions Our findings suggest that ALOX12B-related ARCI may involve secondary immune dysregulation, driven by chronic compromise of the epidermal barrier. An immunologic evaluation is warranted in selected cases, particularly those with a history of susceptibility to infections. Multidisciplinary care, encompassing dermatology, immunology, and genetics, is crucial for achieving optimal outcomes in ARCI.
2025-10-13 | Clinical and immunological characterization of a Netherton syndrome infant with a large SPINK gene cluster deletion and a c.1258A>G polymorphism in SPINK5.
Netherton syndrome (NS) is a rare autosomal recessive disorder caused by mutations in the SPINK5 gene, which encodes the serine protease inhibitor LEKTI. It is characterized by congenital ichthyosis, hair shaft abnormalities, and atopic manifestations. Previous reports suggest that intravenous immunoglobulin (IVIG) may provide partial clinical benefit in NS. Here, we report the clinical and immunological characterization of an infant with NS effectively treated with IVIG therapy. Clinical information was collected and reviewed from a 1-year-6-month-old boy presenting with NS. Hair shaft abnormalities were examined by scanning electron microscopy. Pathogenic variants in SPINK5 were identified using whole-exome and Sanger sequencing. Protein expression was assessed by Western blotting and ELISA. Peripheral lymphocyte subsets were analyzed by flow cytometry, and cytokine levels were evaluated with the Olink® Target 48 Cytokine panel. The patient presented with typical clinical manifestations of NS. Genetic analysis identified a novel heterozygous deletion spanning the SPINK5 gene (chr5:147,443,561-147,719,327), together with the c.1258A>G (p.K420E) polymorphism. LEKTI expression was markedly decreased, consistent with the genetic findings. Immune profiling revealed markedly reduced unswitched memory and marginal zone-like B cells, increased naïve B cells, and elevated γδ T cells compared with healthy controls. Cytokine analysis showed significantly increased levels of multiple pro-inflammatory cytokines, including TGFA, IL17 family members, CXCL8, CCL2, TNF, CCL19, and IL18. Following IVIG therapy, the patient demonstrated significant clinical improvement, with recovery of skin manifestations, and partial normalization of lymphocyte subsets and cytokine levels, indicating restoration of immune regulation. This study reports a novel compound heterozygous SPINK5 mutation in an infant with NS, comprising a large deletion and c.1258A>G polymorphism, resulting in LEKTI deficiency and immune dysregulation. IVIG therapy effectively alleviated clinical symptoms and restored immune balance, highlighting its potential as a therapeutic option for NS and related immunodeficiency disorders.
small molecules
2026-06-09 | Role of hydrogel-based systems in the management of lamellar ichthyosis: A comprehensive review
A rare autosomal recessive congenital skin condition called lamellar ichthyosis is typified by aberrant keratinization and compromised epidermal barrier function. Mutations in genes including TGM1, ABCA12, ALOX12B, ALOXE3, and NIPAL4, which are essential for protein cross-linking and lipid metabolism in the stratum corneum, are the main cause of the disorder. Clinically, affected people frequently have a collodion membrane at birth that eventually sheds, exposing the body's massive, black, plate-like scales. Ectropion, eclabium, hypohidrosis, and heightened vulnerability to infections as a result of weakened skin integrity are other characteristics. According to epidemiology, lamellar ichthyosis is an uncommon condition that affects both sexes equally and has a global prevalence of between 1 in 100,000 and 300,000 people. Genetic testing may be used to assist the diagnosis, which is mostly clinical. In extreme cases, emollients, humectants, keratolytic agents, and systemic retinoids are used to relieve symptoms. The potential use of hydrogels as a successful therapeutic strategy for treating this illness has been brought to light by recent developments. Because of their high water content and biocompatibility, hydrogels improve medication penetration into the stratum corneum, decrease scaling, and offer constant hydration. Treatment results are further enhanced by their capacity to provide sustained and regulated drug release. All things considered, lamellar ichthyosis necessitates lifelong care, and new treatments like hydrogel-based formulations offer encouraging opportunities to enhance patient care and quality of life.
2026-01-20 | Harlequin ichthyosis: diagnosis, standards of care, and treatment — a systematic review
Background. Harlequin ichthyosis (HI) is the most severe form of autosomal recessive congenital ichthyosis (ARCI), caused by mutations in the ABCA12 gene. Impaired lipid transport in keratinocytes leads to profound dysfunction of the epidermal barrier and, consequently, to the severe clinical phenotype already evident at birth. Despite the rarity of this condition, HI remains one of the most dramatic dermatological disorders of the neonatal period. The aim of this study is to present the current state of knowledge on the etiology, clinical presentation, diagnosis and treatment methods of HI. This paper seeks to compile the available data in one place and to discuss the diagnostic and therapeutic challenges. Methods. A systematic analysis of the available scientific literature was carried out, including clinical studies, case reports, review articles, and reports on modern diagnostic and therapeutic techniques. Results. The development of methods enabling genetic diagnosis has allowed for early and precise detection of ABCA12 gene mutations, which has improved the possibilities for prenatal diagnosis and perinatal care planning. Multidisciplinary care and early use of retinoids have reduced mortality in newborns with HI. Nevertheless, the disease remains associated with a high risk of systemic complications and long-term sequelae. Conclusions. Harlequin ichthyosis remains a severe disease that requires rapid diagnosis, interdisciplinary management and continuous monitoring. Technological and therapeutic advances have improved the prognosis; however, further studies are needed to optimize retinoid therapy, management protocols and strategies supporting skin barrier regeneration in patients affected by HI.
2026-01-01 | O09 Janus kinase inhibitors to restore skin barrier function in an in vivo model of harlequin ichthyosis
Abstract Introduction and aims Harlequin ichthyosis (HI) is the most severe form of autosomal recessive congenital ichthyosis (ARCI) with aberrant lipid transport in the epidermis leading to a severe barrier defect. It is caused by variants in ABCA12, a lipid transporter involved in the transport of glucosylceramides from the lamellar body to the lipid lamellae. The aim of this study was to explore further the effect of Janus kinase inhibitors (JAKis) on the epidermal barrier in in vitro and in vivo models of HI. Methods Three-dimensional skin equivalents (3DSEs) were generated from human ABCA12 CRISPR-Cas9 knockout and wildtype keratinocytes and treated with the JAKi abrocitinib and upadacitinib (UPA) and bulk RNA sequencing (RNAseq) and lipidomics were performed. UPA was tested in an in vivo HI mouse model followed by haematoxylin and eosin, Nile red, ABCA12, glucosylceramide and immune cell staining. Results Bulk RNAseq on treated and control 3DSEs showed upregulation of genes involved in keratinocyte metabolism, differentiation and skin barrier function as well as downregulation in immune response genes post-JAKi. Lipidomic analysis showed upregulation of cholesterol sulfate and phosphatidylethanolamine post-JAKi. UPA was selected to test at a concentration of 5 mg kg−1 in 10% dimethyl sulfoxide/corn oil on adult male and female inducible Abca12flox/flox K14CreER and control mice (n = 4 per group, two repeats). One day after topical 4-OH-tamoxifen treatment, UPA or vehicle were administered via oral gavage for nine consecutive days before collecting back skin. The UPA-treated HI mice had significantly reduced epidermal thickness compared with controls. Nile red and glucosylceramide staining showed restoration of neutral and polar lipids and upper epidermal glucosylceramide in the UPA-treated mice compared with controls. A reduction in T cells and dendritic cells was also observed in the JAK1i-treated mice. Conclusions These results suggest that UPA restores the skin barrier in severe ichthyosis and may be a promising treatment for this group of patients.
2026-01-01 | Incomplete Netherton Syndrome treated successfully with Isotretinoin
Netherton syndrome is a rare autosomal recessive ichthyosis caused by serine peptidase inhibitor Kazal 5 mutation, characterized by congenital ichthyosis, trichorrhexis invaginata, atopy, high serum immunoglobulin E levels, and hyper eosinophilia. The demonstration of bamboo hair by microscopy is used as a method to diagnose Netherton syndrome. We report a rare patient with Netherton syndrome confirmed by genetic analysis and protein expression studies who had normal hair and was successfully treated with low dose isotretinoin, without any adverse events.
2025-12-19 | Harlequin ichthyosis in a newborn: a rare and severe congenital ichthyosis
A full-term newborn male was delivered via spontaneous vaginal delivery, with a birth weight of 2.9 kg. At birth, the neonate presented with multiple dysmorphic features and extensive congenital skin abnormalities. The infant´s entire body showed taut, thickened, parchment-like skin with deep fissures and rigid posturing of the limbs and mouth, consistent with a collodion membrane. The baby had eclabium (eversion of the lips), ectropion (eversion of the eyelids), a flattened nose, and sparse or absent scalp hair. The umbilical cord appeared normal. No other systemic anomalies were noted at the time of initial evaluation. The baby was placed under close monitoring in a neonatal intensive care unit with supportive care, including maintenance of skin hydration, temperature regulation, and prevention of infection. Dermatological evaluation confirmed the clinical diagnosis of Harlequin ichthyosis is rare, severe autosomal recessive disorder of keratinization caused by mutations in the ABCA12 gene. This condition is characterized by defective lipid transport in the epidermis, resulting in abnormal skin barrier formation. Prognosis remains guarded, with neonatal mortality primarily due to sepsis, dehydration, or respiratory failure. Management includes systemic retinoids such as acitretin, which may help accelerate shedding of the collodion membrane and improve long-term outcomes. Genetic counselling was offered to the parents, who had no prior family history of skin disorders or consanguinity.
gene therapies
2026-06-15 | Potential of 3D Skin Models and N/TERT-2G Cell Line in Genetic Research on Autosomal Recessive Nonsyndromic Epidermal Differentiation Disorders.
Autosomal recessive nonsyndromic epidermal differentiation disorders (AR-nEDDs), also known as autosomal recessive congenital ichthyosis (ARCI), are rare genetic skin diseases that lack curative treatments and can only be managed symptomatically. Their study is hampered by the limited availability of biological samples and donor tissues. Artificial skin models offer a valuable alternative for experimental research. Here, we generated epidermal skin equivalents (ESE) using primary keratinocytes from patients with AR-nEDDs carrying pathogenic variants in ALOX12B, CYP4F22, and CERS3, as well as immortalized N/TERT-2G cells. Whereas primary cells undergo senescence, N/TERT-2G cells offer a promising alternative to overcome this limitation. Histological staining and qPCR were applied to assess key epidermal proteins and AR-nEDD-related gene expression in patient- and control-derived models. Patient-derived ESE reproduced the major histopathological features and protein expression patterns characteristic of AR-nEDDs. In contrast, N/TERT-2G-based models showed earlier expression of 12R-LOX, CYP4F22, and CERS3 proteins in epidermal layers compared to healthy donor equivalents. These findings suggest that N/TERT-2G cells represent a reproducible platform for future gene-editing approaches of modelling epidermal differentiation disorders. However, as they do not inherently carry pathogenic variants, they are particularly suitable for gene-editing approaches such as CRISPR/Cas9-mediated disease modelling. Conversely, patient-derived keratinocyte models remain indispensable for validating disease mechanisms and evaluating therapeutic strategies.
2026-02-07 | Editing the skin in place: In vivo genome correction of rare skin disease.
In this issue, Apaydin and Sadhnani et al. report in situ genome editing of human skin to correct a common disease-causing mutation underlying autosomal recessive congenital ichthyosis (ARCI).1 They combine a base editor, transient barrier modulation, and topical mRNA-lipid nanoparticle administration to restore clinically meaningful levels of transglutaminase 1 activity.
2026-01-29 | Lipid nanoparticle-based non-viral in situ gene editing of congenital ichthyosis-causing mutations in human skin models.
Autosomal recessive congenital ichthyosis (ARCI) refers to a group of rare, highly debilitating skin disorders that significantly impair patients' quality of life and lack any effective treatment options. Here, we report clinically relevant in situ correction of the most common ARCI-causing mutation, TGM1 c.877-2A>G, a splice-site aberration, in human disease models. Targeted skin barrier modulation followed by topical application of the cytosine base editor eTd packaged into lipid nanoparticles yielded functional restoration of ∼30% of wild-type transglutaminase 1 activity in skin tissue. Toxicity studies and comprehensive off-target analysis demonstrated an excellent safety profile even after repeated application, without systemic distribution of the lipid nanoparticles or the genetic cargo as determined via highly sensitive methods, including desorption electrospray ionization (DESI) metabolic imaging. This study presents comprehensive preclinical data on the feasibility of in situ gene correction of genodermatoses-causing mutations, showcasing its therapeutic potential and paving the way for curative next-generation treatments for severe genetic skin diseases.
2025-12-09 | Harlequin Ichthyosis: A Comprehensive Review of Pathogenesis, Diagnosis, and Management
Harlequin ichthyosis, one of the rarest and most severe skin disorders, is mainly characterized by extreme hyperkeratosis, severely impairing the natural barrier function of the skin. This congenital disease results from a mutation in the ABCA12 gene responsible for lipid transport, whereby healthy skin development is assured. Harlequin ichthyosis is an autosomal recessive condition that requires parents to carry a defective gene copy for the disorder to manifest in their offspring. Babies born with Harlequin ichthyosis have thick skin plates that crack and flake off; they easily become dehydrated, infected, and may suffer from respiratory complications. With new improvements in neonatal care and systemic therapy, notably retinoid therapy, infants’ survival rates have improved. This review provides an inclusive overview of the pathophysiology, clinical features, diagnostic methods, management, and potential future therapies for Harlequin ichthyosis. In addition, a discussion on genetic counseling and its importance in managing family risk factors is also included, as well as a look into cutting-edge research focused on gene therapy and potential curative treatments.
2025-10-29 | Evaluation of the Efficacy of Transglutaminase 1 Gene Delivery by Adeno-Associated Virus into Rat and Pig Skin and Safety of ARCI Gene Therapy.
Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of inherited keratinization disorders with diffuse skin lesions. It includes lamellar ichthyosis, congenital ichthyosiform erythroderma, and fetal ichthyosis. The common pathognomonic feature is generalized neonatal erythroderma. Lamellar ichthyosis is caused by mutations in the TGM1 gene encoding transglutaminase 1 (TGM1), leading to a functional deficiency of the enzyme in the epidermis. TGM1 deficiency causes severe keratinization defects and skin barrier impairment (leading to metabolic disorders, growth delay, and bacterial infections), with severe cases risking potentially fatal sepsis. Current therapeutic approaches are only symptomatic. In this study, we analyzed the functionality and safety of an adeno-associated viral vector of serotype 2 encoding TGM1 (AAV2-TGM1) for gene therapy of lamellar ichthyosis. The functionality of AAV2-TGM1 was confirmed in vitro on HEK293, HaCaT, and SH-SY5Y cells and human primary fibroblasts. A significant increase in TGM1 mRNA, protein levels, and enzymatic activity was shown. The vector was characterized and applied in vivo in rats and pigs. Intradermal injection and topical application resulted in increased protein levels in the skin, as shown by PCR and immunofluorescence. Safety was confirmed by the absence of significant histological, biochemical, and cellular changes. The results demonstrate the promise of AAV2-TGM1 for dermal application in gene therapy of lamellar ichthyosis.
proteins
2023-05-01 | 773 Purified recombinant PNPLA1 catalyzes the synthesis of acylceramides and acylacids of the mammalian skin barrier
Loss-of-function mutations in patatin-like phospholipase domain-containing protein 1 (PNPLA1) cause autosomal recessive congenital ichthyosis. Altered PNPLA1 activity is also implicated in the pathogenesis of atopic dermatitis and other common skin diseases. PNPLA1 has been proposed to synthesizeesterified omega-hydroxy acylsphingosine (EOS) and related acylceramides and acylacids, a unique family of epidermal barrier lipids that are enriched in the essential fatty acid linoleate. To test this hypothesis, we expressed and purified a soluble, truncated form of PNPLA1 in E. coli, along with the related protein PNPLA2 (ATGL, adipose triglyceride lipase), and co-activator CGI-58. Lipid substrates were prepared as liposomes, incubated with recombinant enzymes for 0.5 – 24 h and products were analyzed by HPLC-UV and LC-MS in comparison to authentic lipid standards. PNPLA1, like ATGL, catalyzed CGI-58-dependent lipolysis and acyltransferase reactions using triglyceride or diglyceride substrates. These reactions were rapid (1 – 2 h), with quantitative conversion (nmols per reaction) into free fatty acid and monoglyceride. Both PNPLA1 and ATGL also transferred acyl groups from glycerides to omega-hydroxy ceramide and omega-hydroxy fatty acid acceptors to form EOS and acyl acid, respectively, albeit in smaller quantities (pmols per reaction). PNPLA1 formed EOS more efficiently than ATGL, and exhibited a selectivity for the transfer of linoleate over oleate. Triglyceride or diglyceride was effective as acyl donor, and omega-hydroxy fatty acid, omega-hydroxy ceramide or glucosyl omega-hydroxy ceramide were effective as acceptor. These results support the hypothesis that PNPLA1 is involved in the synthesis of EOS and other acylceramides and acylacids in epidermis and suggest that the enrichment of these lipids with linoleic acid could result in part from the substrate selectivity of PNPLA1.
2023-03-02 | Ichthyosis linked to sphingosine 1-phosphate lyase insufficiency is due to aberrant sphingolipid and calcium regulation
Sphingosine 1-phosphate lyase (SGPL1) insufficiency (SPLIS) is a syndrome which presents with adrenal insufficiency, steroid-resistant nephrotic syndrome, hypothyroidism, neurological disease, and ichthyosis. Where a skin phenotype is reported, 94% had abnormalities such as ichthyosis, acanthosis, and hyperpigmentation. To elucidate the disease mechanism and the role SGPL1 plays in the skin barrier we established clustered regularly interspaced short palindromic repeats-Cas9 SGPL1 KO and a lentiviral-induced SGPL1 overexpression (OE) in telomerase reverse-transcriptase immortalised human keratinocytes (N/TERT-1) and thereafter organotypic skin equivalents. Loss of SGPL1 caused an accumulation of S1P, sphingosine, and ceramides, while its overexpression caused a reduction of these species. RNAseq analysis showed perturbations in sphingolipid pathway genes, particularly in SGPL1_KO, and our gene set enrichment analysis revealed polar opposite differential gene expression between SGPL1_KO and _OE in keratinocyte differentiation and Ca2+ signaling genesets. SGPL1_KO upregulated differentiation markers, while SGPL1_OE upregulated basal and proliferative markers. The advanced differentiation of SGPL1_KO was confirmed by 3D organotypic models that also presented with a thickened and retained stratum corneum and a breakdown of E-cadherin junctions. We conclude that SPLIS associated ichthyosis is a multifaceted disease caused possibly by sphingolipid imbalance and excessive S1P signaling, leading to increased differentiation and an imbalance of the lipid lamellae throughout the epidermis.
2022-07-19 | New developments in the molecular treatment of ichthyosis: review of the literature.
Ichthyosis covers a wide spectrum of diseases affecting the cornification of the skin. In recent years, new advances in understanding the pathophysiology of ichthyosis have been made. This knowledge, combined with constant development of pathogenesis-based therapies, such as protein replacement therapy and gene therapy, are rather promising for patients with inherited skin diseases. Several ongoing trials are investigating the potency of these new approaches and various studies have already been published. Furthermore, a lot of case series report that biological therapeutics are effective treatment options, mainly for Netherton syndrome and autosomal recessive congenital ichthyosis. It is expected that some of these new therapies will prove their efficacy and will be incorporated in the treatment of ichthyosis.
2022-05-03 | Development of peptide-based biosensors for measuring cross-linking and deamidation activities of transglutaminases
Abstract Transglutaminases (TGs) are a protein family that catalyzes isopeptide bond formation between glutamine and lysine residues of various proteins. There are eight TG isozymes in humans, and each is involved in diverse biological phenomena due to their characteristic distribution. Abnormal activity of TG1 and TG2, which are major TG isozymes, is believed to cause various diseases, such as ichthyosis, and celiac disease. To elucidate TGs’ mechanisms of action and develop new therapeutic strategies, it is essential to develop bioprobes that can specifically examine the activity of each TG isozyme, which has not been sufficiently studied. We previously have identified several substrate peptide sequences containing Gln residues for each isozyme and developed a method to detect isozyme-specific activities by incorporating a labeled substrate peptide into lysine residues of proteins. We prepared the fluorescein isothiocyanate (FITC)-labeled Gln substrate peptide (FITC-K5 and FITC-T26) and Rhodamine B-labeled Lys substrate peptide (RhoB-Kpep). Each TG reaction specifically cross-linked these probe pairs, and the proximity of FITC and Rhodamine B significantly decreased the fluorescence intensity of FITC depending on the concentration and reaction time of each TG. In this study, we developed a peptide-based biosensor that quickly and easily measures TG isozyme-specific activity. This probe is expected to be helpful in elucidating TG’s physiological and pathological functions and in developing compounds that modulate TG activity.
2021-12-23 | Juvenile idiopathic arthritis in Harlequin ichthyosis, a rare combination or the clinical spectrum of the disease? Report of a child treated with etanercept and review of the literature.
Harlequin ichthyosis (HI) is the most severe phenotype of autosomal recessive congenital ichthyosis. Juvenile Idiopathic Arthritis (JIA) represents a heterogenous group of disorders all sharing the clinical manifestation of chronic arthritis. Association of HI and chronic arthritis has been reported in few cases. We report the case of a child with HI who developed a severe form of chronic polyarthritis during the first years of life, treated with repeated multiple joint injections, methotrexate and etanercept with good response and without any adverse events. The reported case and the literature review highlighted the presence of a peculiar severe seronegative polyarthritis with early onset in a series of patients with HI, suggesting that polyarthritis may be a specific manifestation of HI, rather than a rare combination of two separate conditions.
antibodies
2026-06-15 | Secukinumab for lamellar ichthyosis in an adolescent: a case report.
Lamellar ichthyosis (LI) is a rare hereditary disorder of keratinization, most commonly inherited in an autosomal recessive manner and frequently associated with pathogenic variants in the TGM1 gene. Patients usually present with generalized scaling, xerosis, and pruritus from birth. Current therapeutic options remain limited, and systemic retinoids are often associated with considerable adverse effects. A 14-year-old female individual presented with generalized pruritic, lamellar scale-like skin changes present since birth. The diagnosis of LI was established based on clinical findings, histopathological evaluation, and genetic testing [two pathogenic variants in the TGM1 gene, consistent with autosomal recessive congenital ichthyosis type 1, Online Mendelian Inheritance in Man (OMIM): 242300]. Oral administration of acitretin (10 mg twice daily) was initiated; however, treatment was discontinued due to elevated hepatic transaminase levels and severe xerosis with pruritus. Subcutaneous administration of secukinumab (150 mg weekly) was subsequently initiated. After five weekly doses, the dosing frequency was reduced to once monthly. Over 8 weeks, substantial clinical improvement was observed, with a satisfactory therapeutic response. The patient remained on active treatment at the time of reporting. Secukinumab appeared to be effective in this patient with LI and may warrant further investigation as a potential therapeutic option for inherited ichthyosis.
2026-04-11 | Mutation Analysis in Ten Cases With PNPLA1-Nonsyndromic Epidermal Differentiation Disorder: Evidence of a Founder Effect.
Autosomal recessive congenital ichthyosis (ARCI) belongs to a heterogeneous group of nonsyndromic epidermal differentiation disorders (nEDD). Variants in PNPLA1, which encodes a transacylase essential for the formation of epidermal lipid barrier, underlie ARCI10. This study aims to unveil the underlying genetic basis in ten Chinese cases diagnosed with ARCI, and to determine the origin of a prevalent variant. Ten cases, encompassing twelve patients with ARCI, were recruited for this study. Whole-exome sequencing combined with Sanger sequencing was used to detect the underlying variants. Haplotype analysis using flanking highly polymorphic SNPs was used to trace the origin of the c.1300delG variant in the PNPLA1 gene. All patients developed generalized fine scales and erythema shortly after birth. Marked phenotypic heterogeneity was observed among the affected individuals, leading to diagnosis of either generalized or localized nEDD. In total, we detected three recurrent variants (c.1300delG, p.A434Hfs*22; c.434 T > C, p.Ile145Thr; c.488C > T, p.Pro163Leu) and five novel variants (c.205 + 1G > A, splicing; c.74C > T, p.Ser25Phe; c.473G > A, p.Cys158Tyr; c.731A > G, p.Tyr244Cys; c.1318C > T, p.Arg440*) in PNPLA1. The c.1300delG variant, prevalent in 7 unrelated ARCI cases, was associated with a common haplotype. Furthermore, we presented the beneficial effect of secukinumab treatment in one of our patients. Our findings suggest that the c.1300delG variant is a highly prevalent variant in Chinese PNPLA1-associated nEDD patients, and indicate that the recurrent variant may originate from a common ancestor in southern China, suggesting a regional founder effect. The observed response with secukinumab in one patient suggests that it might represent a potential therapeutic option for PNPLA1-nEDD patients.
2025-12-05 | Beyond the skin: immunological profiles and infectious complications in ALOX12B-associated autosomal recessive congenital ichthyosis.
Pathogenic variants in ALOX12B, a crucial enzyme involved in epidermal lipid processing, are among the most common causes of autosomal recessive congenital ichthyosis (ARCI). Although traditionally considered a cutaneous disorder, the systemic immunological implications of ALOX12B deficiency remain poorly understood. We aimed to broaden the dermatologic and immunologic spectrum of ALOX12B-associated ARCI by characterizing the clinical, immunologic, and genetic features of six patients from three consanguineous families. This prospective study included six patients with ALOX12B-associated ARCI identified through whole-exome sequencing. Detailed dermatological evaluations, infection histories, immunoglobulin profiles, lymphocyte subset analyses, and vaccine response assessments were performed. All patients exhibited early-onset generalized ichthyosis, ranging from delayed-onset lamellar ichthyosis to collodion membrane presentations accompanied by nonbullous erythroderma. Two distinct biallelic ALOX12B variants were identified: a novel p.Thr383Lys and the known p.Cys544Arg. Several patients demonstrated recurrent bacterial or fungal infections (n = 5), markedly elevated serum IgE levels (n = 4), and isolated abnormalities in vaccine responsiveness (n = 2). Lymphocyte counts and other immunoglobulin classes were generally preserved; however, decreased IgG levels were observed in one patient (P3.1). Intravenous immunoglobulin replacement therapy reduced the frequency of infections in patients (P1.1 and P1.2). Our findings suggest that ALOX12B-related ARCI may involve secondary immune dysregulation, driven by chronic compromise of the epidermal barrier. An immunologic evaluation is warranted in selected cases, particularly those with a history of susceptibility to infections. Multidisciplinary care, encompassing dermatology, immunology, and genetics, is crucial for achieving optimal outcomes in ARCI.
2025-11-19 | Data Sheet 1_Beyond the skin: immunological profiles and infectious complications in ALOX12B-associated autosomal recessive congenital ichthyosis.docx
Background Pathogenic variants in ALOX12B, a crucial enzyme involved in epidermal lipid processing, are among the most common causes of autosomal recessive congenital ichthyosis (ARCI). Although traditionally considered a cutaneous disorder, the systemic immunological implications of ALOX12B deficiency remain poorly understood. Objectives We aimed to broaden the dermatologic and immunologic spectrum of ALOX12B-associated ARCI by characterizing the clinical, immunologic, and genetic features of six patients from three consanguineous families. Methods This prospective study included six patients with ALOX12B-associated ARCI identified through whole-exome sequencing. Detailed dermatological evaluations, infection histories, immunoglobulin profiles, lymphocyte subset analyses, and vaccine response assessments were performed. Results All patients exhibited early-onset generalized ichthyosis, ranging from delayed-onset lamellar ichthyosis to collodion membrane presentations accompanied by nonbullous erythroderma. Two distinct biallelic ALOX12B variants were identified: a novel p.Thr383Lys and the known p.Cys544Arg. Several patients demonstrated recurrent bacterial or fungal infections (n = 5), markedly elevated serum IgE levels (n = 4), and isolated abnormalities in vaccine responsiveness (n = 2). Lymphocyte counts and other immunoglobulin classes were generally preserved; however, decreased IgG levels were observed in one patient (P3.1). Intravenous immunoglobulin replacement therapy reduced the frequency of infections in patients (P1.1 and P1.2). Conclusions Our findings suggest that ALOX12B-related ARCI may involve secondary immune dysregulation, driven by chronic compromise of the epidermal barrier. An immunologic evaluation is warranted in selected cases, particularly those with a history of susceptibility to infections. Multidisciplinary care, encompassing dermatology, immunology, and genetics, is crucial for achieving optimal outcomes in ARCI.
2025-10-13 | Clinical and immunological characterization of a Netherton syndrome infant with a large SPINK gene cluster deletion and a c.1258A>G polymorphism in SPINK5.
Netherton syndrome (NS) is a rare autosomal recessive disorder caused by mutations in the SPINK5 gene, which encodes the serine protease inhibitor LEKTI. It is characterized by congenital ichthyosis, hair shaft abnormalities, and atopic manifestations. Previous reports suggest that intravenous immunoglobulin (IVIG) may provide partial clinical benefit in NS. Here, we report the clinical and immunological characterization of an infant with NS effectively treated with IVIG therapy. Clinical information was collected and reviewed from a 1-year-6-month-old boy presenting with NS. Hair shaft abnormalities were examined by scanning electron microscopy. Pathogenic variants in SPINK5 were identified using whole-exome and Sanger sequencing. Protein expression was assessed by Western blotting and ELISA. Peripheral lymphocyte subsets were analyzed by flow cytometry, and cytokine levels were evaluated with the Olink® Target 48 Cytokine panel. The patient presented with typical clinical manifestations of NS. Genetic analysis identified a novel heterozygous deletion spanning the SPINK5 gene (chr5:147,443,561-147,719,327), together with the c.1258A>G (p.K420E) polymorphism. LEKTI expression was markedly decreased, consistent with the genetic findings. Immune profiling revealed markedly reduced unswitched memory and marginal zone-like B cells, increased naïve B cells, and elevated γδ T cells compared with healthy controls. Cytokine analysis showed significantly increased levels of multiple pro-inflammatory cytokines, including TGFA, IL17 family members, CXCL8, CCL2, TNF, CCL19, and IL18. Following IVIG therapy, the patient demonstrated significant clinical improvement, with recovery of skin manifestations, and partial normalization of lymphocyte subsets and cytokine levels, indicating restoration of immune regulation. This study reports a novel compound heterozygous SPINK5 mutation in an infant with NS, comprising a large deletion and c.1258A>G polymorphism, resulting in LEKTI deficiency and immune dysregulation. IVIG therapy effectively alleviated clinical symptoms and restored immune balance, highlighting its potential as a therapeutic option for NS and related immunodeficiency disorders.
small molecules
2026-06-09 | Role of hydrogel-based systems in the management of lamellar ichthyosis: A comprehensive review
A rare autosomal recessive congenital skin condition called lamellar ichthyosis is typified by aberrant keratinization and compromised epidermal barrier function. Mutations in genes including TGM1, ABCA12, ALOX12B, ALOXE3, and NIPAL4, which are essential for protein cross-linking and lipid metabolism in the stratum corneum, are the main cause of the disorder. Clinically, affected people frequently have a collodion membrane at birth that eventually sheds, exposing the body's massive, black, plate-like scales. Ectropion, eclabium, hypohidrosis, and heightened vulnerability to infections as a result of weakened skin integrity are other characteristics. According to epidemiology, lamellar ichthyosis is an uncommon condition that affects both sexes equally and has a global prevalence of between 1 in 100,000 and 300,000 people. Genetic testing may be used to assist the diagnosis, which is mostly clinical. In extreme cases, emollients, humectants, keratolytic agents, and systemic retinoids are used to relieve symptoms. The potential use of hydrogels as a successful therapeutic strategy for treating this illness has been brought to light by recent developments. Because of their high water content and biocompatibility, hydrogels improve medication penetration into the stratum corneum, decrease scaling, and offer constant hydration. Treatment results are further enhanced by their capacity to provide sustained and regulated drug release. All things considered, lamellar ichthyosis necessitates lifelong care, and new treatments like hydrogel-based formulations offer encouraging opportunities to enhance patient care and quality of life.
2026-01-20 | Harlequin ichthyosis: diagnosis, standards of care, and treatment — a systematic review
Background. Harlequin ichthyosis (HI) is the most severe form of autosomal recessive congenital ichthyosis (ARCI), caused by mutations in the ABCA12 gene. Impaired lipid transport in keratinocytes leads to profound dysfunction of the epidermal barrier and, consequently, to the severe clinical phenotype already evident at birth. Despite the rarity of this condition, HI remains one of the most dramatic dermatological disorders of the neonatal period. The aim of this study is to present the current state of knowledge on the etiology, clinical presentation, diagnosis and treatment methods of HI. This paper seeks to compile the available data in one place and to discuss the diagnostic and therapeutic challenges. Methods. A systematic analysis of the available scientific literature was carried out, including clinical studies, case reports, review articles, and reports on modern diagnostic and therapeutic techniques. Results. The development of methods enabling genetic diagnosis has allowed for early and precise detection of ABCA12 gene mutations, which has improved the possibilities for prenatal diagnosis and perinatal care planning. Multidisciplinary care and early use of retinoids have reduced mortality in newborns with HI. Nevertheless, the disease remains associated with a high risk of systemic complications and long-term sequelae. Conclusions. Harlequin ichthyosis remains a severe disease that requires rapid diagnosis, interdisciplinary management and continuous monitoring. Technological and therapeutic advances have improved the prognosis; however, further studies are needed to optimize retinoid therapy, management protocols and strategies supporting skin barrier regeneration in patients affected by HI.
2026-01-01 | O09 Janus kinase inhibitors to restore skin barrier function in an in vivo model of harlequin ichthyosis
Abstract Introduction and aims Harlequin ichthyosis (HI) is the most severe form of autosomal recessive congenital ichthyosis (ARCI) with aberrant lipid transport in the epidermis leading to a severe barrier defect. It is caused by variants in ABCA12, a lipid transporter involved in the transport of glucosylceramides from the lamellar body to the lipid lamellae. The aim of this study was to explore further the effect of Janus kinase inhibitors (JAKis) on the epidermal barrier in in vitro and in vivo models of HI. Methods Three-dimensional skin equivalents (3DSEs) were generated from human ABCA12 CRISPR-Cas9 knockout and wildtype keratinocytes and treated with the JAKi abrocitinib and upadacitinib (UPA) and bulk RNA sequencing (RNAseq) and lipidomics were performed. UPA was tested in an in vivo HI mouse model followed by haematoxylin and eosin, Nile red, ABCA12, glucosylceramide and immune cell staining. Results Bulk RNAseq on treated and control 3DSEs showed upregulation of genes involved in keratinocyte metabolism, differentiation and skin barrier function as well as downregulation in immune response genes post-JAKi. Lipidomic analysis showed upregulation of cholesterol sulfate and phosphatidylethanolamine post-JAKi. UPA was selected to test at a concentration of 5 mg kg−1 in 10% dimethyl sulfoxide/corn oil on adult male and female inducible Abca12flox/flox K14CreER and control mice (n = 4 per group, two repeats). One day after topical 4-OH-tamoxifen treatment, UPA or vehicle were administered via oral gavage for nine consecutive days before collecting back skin. The UPA-treated HI mice had significantly reduced epidermal thickness compared with controls. Nile red and glucosylceramide staining showed restoration of neutral and polar lipids and upper epidermal glucosylceramide in the UPA-treated mice compared with controls. A reduction in T cells and dendritic cells was also observed in the JAK1i-treated mice. Conclusions These results suggest that UPA restores the skin barrier in severe ichthyosis and may be a promising treatment for this group of patients.
2026-01-01 | Incomplete Netherton Syndrome treated successfully with Isotretinoin
Netherton syndrome is a rare autosomal recessive ichthyosis caused by serine peptidase inhibitor Kazal 5 mutation, characterized by congenital ichthyosis, trichorrhexis invaginata, atopy, high serum immunoglobulin E levels, and hyper eosinophilia. The demonstration of bamboo hair by microscopy is used as a method to diagnose Netherton syndrome. We report a rare patient with Netherton syndrome confirmed by genetic analysis and protein expression studies who had normal hair and was successfully treated with low dose isotretinoin, without any adverse events.
2025-12-19 | Harlequin ichthyosis in a newborn: a rare and severe congenital ichthyosis
A full-term newborn male was delivered via spontaneous vaginal delivery, with a birth weight of 2.9 kg. At birth, the neonate presented with multiple dysmorphic features and extensive congenital skin abnormalities. The infant´s entire body showed taut, thickened, parchment-like skin with deep fissures and rigid posturing of the limbs and mouth, consistent with a collodion membrane. The baby had eclabium (eversion of the lips), ectropion (eversion of the eyelids), a flattened nose, and sparse or absent scalp hair. The umbilical cord appeared normal. No other systemic anomalies were noted at the time of initial evaluation. The baby was placed under close monitoring in a neonatal intensive care unit with supportive care, including maintenance of skin hydration, temperature regulation, and prevention of infection. Dermatological evaluation confirmed the clinical diagnosis of Harlequin ichthyosis is rare, severe autosomal recessive disorder of keratinization caused by mutations in the ABCA12 gene. This condition is characterized by defective lipid transport in the epidermis, resulting in abnormal skin barrier formation. Prognosis remains guarded, with neonatal mortality primarily due to sepsis, dehydration, or respiratory failure. Management includes systemic retinoids such as acitretin, which may help accelerate shedding of the collodion membrane and improve long-term outcomes. Genetic counselling was offered to the parents, who had no prior family history of skin disorders or consanguinity.
gene therapies
2026-06-15 | Potential of 3D Skin Models and N/TERT-2G Cell Line in Genetic Research on Autosomal Recessive Nonsyndromic Epidermal Differentiation Disorders.
Autosomal recessive nonsyndromic epidermal differentiation disorders (AR-nEDDs), also known as autosomal recessive congenital ichthyosis (ARCI), are rare genetic skin diseases that lack curative treatments and can only be managed symptomatically. Their study is hampered by the limited availability of biological samples and donor tissues. Artificial skin models offer a valuable alternative for experimental research. Here, we generated epidermal skin equivalents (ESE) using primary keratinocytes from patients with AR-nEDDs carrying pathogenic variants in ALOX12B, CYP4F22, and CERS3, as well as immortalized N/TERT-2G cells. Whereas primary cells undergo senescence, N/TERT-2G cells offer a promising alternative to overcome this limitation. Histological staining and qPCR were applied to assess key epidermal proteins and AR-nEDD-related gene expression in patient- and control-derived models. Patient-derived ESE reproduced the major histopathological features and protein expression patterns characteristic of AR-nEDDs. In contrast, N/TERT-2G-based models showed earlier expression of 12R-LOX, CYP4F22, and CERS3 proteins in epidermal layers compared to healthy donor equivalents. These findings suggest that N/TERT-2G cells represent a reproducible platform for future gene-editing approaches of modelling epidermal differentiation disorders. However, as they do not inherently carry pathogenic variants, they are particularly suitable for gene-editing approaches such as CRISPR/Cas9-mediated disease modelling. Conversely, patient-derived keratinocyte models remain indispensable for validating disease mechanisms and evaluating therapeutic strategies.
2026-02-07 | Editing the skin in place: In vivo genome correction of rare skin disease.
In this issue, Apaydin and Sadhnani et al. report in situ genome editing of human skin to correct a common disease-causing mutation underlying autosomal recessive congenital ichthyosis (ARCI).1 They combine a base editor, transient barrier modulation, and topical mRNA-lipid nanoparticle administration to restore clinically meaningful levels of transglutaminase 1 activity.
2026-01-29 | Lipid nanoparticle-based non-viral in situ gene editing of congenital ichthyosis-causing mutations in human skin models.
Autosomal recessive congenital ichthyosis (ARCI) refers to a group of rare, highly debilitating skin disorders that significantly impair patients' quality of life and lack any effective treatment options. Here, we report clinically relevant in situ correction of the most common ARCI-causing mutation, TGM1 c.877-2A>G, a splice-site aberration, in human disease models. Targeted skin barrier modulation followed by topical application of the cytosine base editor eTd packaged into lipid nanoparticles yielded functional restoration of ∼30% of wild-type transglutaminase 1 activity in skin tissue. Toxicity studies and comprehensive off-target analysis demonstrated an excellent safety profile even after repeated application, without systemic distribution of the lipid nanoparticles or the genetic cargo as determined via highly sensitive methods, including desorption electrospray ionization (DESI) metabolic imaging. This study presents comprehensive preclinical data on the feasibility of in situ gene correction of genodermatoses-causing mutations, showcasing its therapeutic potential and paving the way for curative next-generation treatments for severe genetic skin diseases.
2025-12-09 | Harlequin Ichthyosis: A Comprehensive Review of Pathogenesis, Diagnosis, and Management
Harlequin ichthyosis, one of the rarest and most severe skin disorders, is mainly characterized by extreme hyperkeratosis, severely impairing the natural barrier function of the skin. This congenital disease results from a mutation in the ABCA12 gene responsible for lipid transport, whereby healthy skin development is assured. Harlequin ichthyosis is an autosomal recessive condition that requires parents to carry a defective gene copy for the disorder to manifest in their offspring. Babies born with Harlequin ichthyosis have thick skin plates that crack and flake off; they easily become dehydrated, infected, and may suffer from respiratory complications. With new improvements in neonatal care and systemic therapy, notably retinoid therapy, infants’ survival rates have improved. This review provides an inclusive overview of the pathophysiology, clinical features, diagnostic methods, management, and potential future therapies for Harlequin ichthyosis. In addition, a discussion on genetic counseling and its importance in managing family risk factors is also included, as well as a look into cutting-edge research focused on gene therapy and potential curative treatments.
2025-10-29 | Evaluation of the Efficacy of Transglutaminase 1 Gene Delivery by Adeno-Associated Virus into Rat and Pig Skin and Safety of ARCI Gene Therapy.
Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of inherited keratinization disorders with diffuse skin lesions. It includes lamellar ichthyosis, congenital ichthyosiform erythroderma, and fetal ichthyosis. The common pathognomonic feature is generalized neonatal erythroderma. Lamellar ichthyosis is caused by mutations in the TGM1 gene encoding transglutaminase 1 (TGM1), leading to a functional deficiency of the enzyme in the epidermis. TGM1 deficiency causes severe keratinization defects and skin barrier impairment (leading to metabolic disorders, growth delay, and bacterial infections), with severe cases risking potentially fatal sepsis. Current therapeutic approaches are only symptomatic. In this study, we analyzed the functionality and safety of an adeno-associated viral vector of serotype 2 encoding TGM1 (AAV2-TGM1) for gene therapy of lamellar ichthyosis. The functionality of AAV2-TGM1 was confirmed in vitro on HEK293, HaCaT, and SH-SY5Y cells and human primary fibroblasts. A significant increase in TGM1 mRNA, protein levels, and enzymatic activity was shown. The vector was characterized and applied in vivo in rats and pigs. Intradermal injection and topical application resulted in increased protein levels in the skin, as shown by PCR and immunofluorescence. Safety was confirmed by the absence of significant histological, biochemical, and cellular changes. The results demonstrate the promise of AAV2-TGM1 for dermal application in gene therapy of lamellar ichthyosis.
proteins
2023-05-01 | 773 Purified recombinant PNPLA1 catalyzes the synthesis of acylceramides and acylacids of the mammalian skin barrier
Loss-of-function mutations in patatin-like phospholipase domain-containing protein 1 (PNPLA1) cause autosomal recessive congenital ichthyosis. Altered PNPLA1 activity is also implicated in the pathogenesis of atopic dermatitis and other common skin diseases. PNPLA1 has been proposed to synthesizeesterified omega-hydroxy acylsphingosine (EOS) and related acylceramides and acylacids, a unique family of epidermal barrier lipids that are enriched in the essential fatty acid linoleate. To test this hypothesis, we expressed and purified a soluble, truncated form of PNPLA1 in E. coli, along with the related protein PNPLA2 (ATGL, adipose triglyceride lipase), and co-activator CGI-58. Lipid substrates were prepared as liposomes, incubated with recombinant enzymes for 0.5 – 24 h and products were analyzed by HPLC-UV and LC-MS in comparison to authentic lipid standards. PNPLA1, like ATGL, catalyzed CGI-58-dependent lipolysis and acyltransferase reactions using triglyceride or diglyceride substrates. These reactions were rapid (1 – 2 h), with quantitative conversion (nmols per reaction) into free fatty acid and monoglyceride. Both PNPLA1 and ATGL also transferred acyl groups from glycerides to omega-hydroxy ceramide and omega-hydroxy fatty acid acceptors to form EOS and acyl acid, respectively, albeit in smaller quantities (pmols per reaction). PNPLA1 formed EOS more efficiently than ATGL, and exhibited a selectivity for the transfer of linoleate over oleate. Triglyceride or diglyceride was effective as acyl donor, and omega-hydroxy fatty acid, omega-hydroxy ceramide or glucosyl omega-hydroxy ceramide were effective as acceptor. These results support the hypothesis that PNPLA1 is involved in the synthesis of EOS and other acylceramides and acylacids in epidermis and suggest that the enrichment of these lipids with linoleic acid could result in part from the substrate selectivity of PNPLA1.
2023-03-02 | Ichthyosis linked to sphingosine 1-phosphate lyase insufficiency is due to aberrant sphingolipid and calcium regulation
Sphingosine 1-phosphate lyase (SGPL1) insufficiency (SPLIS) is a syndrome which presents with adrenal insufficiency, steroid-resistant nephrotic syndrome, hypothyroidism, neurological disease, and ichthyosis. Where a skin phenotype is reported, 94% had abnormalities such as ichthyosis, acanthosis, and hyperpigmentation. To elucidate the disease mechanism and the role SGPL1 plays in the skin barrier we established clustered regularly interspaced short palindromic repeats-Cas9 SGPL1 KO and a lentiviral-induced SGPL1 overexpression (OE) in telomerase reverse-transcriptase immortalised human keratinocytes (N/TERT-1) and thereafter organotypic skin equivalents. Loss of SGPL1 caused an accumulation of S1P, sphingosine, and ceramides, while its overexpression caused a reduction of these species. RNAseq analysis showed perturbations in sphingolipid pathway genes, particularly in SGPL1_KO, and our gene set enrichment analysis revealed polar opposite differential gene expression between SGPL1_KO and _OE in keratinocyte differentiation and Ca2+ signaling genesets. SGPL1_KO upregulated differentiation markers, while SGPL1_OE upregulated basal and proliferative markers. The advanced differentiation of SGPL1_KO was confirmed by 3D organotypic models that also presented with a thickened and retained stratum corneum and a breakdown of E-cadherin junctions. We conclude that SPLIS associated ichthyosis is a multifaceted disease caused possibly by sphingolipid imbalance and excessive S1P signaling, leading to increased differentiation and an imbalance of the lipid lamellae throughout the epidermis.
2022-07-19 | New developments in the molecular treatment of ichthyosis: review of the literature.
Ichthyosis covers a wide spectrum of diseases affecting the cornification of the skin. In recent years, new advances in understanding the pathophysiology of ichthyosis have been made. This knowledge, combined with constant development of pathogenesis-based therapies, such as protein replacement therapy and gene therapy, are rather promising for patients with inherited skin diseases. Several ongoing trials are investigating the potency of these new approaches and various studies have already been published. Furthermore, a lot of case series report that biological therapeutics are effective treatment options, mainly for Netherton syndrome and autosomal recessive congenital ichthyosis. It is expected that some of these new therapies will prove their efficacy and will be incorporated in the treatment of ichthyosis.
2022-05-03 | Development of peptide-based biosensors for measuring cross-linking and deamidation activities of transglutaminases
Abstract Transglutaminases (TGs) are a protein family that catalyzes isopeptide bond formation between glutamine and lysine residues of various proteins. There are eight TG isozymes in humans, and each is involved in diverse biological phenomena due to their characteristic distribution. Abnormal activity of TG1 and TG2, which are major TG isozymes, is believed to cause various diseases, such as ichthyosis, and celiac disease. To elucidate TGs’ mechanisms of action and develop new therapeutic strategies, it is essential to develop bioprobes that can specifically examine the activity of each TG isozyme, which has not been sufficiently studied. We previously have identified several substrate peptide sequences containing Gln residues for each isozyme and developed a method to detect isozyme-specific activities by incorporating a labeled substrate peptide into lysine residues of proteins. We prepared the fluorescein isothiocyanate (FITC)-labeled Gln substrate peptide (FITC-K5 and FITC-T26) and Rhodamine B-labeled Lys substrate peptide (RhoB-Kpep). Each TG reaction specifically cross-linked these probe pairs, and the proximity of FITC and Rhodamine B significantly decreased the fluorescence intensity of FITC depending on the concentration and reaction time of each TG. In this study, we developed a peptide-based biosensor that quickly and easily measures TG isozyme-specific activity. This probe is expected to be helpful in elucidating TG’s physiological and pathological functions and in developing compounds that modulate TG activity.
2021-12-23 | Juvenile idiopathic arthritis in Harlequin ichthyosis, a rare combination or the clinical spectrum of the disease? Report of a child treated with etanercept and review of the literature.
Harlequin ichthyosis (HI) is the most severe phenotype of autosomal recessive congenital ichthyosis. Juvenile Idiopathic Arthritis (JIA) represents a heterogenous group of disorders all sharing the clinical manifestation of chronic arthritis. Association of HI and chronic arthritis has been reported in few cases. We report the case of a child with HI who developed a severe form of chronic polyarthritis during the first years of life, treated with repeated multiple joint injections, methotrexate and etanercept with good response and without any adverse events. The reported case and the literature review highlighted the presence of a peculiar severe seronegative polyarthritis with early onset in a series of patients with HI, suggesting that polyarthritis may be a specific manifestation of HI, rather than a rare combination of two separate conditions.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
17 orphan drug designations for Autosomal recessive congenital ichthyosis.
17 orphan drug designations for Autosomal recessive congenital ichthyosis.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
mRNA encoding Cas9-deaminase and single guide RNA against TGM1 | gene editing enzymes | FDA | 2025-03-06 | — | Charité Universitaetsmedizin Berlin KöR |
mRNA encoding Cas9-deaminase, single guide RNA against the human TGM1 gene | gene editing enzymes | EMA | 2024-12-13 | — | Charite Universitaetsmedizin Berlin KöR |
Isotretinoin | small molecules | EMA | 2022-10-11 | — | Granzer Regulatory Consulting & Services GmbH |
Trifarotene | small molecules | EMA | 2020-03-24 | — | Premier Research Group S.L. |
Replication-incompetent, non-integrating, herpes simplex virus 1 vector expressing the human transglutaminase-1 enzyme | gene therapies | EMA | 2019-11-13 | — | Krystal Biotech Netherlands B.V. |
A replication-incompetent, non-integrating Herpes simplex type 1 (HSV-1) vector expressing the human transglutaminase-1 (TGM-1) enzyme | gene therapies | FDA | 2018-08-07 | — | Krystal Biotech, Inc. |
2-(3-amino-6-chloroquinolin-2-yl)-propan-2-ol | small molecules | FDA | 2017-04-17 | — | Aldeyra Therapeutics |
trifarotene | small molecules | FDA | 2014-06-06 | — | Mayne Pharma LLC. |
isotretinoin | small molecules | FDA | 2014-04-10 | — | Timber Pharmaceuticals |
Recombinant human transglutaminase 1 encapsulated into liposomes | proteins | EMA | 2013-06-07 | — | Universitaet Muenster |
Talarozole | small molecules | EMA | 2012-07-04 | — | [INACTIVE] Stiefel Laboratories (Maidenhead) Limited |
talarazole | small molecules | FDA | 2012-03-16 | — | Stiefel Laboratories, Inc. |
salicylic acid 6% | small molecules | FDA | 2012-02-17 | — | Orenova Group, LLC |
Tazarotene | small molecules | EMA | 2006-12-18 | — | [INACTIVE] Orfagen |
liarozole | small molecules | FDA | 2004-06-18 | — | Stiefel Laboratories, Inc. |
Liarozole | small molecules | EMA | 2003-06-10 | — | Stiefel Laboratories (UK) Limited |
Monolaurin | small molecules | FDA | 1993-04-29 | — | Glaxo Wellcome Inc. |
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI’s forecasts to outperform average preclinical success rates. Whether you’re expanding your R&D pipeline, evaluating a partnership, or simply have a question — we’d love to hear from you.