RARE DISEASE
Ichthyosis
Ichthyosis
Ichthyosis
Drug discovery
1
drug
With orphan designation
Overview
Ichthyosis encompasses genetic and acquired disorders of keratinization characterized by dry, thickened, scaling skin due to impaired barrier function and abnormal desquamation. While most forms are inherited (e.g., ichthyosis vulgaris, X-linked, lamellar), acquired cases may arise from systemic diseases or medications. Symptoms range from mild xerosis to life-threatening erythroderma, often with complications like infections, ectropion, and heat intolerance. Management focuses on symptomatic relief through emollients, keratolytics, and retinoids, with emerging therapies targeting underlying genetic mechanisms [1][8][12].
Burden
Categories: rare skin diseases
Research Papers
868 drug discovery papers about Ichthyosis, with 6 first-in-class and 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
868 drug discovery papers about Ichthyosis, with 6 first-in-class and 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-11 | X-linked ichthyosis with seizures, ADHD, and autism spectrum disorder: a case report with an uncommon clinical presentation.
X-linked ichthyosis (XLI) is a genetic condition characterized by scaly skin due to steroid sulfatase (STS) deficiency, often associated with additional neurodevelopmental issues. A 10-year-old male child was admitted to the dermatology department. The child had been born prematurely at 26 weeks' gestation with a low birth weight of 1.6 kg. He presented with seizures characterized by abnormal upper-limb movements and was diagnosed with congenital ichthyosis. The child exhibited delayed language and motor development, learning difficulties, microcephaly, and dry, scaly skin, which he habitually peeled and ingested. Genetic analysis (single-nucleotide polymorphism and combined comparative genomic hybridization) revealed a 1.65 Mb deletion on chromosome Xp22.31 affecting the STS gene and other adjacent genes. The patient had low STS enzyme activity (3.5 nmol/hour/protein) in adipose tissue. Neuroimaging showed no structural abnormalities, though an electroencephalogram indicated mild slowing. Given the established association between STS deletions and neurodevelopmental as well as psychiatric comorbidities, early recognition of emerging psychiatric features is essential. Given the established association between STS deletions and neurodevelopmental as well as psychiatric comorbidities, early recognition of emerging psychiatric manifestations is essential. Management should follow evidence-based recommendations for first-episode or early psychotic symptoms, emphasizing careful assessment, individualized pharmacological treatment when indicated, and multidisciplinary psychosocial support. Such an approach may improve clinical stabilization while avoiding premature diagnostic labeling. This case highlights the importance of early genetic diagnosis and personalized treatment approaches, integrating dermatological, neurological, and psychiatric care to optimize outcomes in XLI.
2026-09-01 | Long-term improvement in congenital ichthyosis vulgaris with individualized homeopathic treatment at Dr Batra’s® Homeopathy Clinic: a case report
Ichthyosis vulgaris is a chronic inherited keratinization disorder characterized by generalized xerosis, scaling, hyperpigmentation, and recurrent exacerbations, significantly affecting quality of life. Conventional management primarily relies on emollients and topical therapies with limited long-term control. This case report describes a school-going female child suffering from congenital ichthyosis vulgaris since birth, with persistent dryness, scaling, hyperpigmentation, itching, and recurrent flare-ups despite prolonged conventional treatment including topical steroids. Detailed constitutional assessment revealed a chilly, intellectually bright, disciplined child with good academic performance and active participation in extracurricular activities. Individualized homeopathic treatment resulted in progressive reduction in scaling, dryness, itching, hyperpigmentation, and skin thickening, with regeneration of healthy skin. Significant clinical improvement was observed during follow-up, reducing dependence on topical steroid applications. This case highlights the role of individualized homeopathic treatment in the management of congenital ichthyosis vulgaris at Dr Batra’s® Homeopathy Clinic.
2026-07-03 | Two clinical observations of keratitis-ichthyosis-deafness syndrome (KID syndrome)
Keratitis-ichthyosis-deafness (KID) syndrome is a rare genetic disorder characterized by erythrokeratoderma, vascular keratitis and sensorineural hearing loss. The disease develops as a result of a mutation in the GJB2 gene encoding the connexin 26 protein, which is expressed in the epidermis and is involved in the formation of gap junctions between epithelial cells that carry out transport of ions and small molecules. Changes in the skin are usually noticed from birth, they may manifest as erythrokeratoderma, psoriasis-like lesions, hyperkeratosis foci, palmoplantar keratoderma. Alopecia totalis progresses with age. Congenital bilateral prelingual sensorineural hearing loss is diagnosed in 90% of patients, and neovascular keratitis — in 95%. Half of the patients experience persistent skin infection, and the development of benign and malignant tricholemmal tumors as well as squamous cell carcinoma is possible. In recent years, a search for drugs capable of restoring the patency of gap junction channels, which significantly improves the skin condition in research animals, has been performed. Effective therapeutic agents will be discovered in the future. Currently, patients are primarily treated symptomatically. We present a case report of two patients suffering from KID syndrome. In both cases, the disease began from birth and was manifested by ichthyosiform erythroderma, palmoplantar keratoderma, alopecia totalis, onychodystrophy, sensorineural deafness, chronic keratitis and photophobia. Despite the full set of diagnostic symptoms, the first patient was diagnosed with KID syndrome at the age of 29, and the second patient — at the age of 10. In the second case, genetic analysis confirmed the GJB2 gene mutation (p.Asp50Asn). The course of the disease was accompanied by a persistent bacterial infection, manifesting as the formation of abscesses, predominantly in the head area, and cracks on the skin of the extremities. An improvement in the skin condition was observed in presence of symptomatic therapy with antibacterial agents, emollients and retinoids.
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.
2026-06-08 | A Case Report on Preterm Harlequin Ichthyosis with Congenital Hypothyroidism: Management with Early Retinoid Therapy and Multidisciplinary Care
Introduction: Harlequin ichthyosis (HI) is the most severe and rarest form of autosomal recessive congenital ichthyosis, often presenting with a distinctive, devastating phenotype. Affected neonates are typically born prematurely with thick, keratinous plates, severe ectropion, eclabium, and contractures. Historically, the condition was almost universally fatal in the neonatal period due to sepsis, respiratory failure, and dehydration. Advancements in neonatal intensive care, early systemic retinoid therapy, and a multidisciplinary approach have significantly improved survival and long-term outcomes. We report a case of a preterm male infant with HI and congenital hypothyroidism, managed successfully with early oral acitretin. Case presentation: A 33 weeks and 5 days male infant was born to a 22 year old primigravida mother by a lower segment C-section. The parents are third degree consanguineous. The mother had a brother with the same disease who died at 10 months. Upon birth, the baby cried out immediately and had an APGAR score of 8 (1 minute) and 9 (5 minutes). The baby weighed 1810 g. A clinical examination of the baby showed the typical signs of HI: diffuse dry thickened skin scaling with fissures; bilateral contracted fingers; severely ectropion on both eyes; and loss of eyelashes. Infant was taken to NICU via an incubator. Management of HI and resulting outcomes: From day one, there was a multidisciplinary approach to the care of this infant through neonatologists, dermatologists, and ophthalmologists. Supportive care included strict temperature maintenance. Meticulous skin care was performed with use of liquid paraffin and TBact (topical antibiotics) were placed on cracks to avoid secondary infections. Acitretin was started on day one at 1 mg/kg/day (systemic) for one month. For the first 6 hours of life, the infant required hooded oxygen due to mild respiratory distress and returned to room air after that period. Routine screening demonstrated a TSH of 19.9 uIU/mL and diagnosis of congenital hypothyroidism was made; therefore, baby was started on thyroxine. Complete blood count and liver function tests were within normal limits. Blood culture on day 1 was positive for Klebsiella pneumoniae; treated with 14 days of IV Piperacillin-Tazobactam and Gentamicin. The use of early retinoid therapy and aggressive management led to a favorable outcome for this infant diagnosed with Harlequin Ichthyosis. Whole exome sequencing established that this infant had a homozygous missense variant in the ABCA12 gene (c.4621G>A, p.Glu1541Lys); it was determined to be a variant of uncertain significance (VUS) although, in this case, it was closely associated with the clinical phenotype. This infant's skin condition improved remarkably over the next few weeks, with a significant decrease in scaling. On day 21 of life, with a corrected gestational age of 36 weeks, this infant was discharged hemodynamically stable, had demonstrated good weight gain, and was on a tapering dose of acitretin (0.75 mg/kg/day at first follow-up visit after discharge).
gene therapies
2026-09-08 | Gene therapy for genodermatoses at the crossroads of innovation and clinical translation.
Inherited genodermatoses are a heterogeneous group of rare monogenic disorders. Among these, epidermolysis bullosa (EB) and ichthyoses represent paradigmatic disorders characterized by severe skin fragility and hyperkeratosis, respectively, and impaired barrier function, often with profound effects on quality of life and systemic health. Current management remains largely palliative, underscoring the urgent need for disease-modifying therapies. Over the past 2 decades, advances in epithelial stem cell biology, vector engineering and genome editing technologies have transformed the therapeutic landscape for genodermatoses. Ex vivo gene therapy has provided the first proof that genetically corrected epidermal stem cells can achieve long-term tissue regeneration in EB skin patients, establishing a new paradigm for regenerative medicine. In parallel, the emergence of programmable genome engineering platforms, including CRISPR/Cas nucleases, base editors and prime editors, have enabled increasingly precise strategies for mutation-specific correction in both recessive and dominant disorders. Furthermore, the development of in vivo topical approaches is expanding the possibility of directly targeting the skin. Despite these advances, substantial translational barriers continue to limit broad clinical implementation. Efficient and durable targeting of epidermal stem cells within a highly regenerative tissue, together with safe delivery across the skin barrier, stringent control of off-target activity, scalable manufacturing and demonstration of long-term safety, remain major challenges for the clinical translation of these approaches. In this Review, we discuss the current state of gene therapy for genodermatoses, highlighting key clinical milestones, emerging genome editing technologies and next-generation delivery systems. We further examine the biological and regulatory challenges that need to be overcome to bridge the gap between experimental innovation and clinically accessible therapies for patients with inherited skin diseases.
2026-06-23 | P34 Targeted base editing restores genetic integrity in epidermolytic ichthyosis patient cells
Abstract Introduction and aims Epidermolytic ichthyosis (EI) is an epidermal differentiation disorder caused by pathogenic variants in KRT1 and KRT10, reducing cytoskeletal stability in suprabasal keratinocytes. Many of these pathogenic variants are single-nucleotide substitutions suitable for correction by base editing, a precise CRISPR-based genome editing approach that enables targeted conversion of one nucleotide to another. We propose that genetic correction of EI-associated variants using base editors could offer a curative therapeutic strategy. Methods Our current work utilizes two-dimensional, patient-derived keratinocyte and fibroblast cultures heterozygous for the KRT10c.467G>A variant. These keratinocytes display characteristic EI phenotypes, including cytoskeletal abnormalities, reduced proliferative potential, flattened morphology from passage three, and senescence by passage five. This has prompted us to develop and validate immortalized EI keratinocyte lines for future studies. In contrast, EI fibroblasts exhibit rapid growth and long-term culture stability, making them valuable for initial optimization of editing conditions. Our initial editing has utilized lipid nanoparticle (LNP)-delivered ABE8e adenine base editor, and assessed outcomes by Sanger and amplicon sequencing. Results To date, we have performed base editing on primary EI keratinocytes using the ABE8e. We achieved 100% on-target editing efficiency, accompanied by a 23% undesired bystander edit. We are now optimizing ABE8e dosage to minimize bystander effects and are synthesizing a next-generation ABE9 variant with a narrower editing window to avoid bystander edits at this locus. Next, we will assess functional correction of the pathogenic variant through protein analysis and visualization of cytoskeletal aggregates under stress conditions. For further validation, we aim to establish a three-dimensional EI skin model and evaluate topical delivery of our editing system using LNP formulations currently being developed in our laboratory. Conclusions In conclusion, our findings demonstrate the feasibility of base editing as an efficient gene-editing strategy for EI and outline a translational pipeline that could ultimately provide a new therapeutic avenue for patients.
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.
proteins
2026-08-18 | [Use of recombinant nerve growth factor in the treatment of neurotrophic keratitis associated with ichthyosis follicularis, atrichia, and photophobia (IFAP syndrome)].
Treatment of neurotrophic keratitis (NTK) remains one of the challenges in ophthalmology. This article presents a case of successful use of recombinant nerve growth factor in the treatment of NK in a child with ichthyosis follicularis, atrichia, and photophobia (IFAP syndrome), type 2. The child had blepharospasm and extensive corneal epithelial defects with superficial vascularization in both eyes since birth. Despite local trophic therapy, the erosions persisted. The child was diagnosed with the systemic condition «ichthyosis follicularis, atrichia, and photophobia (IFAP syndrome), type 2». Despite long-term trophic therapy, corneal epithelial defects in both eyes persisted. Due to the ineffectiveness of standard treatment, the patient was prescribed cenegermin drug. Complete epithelialization of the epithelial defects was observed by day 34 of specific neurotrophic therapy, and a reliable corneal pain response appeared during the cotton wisp test. Complete restoration of the epithelial layer and corneal sensitivity persisted two months after completion of the treatment course. The use of the drug cenegermin effectively restored the epithelium and corneal sensitivity in long-persisting corneal erosions in a child with ichthyosis follicularis, atrichia, and photophobia (IFAP syndrome).
2026-08-01 | Ichthyosis prematurity syndrome mimicking hyper‐ IgE syndrome due to a novel SLC27A4 variant
For transparency, the peer review documents associated with this article are available at https://doi.org/10.1111/pai.70459. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
2026-07-15 | Physiological and Behavioural Characterisation of a Novel Steroid Sulfatase-Deficient Mouse.
Steroid sulfatase (STS) cleaves sulphate groups from steroid hormones. In humans, STS deficiency is associated with X-linked ichthyosis, an increased predisposition to neurodevelopmental and mood conditions (including Attention Deficit Hyperactivity Disorder, autism, depression and anxiety), and cardiac arrhythmia risk. Until recently, no single-gene 'knockout' mammalian model existed; previous work in such a model is limited to skin phenotypes. We generated a novel C57BL/6J mouse model with a deletion in exon 2 of Sts. We examined gene expression and enzyme activity in liver and brain samples of homozygous mice, and assessed the breeding performance and health of male and female deletion-carriers. Subsequently, we compared performance across a range of behavioural paradigms in wildtype and homozygous male and female mice: elevated plus maze, open field, rotarod, spontaneous alternation, and acoustic startle/prepulse inhibition. We also investigated serum steroid hormone levels by liquid chromatography-mass spectrometry and measured heart weights and two morphological indices (bodyweight/tibia length) post mortem. Homozygous mice almost completely lacked STS expression/activity. Genetically-altered mice exhibited grossly-normal breeding performance, health, and endocrinology. Homozygous mice were more active and had higher normalised heart weights than wildtype mice. We also found significant genotype × sex interactions on bodyweight and on two behavioural measures (potentially reflecting lower anxiety in homozygous males and heightened anxiety in homozygous females). The 'Sts-deletion' mouse represents an experimentally-tractable model in which to identify and characterise phenotypes associated with STS deficiency. The mechanistic basis of the associations described here requires further investigation, and whether these translate to humans remains to be tested.
2026-06-01 | Lamellar ichthyosis: A genetic review of a rare skin disorder
Lamellar ichthyosis is a condition that mainly affects the skin. Infants with this condition are typically born with a tight, clear sheath covering their skin called a collodion membrane. This membrane usually dries and peels off during the first few weeks of life, and then it becomes obvious that affected babies have scaly skin, and eyelids and lips that are turned outward. People with lamellar ichthyosis typically have large, dark, plate-like scales covering their skin on most of their body. Infants with lamellar ichthyosis may develop infections, an excessive loss of fluids (dehydration), and respiratory problems. Affected individuals may also have hair loss (alopecia), abnormally formed fingernails and toenails (nail dystrophy), a decreased ability to sweat (hypohidrosis), an increased sensitivity to heat, and a thickening of the skin on the palms of the hands and soles of the feet (keratoderma). Less frequently, affected individuals have reddened skin (erythema) and joint deformities (contractures).(1)
2026-04-01 | Mutation mapping and functional characterization of a missense mutation p.Arg228Cys in ALDH3A2 gene causing Sjögran-Larson syndrome.
BACKGROUND: This study examined a consanguineous family affected by autosomal recessive Sjögren-Larsson syndrome (SLS) that is characterized by congenital ichthyosis, intellectual disabilities, and spastic diplegia. SLS is a rare inborn error of lipid metabolism resulting from mutations in the ALDH3A2 gene, leading to a deficiency in the fatty aldehyde dehydrogenase (FALDH) enzyme. METHODS AND RESULTS: We employed homozygosity-by-descent (HBD) mapping followed by whole-exome sequencing (WES) for mutation identification and conducted protein structure modeling and enzyme assays to determine the functional consequences of the mutation. HBD mapping and WES in a patient with SLS identified a recurrent missense mutation NM_000382:c.C682T: p.(Arg228Cys) in the 5th exon of the ALDH3A2 gene. Protein structural modeling and docking studies indicated significant alterations in the structural and interactional properties of the mutant ALDH3A2. Enzyme analysis of serum extracts revealed reduced ALDH enzyme activity in both affected and carrier individuals. CONCLUSION: This study confirmed the association between diminished ALDH activity and the severity of clinical manifestations, including developmental delay, ichthyosis, spasticity, and cognitive disability. To our knowledge, this is the first report of an ALDH3A2 mutation in a Pakistani family. Our findings reinforce evidence that the NM_000382:c.C682T: p.(Arg228Cys) mutation in ALDH3A2 is causative of SLS, underscoring the importance of genetic counseling and early biochemical diagnosis for families at risk of SLS.
antibodies
2026-08-26 | Real-World Effectiveness of Secukinumab in Congenital Ichthyoses: A Retrospective Monocentric Case Series.
Background/Objectives: Congenital ichthyoses (CI) are inherited disorders of keratinization characterized by epidermal barrier dysfunction, abnormal desquamation, and variable degrees of inflammation. Increasing evidence suggests a role for IL-23/Th17-mediated immune dysregulation in some CI subtypes, providing a rationale for targeted biologic therapies. Secukinumab, an anti-IL-17A monoclonal antibody, has emerged as a potential therapeutic option, although real-world evidence remains limited. This study evaluated the effectiveness of secukinumab in adult patients with severe CI. Methods: We performed a retrospective monocentric case series including eight adult patients with severe congenital ichthyosis treated with secukinumab for at least six months and followed for up to 56 months. Clinical outcomes included Investigator Global Assessment (IGA) scores for erythema, scaling, scalp involvement, and palmoplantar hyperkeratosis, together with pruritus assessed by Numeric Rating Scale (NRS). Results: Erythema and scaling showed most of their improvement during the first six months of treatment, after which mean clinical scores remained relatively stable throughout follow-up. At the last available assessment, improvement rates were 100% for erythema, 87.5% for trunk and limb scaling, 100% for scalp scaling, and 75% for palmoplantar hyperkeratosis. Hyperkeratosis showed a less pronounced response than inflammatory manifestations. Pruritus improved within the first 3-4 months of treatment and was sustained over time, with mean NRS scores decreasing from 6.5 at baseline to below 4 within 3-4 months. No discontinuations due to adverse events or lack of efficacy were recorded. Conclusions: Secukinumab was associated with clinically meaningful improvements in inflammatory manifestations of CI, particularly erythema and pruritus, while showing a more limited effect on hyperkeratotic features. These findings support the potential role of IL-17 inhibition in selected CI phenotypes.
2026-07-28 | Dupilumab Provides Meaningful Clinical Responses in Harlequin Ichthyosis (ABCA12-nEDD): A Report of Two Cases.
Harlequin ichthyosis (HI) is a rare epidermal differentiation disorder characterized by thick hyperkeratotic plates, fissuring, and high neonatal morbidity. Long-term management remains challenging. We report two children with genetically confirmed HI who demonstrated meaningful improvement in pruritus, erythema, scaling, and overall well-being following dupilumab therapy, suggesting a potential role for IL-4/IL-13 blockade as an adjunct or alternative treatment in HI.
2026-07-06 | The role of dupilumab in skin microbiome shifts in the Netherton genodermatosis: a case report and review of literature.
Skin dysbiosis plays a crucial role in inflammatory skin diseases, particularly in genodermatoses such as Netherton syndrome (NS). This case report aimed to investigate changes in the skin microbiome of a patient with Netherton syndrome before and during dupilumab therapy, with the goal of expanding the limited evidence currently available on this topic. We report the case of a 35-year-old woman diagnosed with NS at birth, who, prior to dupilumab therapy, presented with atopic dermatitis (AD), ichthyosis linearis circumflexa, and severe pruritus. Dupilumab therapy was initiated, and skin swabs were collected from lesional sites at three different time points: at baseline, after 1 month, and after 1 year of continuous dupilumab therapy. At baseline, a microbiome analysis revealed low microbial diversity with a predominance of Pantoea and Pseudomonas species. After 1 year, a significant increase in microbial diversity, with a predominance of Staphylococcus species and an increase in Malassezia species, was observed. Clinically, the patient experienced remission in parallel with these microbiome shifts. Post-treatment, the skin microbiome showed increased microbial diversity and re-establishment of beneficial commensals, more closely resembling healthy skin. The findings of this case report underscore the role of dupilumab in restoring a healthy skin microbiome along with symptomatological and clinical improvement in the genodermatosis Netherton syndrome.
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.
2026-04-19 | Selective Reduction in Scale Thickness After IL ‐13 Blockade with Lebrikizumab in a Lamellar Ichthyosis Phenotype
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. Figure S1: jde70280-sup-0001-FigureS1.docx. Additional clinical images demonstrating changes in scale thickness. Representative close-up images of the lower leg at baseline (0 weeks) and after 44 weeks of lebrikizumab treatment. Although image resolution is limited, a reduction in the thickness of lamellar scales can be appreciated while the overall polygonal pattern of scaling is preserved. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
other
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.
2026-03-28 | Macrophage Extracellular Vesicles: Therapeutic Strategies for Corneal Fibrosis in Rare Diseases.
Corneal scarring (fibrosis) is a blinding condition affecting millions of sufferers worldwide. It is not only in common ocular injuries but also in genetically inherited rare diseases such as epidermolysis bullosa (EB), keratitis-ichthyosis-deafness (KID) syndrome and aniridia. In rare diseases like EB or KID syndrome, corneal fibrosis arises from chronic inflammation, structural instability and neuro-immune dysfunction driven by genetic mutations. Current therapies are not effective in addressing the needs of affected individuals due to limited efficacy nor the considerable side effects of treatment. Extracellular vesicles (EVs) from various cell types such as mesenchymal stem cells not only possess high biocompatibility but have shown promising results in limiting corneal fibrosis. Rather than targeting a single molecular signaling pathway, EVs which contain regulatory RNAs and proteins are hypothesized to target multiple pathways synergistically. Macrophage-derived EVs (Mac-EVs) with an immunomodulatory nature may offer a promising therapeutic effect for rare diseases. Various EV delivery platforms have been proposed in preclinical studies. However, not all of these delivery techniques are appropriate for the cornea in rare diseases. In this review, we delineate recent advances in understanding corneal fibrosis from a rare disease point of view, including the impact on corneal immune cells and nerves. We then provide critical considerations of therapeutic development for corneal fibrosis in rare diseases. Furthermore, we used this knowledge to comprehensively consider the various EVs, especially Mac-EVs, synthesis methods and delivery techniques. Ultimately, this review aims to enable biomolecule researchers to develop EV-based therapies that not only exert anti-fibrotic effects but also address clinical compatibility for corneal fibrosis in rare diseases.
2025-12-22 | Gapmer Antisense Oligonucleotide Targeting E-Cadherin Rescues Abnormal Keratinization in X-Linked Ichthyosis Models.
X-linked ichthyosis (XLI) is an inherited disorder of keratinization resulting from a deficiency of steroid sulfatase (STS), for which no effective therapy is currently available. E-cadherin, a key upstream regulator of keratinocyte differentiation, has been found to be markedly overexpressed in STS-deficient HaCaT cells, suggesting its potential as a therapeutic target in XLI. To investigate the functional role of E-cadherin and explore its therapeutic potential, we introduced mutations into the N-terminal region of E-cadherin and examined the resulting effects on keratinocyte differentiation. In addition, a microRNA (miR-6766) and a rationally designed gapmer antisense oligonucleotide (gASO) targeting the same E-cadherin mRNA sequence were employed to modulate E-cadherin expression in HaCaT cells. Mutations within the N-terminal region of E-cadherin significantly reduced keratin 1 expression, underscoring the critical role of this domain in regulating keratinocyte differentiation. Treatment with miR-6766 led to downregulation of both early and terminal differentiation markers. Building on this, the gASO modified with 2'-O-methoxyethyl and phosphorothioate linkages exhibited enhanced potency and stability, resulting in stronger suppression of E-cadherin and keratin 1 expression compared with miR-6766 (maintained 37.7% greater inhibition of E-cadherin at 96 h and 35.7% greater inhibition of keratin 1 at 96 h). Furthermore, gASO treatment induced a concentration-dependent reduction in early (keratin 1 and keratin 10) and terminal (transglutaminase 1, involucrin, and loricrin) differentiation markers. These findings demonstrate that an E-cadherin-targeting gASO effectively suppresses abnormal keratinocyte differentiation and may serve as a promising therapeutic strategy for X-linked ichthyosis.
2025-10-27 | Targeting E-cadherin with a gapmer antisense oligonucleotide for treating X-linked ichthyosis
X-linked ichthyosis (XLI) is a keratinization disorder steroid sulfatase (STS) deficiency, with no effective treatment currently available. E-cadherin, an essential upstream regulator of keratinocyte differentiation, was markedly overexpressed in STS-deficient HaCaT cells, indicating its potential as a therapeutic target. Additionally, mutations introduced into the N-terminal region of E-cadherin significantly reduced keratin 1 expression, underscoring the critical role of this domain in regulating keratin 1 expression in keratinocytes. Treatment with miR-6766, which targets E-cadherin mRNA, downregulated early and terminal keratinocyte differentiation markers. Building on these results, a gapmer antisense oligonucleotide (gASO) with 2′-O-Methoxyethyl-modifications and phosphorothioate linkages was rationally designed to target the same E-cadherin RNA sequence recognized by miR-6766, offering enhanced potency and stability. gASO treatment resulted in stronger suppression of E-cadherin and keratin 1 expression than that of miR-6766, indicating superior inhibitory efficacy. gASO treatment at various concentrations (0, 25, 50, or 100 nM) in HaCaT cells led to a dose-dependent reduction in the expression of early (keratin 1 and keratin 10) and terminal (Transglutaminase1, involucrin, and loricrin) differentiation markers. A similar reduction in differentiation marker expression was observed under STS-deficient conditions. Therefore, this study aimed to evaluate the therapeutic potential of an E-cadherin-targeting gASO as a novel strategy to suppress abnormal keratinocyte differentiation in XLI. These findings suggest that a gASO targeting E-cadherin may serve as a promising therapeutic strategy for XLI by effectively suppressing keratinocyte differentiation.
2024-08-14 | Treating epidermolytic ichthyosis and ichthyosis with confetti with epidermal autografts cultured from revertant skin.
No efficient treatment has yet been established for epidermolytic ichthyosis (EI), which is caused by pathogenic variants of KRT1 or KRT10. Patients with ichthyosis with confetti (IWC) have multiple normal-appearing spots, caused by the revertant somatic recombination of pathogenic variants that occurs at each spot independently. Additionally, some patients with EI have large areas of normal skin due to revertant postzygotic mosaicism. To assess the feasibility of transplanting cultured epidermal autografts (CEAs) produced from revertant epidermal keratinocytes in patients with EI and IWC. We performed a clinical trial of treatment with CEAs produced from each patient's own revertant epidermal keratinocytes as a proof-of-concept study. This was a single-arm, open, unmasked, uncontrolled, single-assignment, treatment-purpose study. The primary outcome was the percentage area that lacked recurrence of ichthyosis lesions 4 weeks after the final transplant. The secondary outcome was the percentage area lacking recurrence of ichthyosis lesions 24 weeks after the initial transplantation. The trial was registered with the Japan Registry of Clinical Trials (jRCTb041190097). We successfully produced CEAs from genetically confirmed revertant skin from two patients with mosaic EI and from one patient with IWC and confirmed by amplicon sequencing and droplet digital polymerase chain reaction analysis that the CEAs mainly consisted of revertant wild-type cells. Single-cell RNA sequencing analysis confirmed the normal proliferation and safety profiling of CEAs. CEAs were transplanted onto desquamated lesional sites in the patients. Four weeks post-transplantation, the percentage area lacking recurrence of ichthyosis lesions in the three patients was 40%, 100% and 100% respectively, although recurrence of ichthyosis lesions was seen at the site of CEA transplantation in all three patients at 24 weeks post-transplantation. CEAs from normal skin have the potential to be a safe and local treatment option for EI and IWC. Epidermolytic ichthyosis is a rare skin condition that causes redness, blistering and thickening of the skin. There is currently no effective treatment for the disease, which is caused by mutations in the genes KRT1 or KRT10. People with a type of the disease called ‘ichthyosis with confetti’ have many normal-appearing spots that are caused by the natural repair of the gene mutations. Some people with epidermolytic ichthyosis have large areas of healthy skin as a result of genetic mutations having been corrected. In this study, we successfully produced skin grafts from the healthy skin of two patients with epidermolytic ichthyosis and one with ‘ichthyosis with confetti’. We confirmed that the skin grafts mainly consisted of repaired skin cells. A technique called ‘single-cell RNA sequencing’ confirmed the skin cells in the skin grafts behaved like healthy skin cells and that the grafts were safe. Overall, our study findings suggest that skin grafts taken from skin consisting of genetically normal keratinocytes that have undergone self-repair have potential to be a safe treatment option for patients with severe epidermolytic ichthyosis and ‘ichthyosis with confetti’.
small molecules
2026-09-11 | X-linked ichthyosis with seizures, ADHD, and autism spectrum disorder: a case report with an uncommon clinical presentation.
X-linked ichthyosis (XLI) is a genetic condition characterized by scaly skin due to steroid sulfatase (STS) deficiency, often associated with additional neurodevelopmental issues. A 10-year-old male child was admitted to the dermatology department. The child had been born prematurely at 26 weeks' gestation with a low birth weight of 1.6 kg. He presented with seizures characterized by abnormal upper-limb movements and was diagnosed with congenital ichthyosis. The child exhibited delayed language and motor development, learning difficulties, microcephaly, and dry, scaly skin, which he habitually peeled and ingested. Genetic analysis (single-nucleotide polymorphism and combined comparative genomic hybridization) revealed a 1.65 Mb deletion on chromosome Xp22.31 affecting the STS gene and other adjacent genes. The patient had low STS enzyme activity (3.5 nmol/hour/protein) in adipose tissue. Neuroimaging showed no structural abnormalities, though an electroencephalogram indicated mild slowing. Given the established association between STS deletions and neurodevelopmental as well as psychiatric comorbidities, early recognition of emerging psychiatric features is essential. Given the established association between STS deletions and neurodevelopmental as well as psychiatric comorbidities, early recognition of emerging psychiatric manifestations is essential. Management should follow evidence-based recommendations for first-episode or early psychotic symptoms, emphasizing careful assessment, individualized pharmacological treatment when indicated, and multidisciplinary psychosocial support. Such an approach may improve clinical stabilization while avoiding premature diagnostic labeling. This case highlights the importance of early genetic diagnosis and personalized treatment approaches, integrating dermatological, neurological, and psychiatric care to optimize outcomes in XLI.
2026-09-01 | Long-term improvement in congenital ichthyosis vulgaris with individualized homeopathic treatment at Dr Batra’s® Homeopathy Clinic: a case report
Ichthyosis vulgaris is a chronic inherited keratinization disorder characterized by generalized xerosis, scaling, hyperpigmentation, and recurrent exacerbations, significantly affecting quality of life. Conventional management primarily relies on emollients and topical therapies with limited long-term control. This case report describes a school-going female child suffering from congenital ichthyosis vulgaris since birth, with persistent dryness, scaling, hyperpigmentation, itching, and recurrent flare-ups despite prolonged conventional treatment including topical steroids. Detailed constitutional assessment revealed a chilly, intellectually bright, disciplined child with good academic performance and active participation in extracurricular activities. Individualized homeopathic treatment resulted in progressive reduction in scaling, dryness, itching, hyperpigmentation, and skin thickening, with regeneration of healthy skin. Significant clinical improvement was observed during follow-up, reducing dependence on topical steroid applications. This case highlights the role of individualized homeopathic treatment in the management of congenital ichthyosis vulgaris at Dr Batra’s® Homeopathy Clinic.
2026-07-03 | Two clinical observations of keratitis-ichthyosis-deafness syndrome (KID syndrome)
Keratitis-ichthyosis-deafness (KID) syndrome is a rare genetic disorder characterized by erythrokeratoderma, vascular keratitis and sensorineural hearing loss. The disease develops as a result of a mutation in the GJB2 gene encoding the connexin 26 protein, which is expressed in the epidermis and is involved in the formation of gap junctions between epithelial cells that carry out transport of ions and small molecules. Changes in the skin are usually noticed from birth, they may manifest as erythrokeratoderma, psoriasis-like lesions, hyperkeratosis foci, palmoplantar keratoderma. Alopecia totalis progresses with age. Congenital bilateral prelingual sensorineural hearing loss is diagnosed in 90% of patients, and neovascular keratitis — in 95%. Half of the patients experience persistent skin infection, and the development of benign and malignant tricholemmal tumors as well as squamous cell carcinoma is possible. In recent years, a search for drugs capable of restoring the patency of gap junction channels, which significantly improves the skin condition in research animals, has been performed. Effective therapeutic agents will be discovered in the future. Currently, patients are primarily treated symptomatically. We present a case report of two patients suffering from KID syndrome. In both cases, the disease began from birth and was manifested by ichthyosiform erythroderma, palmoplantar keratoderma, alopecia totalis, onychodystrophy, sensorineural deafness, chronic keratitis and photophobia. Despite the full set of diagnostic symptoms, the first patient was diagnosed with KID syndrome at the age of 29, and the second patient — at the age of 10. In the second case, genetic analysis confirmed the GJB2 gene mutation (p.Asp50Asn). The course of the disease was accompanied by a persistent bacterial infection, manifesting as the formation of abscesses, predominantly in the head area, and cracks on the skin of the extremities. An improvement in the skin condition was observed in presence of symptomatic therapy with antibacterial agents, emollients and retinoids.
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.
2026-06-08 | A Case Report on Preterm Harlequin Ichthyosis with Congenital Hypothyroidism: Management with Early Retinoid Therapy and Multidisciplinary Care
Introduction: Harlequin ichthyosis (HI) is the most severe and rarest form of autosomal recessive congenital ichthyosis, often presenting with a distinctive, devastating phenotype. Affected neonates are typically born prematurely with thick, keratinous plates, severe ectropion, eclabium, and contractures. Historically, the condition was almost universally fatal in the neonatal period due to sepsis, respiratory failure, and dehydration. Advancements in neonatal intensive care, early systemic retinoid therapy, and a multidisciplinary approach have significantly improved survival and long-term outcomes. We report a case of a preterm male infant with HI and congenital hypothyroidism, managed successfully with early oral acitretin. Case presentation: A 33 weeks and 5 days male infant was born to a 22 year old primigravida mother by a lower segment C-section. The parents are third degree consanguineous. The mother had a brother with the same disease who died at 10 months. Upon birth, the baby cried out immediately and had an APGAR score of 8 (1 minute) and 9 (5 minutes). The baby weighed 1810 g. A clinical examination of the baby showed the typical signs of HI: diffuse dry thickened skin scaling with fissures; bilateral contracted fingers; severely ectropion on both eyes; and loss of eyelashes. Infant was taken to NICU via an incubator. Management of HI and resulting outcomes: From day one, there was a multidisciplinary approach to the care of this infant through neonatologists, dermatologists, and ophthalmologists. Supportive care included strict temperature maintenance. Meticulous skin care was performed with use of liquid paraffin and TBact (topical antibiotics) were placed on cracks to avoid secondary infections. Acitretin was started on day one at 1 mg/kg/day (systemic) for one month. For the first 6 hours of life, the infant required hooded oxygen due to mild respiratory distress and returned to room air after that period. Routine screening demonstrated a TSH of 19.9 uIU/mL and diagnosis of congenital hypothyroidism was made; therefore, baby was started on thyroxine. Complete blood count and liver function tests were within normal limits. Blood culture on day 1 was positive for Klebsiella pneumoniae; treated with 14 days of IV Piperacillin-Tazobactam and Gentamicin. The use of early retinoid therapy and aggressive management led to a favorable outcome for this infant diagnosed with Harlequin Ichthyosis. Whole exome sequencing established that this infant had a homozygous missense variant in the ABCA12 gene (c.4621G>A, p.Glu1541Lys); it was determined to be a variant of uncertain significance (VUS) although, in this case, it was closely associated with the clinical phenotype. This infant's skin condition improved remarkably over the next few weeks, with a significant decrease in scaling. On day 21 of life, with a corrected gestational age of 36 weeks, this infant was discharged hemodynamically stable, had demonstrated good weight gain, and was on a tapering dose of acitretin (0.75 mg/kg/day at first follow-up visit after discharge).
gene therapies
2026-09-08 | Gene therapy for genodermatoses at the crossroads of innovation and clinical translation.
Inherited genodermatoses are a heterogeneous group of rare monogenic disorders. Among these, epidermolysis bullosa (EB) and ichthyoses represent paradigmatic disorders characterized by severe skin fragility and hyperkeratosis, respectively, and impaired barrier function, often with profound effects on quality of life and systemic health. Current management remains largely palliative, underscoring the urgent need for disease-modifying therapies. Over the past 2 decades, advances in epithelial stem cell biology, vector engineering and genome editing technologies have transformed the therapeutic landscape for genodermatoses. Ex vivo gene therapy has provided the first proof that genetically corrected epidermal stem cells can achieve long-term tissue regeneration in EB skin patients, establishing a new paradigm for regenerative medicine. In parallel, the emergence of programmable genome engineering platforms, including CRISPR/Cas nucleases, base editors and prime editors, have enabled increasingly precise strategies for mutation-specific correction in both recessive and dominant disorders. Furthermore, the development of in vivo topical approaches is expanding the possibility of directly targeting the skin. Despite these advances, substantial translational barriers continue to limit broad clinical implementation. Efficient and durable targeting of epidermal stem cells within a highly regenerative tissue, together with safe delivery across the skin barrier, stringent control of off-target activity, scalable manufacturing and demonstration of long-term safety, remain major challenges for the clinical translation of these approaches. In this Review, we discuss the current state of gene therapy for genodermatoses, highlighting key clinical milestones, emerging genome editing technologies and next-generation delivery systems. We further examine the biological and regulatory challenges that need to be overcome to bridge the gap between experimental innovation and clinically accessible therapies for patients with inherited skin diseases.
2026-06-23 | P34 Targeted base editing restores genetic integrity in epidermolytic ichthyosis patient cells
Abstract Introduction and aims Epidermolytic ichthyosis (EI) is an epidermal differentiation disorder caused by pathogenic variants in KRT1 and KRT10, reducing cytoskeletal stability in suprabasal keratinocytes. Many of these pathogenic variants are single-nucleotide substitutions suitable for correction by base editing, a precise CRISPR-based genome editing approach that enables targeted conversion of one nucleotide to another. We propose that genetic correction of EI-associated variants using base editors could offer a curative therapeutic strategy. Methods Our current work utilizes two-dimensional, patient-derived keratinocyte and fibroblast cultures heterozygous for the KRT10c.467G>A variant. These keratinocytes display characteristic EI phenotypes, including cytoskeletal abnormalities, reduced proliferative potential, flattened morphology from passage three, and senescence by passage five. This has prompted us to develop and validate immortalized EI keratinocyte lines for future studies. In contrast, EI fibroblasts exhibit rapid growth and long-term culture stability, making them valuable for initial optimization of editing conditions. Our initial editing has utilized lipid nanoparticle (LNP)-delivered ABE8e adenine base editor, and assessed outcomes by Sanger and amplicon sequencing. Results To date, we have performed base editing on primary EI keratinocytes using the ABE8e. We achieved 100% on-target editing efficiency, accompanied by a 23% undesired bystander edit. We are now optimizing ABE8e dosage to minimize bystander effects and are synthesizing a next-generation ABE9 variant with a narrower editing window to avoid bystander edits at this locus. Next, we will assess functional correction of the pathogenic variant through protein analysis and visualization of cytoskeletal aggregates under stress conditions. For further validation, we aim to establish a three-dimensional EI skin model and evaluate topical delivery of our editing system using LNP formulations currently being developed in our laboratory. Conclusions In conclusion, our findings demonstrate the feasibility of base editing as an efficient gene-editing strategy for EI and outline a translational pipeline that could ultimately provide a new therapeutic avenue for patients.
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.
proteins
2026-08-18 | [Use of recombinant nerve growth factor in the treatment of neurotrophic keratitis associated with ichthyosis follicularis, atrichia, and photophobia (IFAP syndrome)].
Treatment of neurotrophic keratitis (NTK) remains one of the challenges in ophthalmology. This article presents a case of successful use of recombinant nerve growth factor in the treatment of NK in a child with ichthyosis follicularis, atrichia, and photophobia (IFAP syndrome), type 2. The child had blepharospasm and extensive corneal epithelial defects with superficial vascularization in both eyes since birth. Despite local trophic therapy, the erosions persisted. The child was diagnosed with the systemic condition «ichthyosis follicularis, atrichia, and photophobia (IFAP syndrome), type 2». Despite long-term trophic therapy, corneal epithelial defects in both eyes persisted. Due to the ineffectiveness of standard treatment, the patient was prescribed cenegermin drug. Complete epithelialization of the epithelial defects was observed by day 34 of specific neurotrophic therapy, and a reliable corneal pain response appeared during the cotton wisp test. Complete restoration of the epithelial layer and corneal sensitivity persisted two months after completion of the treatment course. The use of the drug cenegermin effectively restored the epithelium and corneal sensitivity in long-persisting corneal erosions in a child with ichthyosis follicularis, atrichia, and photophobia (IFAP syndrome).
2026-08-01 | Ichthyosis prematurity syndrome mimicking hyper‐ IgE syndrome due to a novel SLC27A4 variant
For transparency, the peer review documents associated with this article are available at https://doi.org/10.1111/pai.70459. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
2026-07-15 | Physiological and Behavioural Characterisation of a Novel Steroid Sulfatase-Deficient Mouse.
Steroid sulfatase (STS) cleaves sulphate groups from steroid hormones. In humans, STS deficiency is associated with X-linked ichthyosis, an increased predisposition to neurodevelopmental and mood conditions (including Attention Deficit Hyperactivity Disorder, autism, depression and anxiety), and cardiac arrhythmia risk. Until recently, no single-gene 'knockout' mammalian model existed; previous work in such a model is limited to skin phenotypes. We generated a novel C57BL/6J mouse model with a deletion in exon 2 of Sts. We examined gene expression and enzyme activity in liver and brain samples of homozygous mice, and assessed the breeding performance and health of male and female deletion-carriers. Subsequently, we compared performance across a range of behavioural paradigms in wildtype and homozygous male and female mice: elevated plus maze, open field, rotarod, spontaneous alternation, and acoustic startle/prepulse inhibition. We also investigated serum steroid hormone levels by liquid chromatography-mass spectrometry and measured heart weights and two morphological indices (bodyweight/tibia length) post mortem. Homozygous mice almost completely lacked STS expression/activity. Genetically-altered mice exhibited grossly-normal breeding performance, health, and endocrinology. Homozygous mice were more active and had higher normalised heart weights than wildtype mice. We also found significant genotype × sex interactions on bodyweight and on two behavioural measures (potentially reflecting lower anxiety in homozygous males and heightened anxiety in homozygous females). The 'Sts-deletion' mouse represents an experimentally-tractable model in which to identify and characterise phenotypes associated with STS deficiency. The mechanistic basis of the associations described here requires further investigation, and whether these translate to humans remains to be tested.
2026-06-01 | Lamellar ichthyosis: A genetic review of a rare skin disorder
Lamellar ichthyosis is a condition that mainly affects the skin. Infants with this condition are typically born with a tight, clear sheath covering their skin called a collodion membrane. This membrane usually dries and peels off during the first few weeks of life, and then it becomes obvious that affected babies have scaly skin, and eyelids and lips that are turned outward. People with lamellar ichthyosis typically have large, dark, plate-like scales covering their skin on most of their body. Infants with lamellar ichthyosis may develop infections, an excessive loss of fluids (dehydration), and respiratory problems. Affected individuals may also have hair loss (alopecia), abnormally formed fingernails and toenails (nail dystrophy), a decreased ability to sweat (hypohidrosis), an increased sensitivity to heat, and a thickening of the skin on the palms of the hands and soles of the feet (keratoderma). Less frequently, affected individuals have reddened skin (erythema) and joint deformities (contractures).(1)
2026-04-01 | Mutation mapping and functional characterization of a missense mutation p.Arg228Cys in ALDH3A2 gene causing Sjögran-Larson syndrome.
BACKGROUND: This study examined a consanguineous family affected by autosomal recessive Sjögren-Larsson syndrome (SLS) that is characterized by congenital ichthyosis, intellectual disabilities, and spastic diplegia. SLS is a rare inborn error of lipid metabolism resulting from mutations in the ALDH3A2 gene, leading to a deficiency in the fatty aldehyde dehydrogenase (FALDH) enzyme. METHODS AND RESULTS: We employed homozygosity-by-descent (HBD) mapping followed by whole-exome sequencing (WES) for mutation identification and conducted protein structure modeling and enzyme assays to determine the functional consequences of the mutation. HBD mapping and WES in a patient with SLS identified a recurrent missense mutation NM_000382:c.C682T: p.(Arg228Cys) in the 5th exon of the ALDH3A2 gene. Protein structural modeling and docking studies indicated significant alterations in the structural and interactional properties of the mutant ALDH3A2. Enzyme analysis of serum extracts revealed reduced ALDH enzyme activity in both affected and carrier individuals. CONCLUSION: This study confirmed the association between diminished ALDH activity and the severity of clinical manifestations, including developmental delay, ichthyosis, spasticity, and cognitive disability. To our knowledge, this is the first report of an ALDH3A2 mutation in a Pakistani family. Our findings reinforce evidence that the NM_000382:c.C682T: p.(Arg228Cys) mutation in ALDH3A2 is causative of SLS, underscoring the importance of genetic counseling and early biochemical diagnosis for families at risk of SLS.
antibodies
2026-08-26 | Real-World Effectiveness of Secukinumab in Congenital Ichthyoses: A Retrospective Monocentric Case Series.
Background/Objectives: Congenital ichthyoses (CI) are inherited disorders of keratinization characterized by epidermal barrier dysfunction, abnormal desquamation, and variable degrees of inflammation. Increasing evidence suggests a role for IL-23/Th17-mediated immune dysregulation in some CI subtypes, providing a rationale for targeted biologic therapies. Secukinumab, an anti-IL-17A monoclonal antibody, has emerged as a potential therapeutic option, although real-world evidence remains limited. This study evaluated the effectiveness of secukinumab in adult patients with severe CI. Methods: We performed a retrospective monocentric case series including eight adult patients with severe congenital ichthyosis treated with secukinumab for at least six months and followed for up to 56 months. Clinical outcomes included Investigator Global Assessment (IGA) scores for erythema, scaling, scalp involvement, and palmoplantar hyperkeratosis, together with pruritus assessed by Numeric Rating Scale (NRS). Results: Erythema and scaling showed most of their improvement during the first six months of treatment, after which mean clinical scores remained relatively stable throughout follow-up. At the last available assessment, improvement rates were 100% for erythema, 87.5% for trunk and limb scaling, 100% for scalp scaling, and 75% for palmoplantar hyperkeratosis. Hyperkeratosis showed a less pronounced response than inflammatory manifestations. Pruritus improved within the first 3-4 months of treatment and was sustained over time, with mean NRS scores decreasing from 6.5 at baseline to below 4 within 3-4 months. No discontinuations due to adverse events or lack of efficacy were recorded. Conclusions: Secukinumab was associated with clinically meaningful improvements in inflammatory manifestations of CI, particularly erythema and pruritus, while showing a more limited effect on hyperkeratotic features. These findings support the potential role of IL-17 inhibition in selected CI phenotypes.
2026-07-28 | Dupilumab Provides Meaningful Clinical Responses in Harlequin Ichthyosis (ABCA12-nEDD): A Report of Two Cases.
Harlequin ichthyosis (HI) is a rare epidermal differentiation disorder characterized by thick hyperkeratotic plates, fissuring, and high neonatal morbidity. Long-term management remains challenging. We report two children with genetically confirmed HI who demonstrated meaningful improvement in pruritus, erythema, scaling, and overall well-being following dupilumab therapy, suggesting a potential role for IL-4/IL-13 blockade as an adjunct or alternative treatment in HI.
2026-07-06 | The role of dupilumab in skin microbiome shifts in the Netherton genodermatosis: a case report and review of literature.
Skin dysbiosis plays a crucial role in inflammatory skin diseases, particularly in genodermatoses such as Netherton syndrome (NS). This case report aimed to investigate changes in the skin microbiome of a patient with Netherton syndrome before and during dupilumab therapy, with the goal of expanding the limited evidence currently available on this topic. We report the case of a 35-year-old woman diagnosed with NS at birth, who, prior to dupilumab therapy, presented with atopic dermatitis (AD), ichthyosis linearis circumflexa, and severe pruritus. Dupilumab therapy was initiated, and skin swabs were collected from lesional sites at three different time points: at baseline, after 1 month, and after 1 year of continuous dupilumab therapy. At baseline, a microbiome analysis revealed low microbial diversity with a predominance of Pantoea and Pseudomonas species. After 1 year, a significant increase in microbial diversity, with a predominance of Staphylococcus species and an increase in Malassezia species, was observed. Clinically, the patient experienced remission in parallel with these microbiome shifts. Post-treatment, the skin microbiome showed increased microbial diversity and re-establishment of beneficial commensals, more closely resembling healthy skin. The findings of this case report underscore the role of dupilumab in restoring a healthy skin microbiome along with symptomatological and clinical improvement in the genodermatosis Netherton syndrome.
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.
2026-04-19 | Selective Reduction in Scale Thickness After IL ‐13 Blockade with Lebrikizumab in a Lamellar Ichthyosis Phenotype
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. Figure S1: jde70280-sup-0001-FigureS1.docx. Additional clinical images demonstrating changes in scale thickness. Representative close-up images of the lower leg at baseline (0 weeks) and after 44 weeks of lebrikizumab treatment. Although image resolution is limited, a reduction in the thickness of lamellar scales can be appreciated while the overall polygonal pattern of scaling is preserved. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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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.
2026-03-28 | Macrophage Extracellular Vesicles: Therapeutic Strategies for Corneal Fibrosis in Rare Diseases.
Corneal scarring (fibrosis) is a blinding condition affecting millions of sufferers worldwide. It is not only in common ocular injuries but also in genetically inherited rare diseases such as epidermolysis bullosa (EB), keratitis-ichthyosis-deafness (KID) syndrome and aniridia. In rare diseases like EB or KID syndrome, corneal fibrosis arises from chronic inflammation, structural instability and neuro-immune dysfunction driven by genetic mutations. Current therapies are not effective in addressing the needs of affected individuals due to limited efficacy nor the considerable side effects of treatment. Extracellular vesicles (EVs) from various cell types such as mesenchymal stem cells not only possess high biocompatibility but have shown promising results in limiting corneal fibrosis. Rather than targeting a single molecular signaling pathway, EVs which contain regulatory RNAs and proteins are hypothesized to target multiple pathways synergistically. Macrophage-derived EVs (Mac-EVs) with an immunomodulatory nature may offer a promising therapeutic effect for rare diseases. Various EV delivery platforms have been proposed in preclinical studies. However, not all of these delivery techniques are appropriate for the cornea in rare diseases. In this review, we delineate recent advances in understanding corneal fibrosis from a rare disease point of view, including the impact on corneal immune cells and nerves. We then provide critical considerations of therapeutic development for corneal fibrosis in rare diseases. Furthermore, we used this knowledge to comprehensively consider the various EVs, especially Mac-EVs, synthesis methods and delivery techniques. Ultimately, this review aims to enable biomolecule researchers to develop EV-based therapies that not only exert anti-fibrotic effects but also address clinical compatibility for corneal fibrosis in rare diseases.
2025-12-22 | Gapmer Antisense Oligonucleotide Targeting E-Cadherin Rescues Abnormal Keratinization in X-Linked Ichthyosis Models.
X-linked ichthyosis (XLI) is an inherited disorder of keratinization resulting from a deficiency of steroid sulfatase (STS), for which no effective therapy is currently available. E-cadherin, a key upstream regulator of keratinocyte differentiation, has been found to be markedly overexpressed in STS-deficient HaCaT cells, suggesting its potential as a therapeutic target in XLI. To investigate the functional role of E-cadherin and explore its therapeutic potential, we introduced mutations into the N-terminal region of E-cadherin and examined the resulting effects on keratinocyte differentiation. In addition, a microRNA (miR-6766) and a rationally designed gapmer antisense oligonucleotide (gASO) targeting the same E-cadherin mRNA sequence were employed to modulate E-cadherin expression in HaCaT cells. Mutations within the N-terminal region of E-cadherin significantly reduced keratin 1 expression, underscoring the critical role of this domain in regulating keratinocyte differentiation. Treatment with miR-6766 led to downregulation of both early and terminal differentiation markers. Building on this, the gASO modified with 2'-O-methoxyethyl and phosphorothioate linkages exhibited enhanced potency and stability, resulting in stronger suppression of E-cadherin and keratin 1 expression compared with miR-6766 (maintained 37.7% greater inhibition of E-cadherin at 96 h and 35.7% greater inhibition of keratin 1 at 96 h). Furthermore, gASO treatment induced a concentration-dependent reduction in early (keratin 1 and keratin 10) and terminal (transglutaminase 1, involucrin, and loricrin) differentiation markers. These findings demonstrate that an E-cadherin-targeting gASO effectively suppresses abnormal keratinocyte differentiation and may serve as a promising therapeutic strategy for X-linked ichthyosis.
2025-10-27 | Targeting E-cadherin with a gapmer antisense oligonucleotide for treating X-linked ichthyosis
X-linked ichthyosis (XLI) is a keratinization disorder steroid sulfatase (STS) deficiency, with no effective treatment currently available. E-cadherin, an essential upstream regulator of keratinocyte differentiation, was markedly overexpressed in STS-deficient HaCaT cells, indicating its potential as a therapeutic target. Additionally, mutations introduced into the N-terminal region of E-cadherin significantly reduced keratin 1 expression, underscoring the critical role of this domain in regulating keratin 1 expression in keratinocytes. Treatment with miR-6766, which targets E-cadherin mRNA, downregulated early and terminal keratinocyte differentiation markers. Building on these results, a gapmer antisense oligonucleotide (gASO) with 2′-O-Methoxyethyl-modifications and phosphorothioate linkages was rationally designed to target the same E-cadherin RNA sequence recognized by miR-6766, offering enhanced potency and stability. gASO treatment resulted in stronger suppression of E-cadherin and keratin 1 expression than that of miR-6766, indicating superior inhibitory efficacy. gASO treatment at various concentrations (0, 25, 50, or 100 nM) in HaCaT cells led to a dose-dependent reduction in the expression of early (keratin 1 and keratin 10) and terminal (Transglutaminase1, involucrin, and loricrin) differentiation markers. A similar reduction in differentiation marker expression was observed under STS-deficient conditions. Therefore, this study aimed to evaluate the therapeutic potential of an E-cadherin-targeting gASO as a novel strategy to suppress abnormal keratinocyte differentiation in XLI. These findings suggest that a gASO targeting E-cadherin may serve as a promising therapeutic strategy for XLI by effectively suppressing keratinocyte differentiation.
2024-08-14 | Treating epidermolytic ichthyosis and ichthyosis with confetti with epidermal autografts cultured from revertant skin.
No efficient treatment has yet been established for epidermolytic ichthyosis (EI), which is caused by pathogenic variants of KRT1 or KRT10. Patients with ichthyosis with confetti (IWC) have multiple normal-appearing spots, caused by the revertant somatic recombination of pathogenic variants that occurs at each spot independently. Additionally, some patients with EI have large areas of normal skin due to revertant postzygotic mosaicism. To assess the feasibility of transplanting cultured epidermal autografts (CEAs) produced from revertant epidermal keratinocytes in patients with EI and IWC. We performed a clinical trial of treatment with CEAs produced from each patient's own revertant epidermal keratinocytes as a proof-of-concept study. This was a single-arm, open, unmasked, uncontrolled, single-assignment, treatment-purpose study. The primary outcome was the percentage area that lacked recurrence of ichthyosis lesions 4 weeks after the final transplant. The secondary outcome was the percentage area lacking recurrence of ichthyosis lesions 24 weeks after the initial transplantation. The trial was registered with the Japan Registry of Clinical Trials (jRCTb041190097). We successfully produced CEAs from genetically confirmed revertant skin from two patients with mosaic EI and from one patient with IWC and confirmed by amplicon sequencing and droplet digital polymerase chain reaction analysis that the CEAs mainly consisted of revertant wild-type cells. Single-cell RNA sequencing analysis confirmed the normal proliferation and safety profiling of CEAs. CEAs were transplanted onto desquamated lesional sites in the patients. Four weeks post-transplantation, the percentage area lacking recurrence of ichthyosis lesions in the three patients was 40%, 100% and 100% respectively, although recurrence of ichthyosis lesions was seen at the site of CEA transplantation in all three patients at 24 weeks post-transplantation. CEAs from normal skin have the potential to be a safe and local treatment option for EI and IWC. Epidermolytic ichthyosis is a rare skin condition that causes redness, blistering and thickening of the skin. There is currently no effective treatment for the disease, which is caused by mutations in the genes KRT1 or KRT10. People with a type of the disease called ‘ichthyosis with confetti’ have many normal-appearing spots that are caused by the natural repair of the gene mutations. Some people with epidermolytic ichthyosis have large areas of healthy skin as a result of genetic mutations having been corrected. In this study, we successfully produced skin grafts from the healthy skin of two patients with epidermolytic ichthyosis and one with ‘ichthyosis with confetti’. We confirmed that the skin grafts mainly consisted of repaired skin cells. A technique called ‘single-cell RNA sequencing’ confirmed the skin cells in the skin grafts behaved like healthy skin cells and that the grafts were safe. Overall, our study findings suggest that skin grafts taken from skin consisting of genetically normal keratinocytes that have undergone self-repair have potential to be a safe treatment option for patients with severe epidermolytic ichthyosis and ‘ichthyosis with confetti’.
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Drug Discovery Landscape
1 orphan drug designation for Ichthyosis.
1 orphan drug designation for Ichthyosis.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
urea | small molecules | FDA | Orenova Group, LLC |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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