RARE DISEASE
Recessive X-linked ichthyosis
Recessive X-linked ichthyosis
Recessive X-linked ichthyosis
Synonyms: RXLI, Steroid sulfatase deficiency, X-linked ichthyosis, XLI
Synonyms: RXLI, Steroid sulfatase deficiency, X-linked ichthyosis, XLI
Synonyms: RXLI, Steroid sulfatase deficiency, X-linked ichthyosis, XLI
Drug discovery
2
drugs
With orphan designations
Overview
Recessive X-linked ichthyosis (RXLI) is an X-linked genetic disorder caused by STS gene mutations, leading to steroid sulfatase deficiency. It primarily affects males (1:2,000-6,000) with generalized dark brown/gray scales most prominent on extensor surfaces, neck, and trunk, sparing palms/soles [1][5][7]. Associated features include cryptorchidism (5-20%), asymptomatic corneal opacities (50%), and neurodevelopmental disorders like ADHD (40%) [5][7][12]. Diagnosis combines clinical findings, biochemical testing (STS activity), and genetic analysis [1][5].
Categories: rare genetic diseases, rare ophthalmic disorders, rare skin diseases
Research Papers
98 drug discovery papers about Recessive X-linked ichthyosis, with 2 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
98 drug discovery papers about Recessive X-linked 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
small molecules
2026-07-02 | Central precocious puberty as the initial manifestation of multisystem involvement caused by de novo heterozygous KMT2B mutation and STS hemizygous deletion: a case report.
Pathogenic loss-of-function variants in the KMT2B gene cause a rare autosomal dominant disorder with two major phenotypes: KMT2B-related dystonia (DYT-KMT2B) and KMT2B-related neurodevelopmental disorder (KMT2B-NDD). Central precocious puberty (CPP) has been documented as a comorbidity in patients with DYT-KMT2B, but has not been reported as the primary clinical manifestation of the disorder in patients without dystonia. Deletions or pathogenic variants in the STS gene cause X-linked ichthyosis (XLI). Concurrent KMT2B and STS alterations have not been well characterised, and GnRH analogue therapy for CPP in KMT2B-related disorders has not been previously described. An 8-year-10-month-old male presented with a 1-2-year history of progressive increase in penile length and girth. Physical examination revealed distinctive craniofacial dysmorphism, classic ichthyotic scaling, pubertal changes consistent with precocious puberty, and normal muscle tone without dystonic features. Biochemical testing confirmed markedly elevated serum total testosterone, a positive gonadotropin-releasing hormone (GnRH) stimulation test consistent with CPP, and bone age advanced by 1.2 years relative to chronological age. Neurocognitive assessment identified mild intellectual disability. Family-based whole-exome sequencing and copy number variation (CNV) analysis identified a de novo heterozygous pathogenic nonsense variant in KMT2B (NM_014727.3: c.4213del, p.Leu1405Ter) and a hemizygous pathogenic full-coding deletion of STS. The patient was treated with leuprorelin acetate for CPP and topical emollients for XLI. At 3-month follow-up, physical signs of puberty remained stable. GnRHa stimulation test showed indicating but incomplete suppression of the hypothalamic-pituitary-gonadal axis. The ichthyotic skin lesions improved markedly with topical therapy. The leuprorelin acetate dose was subsequently increased. The patient is continuing on the current regimen with close monitoring. Precocious puberty has been reported in eleven patients with KMT2B-related dystonia. This case documents the co-occurrence of a KMT2B-related disorder and XLI in a patient, and provides documentation of GnRH analogue therapy and structured endocrine follow-up for CPP in this population. KMT2B haploinsufficiency may contribute to premature activation of the hypothalamic-pituitary-gonadal axis through disruption of ERα-mediated transcriptional regulation and altered epigenetic programming at key hypothalamic developmental genes. Clinically, children with KMT2B-related disorders should undergo comprehensive endocrine assessment to facilitate early diagnosis and timely intervention.
2026-01-01 | The Use of Methylsulfonylmethane‐Containing Products in Dermatology: An Evidence‐Based Systematic Review of Safety and Efficacy
Background Methylsulfonylmethane (MSM) is a biologically active sulfur compound that has been implicated in structural protein synthesis and anti‐inflammatory signaling pathways. We conducted a systematic review to evaluate the efficacy and safety of MSM in skin care products and explore the underlying mechanism of action. Methods This review followed PRISMA guidelines and was registered on PROSPERO (CRD420251274679). PubMed, Embase, ClinicalTrials.gov, Cochrane Library, and Ovid/MEDLINE were searched from inception through December 23, 2025. Eligible studies evaluated topical or oral MSM for dermatologic conditions in human participants. Risk of bias was assessed using the Cochrane Risk of Bias 2.0 tool for randomized control trials and the Newcastle–Ottawa Scale for nonrandomized studies. Results Of the 228 records identified, seven studies ( n = 416) met the inclusion criteria: six randomized controlled trials and one case report, in adults with acne vulgaris, erythematous‐telangiectatic rosacea, nail psoriasis, skin aging, and X‐linked ichthyosis. MSM‐containing interventions (both topical and oral) were associated with statistically significant improvements in clinical severity and skin‐related outcomes, including inflammatory lesion counts, erythema, nail severity scores, and measures of skin hydration, elasticity, firmness, texture, and dermal thickness. Reported adverse events were mild and transient, with no serious adverse events or treatment‐related withdrawals. Conclusions The most reliable evidence supports oral MSM for photoaging, moderate support for acne, erythematous‐telangiectatic rosacea, and nail psoriasis, and weakest evidence for X‐linked ichthyosis. Importantly, studies lasting up to 24 weeks did not identify any serious safety concerns.
2025-04-04 | Syndromic epidermal differentiation disorders: a new classification toward pathogenesis-based therapy.
Since the 2010 classification of ichthyoses, our understanding of hereditary epidermal differentiation disorders (EDDs) has markedly increased, allowing for consideration of new therapeutic targets based on disease pathogenesis. A new gene- and protein product function-based classification focuses on shared mechanisms of disease pathogenesis, with the possibility that grouped disorders may respond similarly to new therapeutics. These EDDs have been subdivided into syndromic (sEDD), nonsyndromic with features limited to skin and appendages, and predominantly palmoplantar skin involvement (nonsyndromic and syndromic). sEDDs have clinically important extracutaneous features related to the gene alteration. Often, recognition based on skin manifestations facilitates early gene-based diagnosis, discussion of prognosis, genetic counselling and the initiation of therapy. All sEDDs are rare; the most common are STS-sEDD (formerly known as X-linked ichthyosis) and SPINK5-sEDD (formerly known as Netherton syndrome). Given the rarity, frequent association with early demise and variable clinical features of sEDDs, the natural history of the diseases with advancing age and genotype-phenotype relationships are poorly defined. Of the 51 sEDDs, associated neurological (n = 36; 71%) and/or ophthalmological (n = 25; 49%) findings are most common, and 39% (n = 20) have associated hair abnormalities. The widespread use of topical lovastatin for cholesterol synthesis-related sEDDs represents the prototype of pathogenesis-based therapy. This concept of upstream inhibition to prevent metabolite accumulation and supplementation with the pathway end product potentially applies to other sEDDs, such as those affecting ceramide synthesis and transport. Topical or systemically administered inhibition of activated pathways is another potential approach, exemplified by the emerging treatment of SPINK5-sEDD with kallikrein inhibitors. Many sEDDs may be amenable to gene editing or the introduction of functional cDNA. However, even systemic treatments targeting cutaneous diseases may not address extracutaneous manifestations that arise during embryological development.
2025-03-22 | Dysregulation of STS in keratinocytes promotes calcium signaling and differentiation.
Steroid sulfatase (STS) is a key enzyme for the desulfation of steroid sulfates, converting them into their biologically active forms. Notably, X-linked ichthyosis (XLI), a genetic disorder characterized by hyperkeratinization, arises as a direct result of STS deficiency. Keratinocyte differentiation is essential for proper keratinization. In this study, gene ontology analysis from STS-deficient mice revealed enhanced differentiation and upregulation of calcium-related signaling. Calcium plays a key role in regulating keratinocyte differentiation, with STS-deficient cells showing a marked increase in intracellular calcium influx. Additionally, these cells significantly upregulated calcium-sensing receptors (CasR), leading to elevated tyrosine phosphorylation, increased differentiation signaling, and the upregulation of early differentiation markers, including keratin 1 and keratin 10, as seen in HaCaT cells and mouse primary keratinocytes. Furthermore, STS inhibitors enhanced the expression of E-cadherin and terminal differentiation markers such as involucrin and loricrin. Due to increased calcium sensitivity, STS-deficient cells treated with calcium exhibited a significant upregulation of differentiation markers and reduced sensitivity to calcium chelation. Collectively, our findings demonstrate that reduced STS expression and inhibition of its activity enhance calcium responsiveness, induce CasR expression, and amplify calcium signaling, thereby promoting keratinocyte differentiation. These findings offer valuable insights into the mechanisms underlying STS deficiency-induced hyperkeratinization.
2024-12-12 | Dysregulation of STS in keratinocytes promotes calcium signaling and hyperkeratinization: Insights into the mechanisms underlying X-linked ichthyosis
Steroid sulfatase (STS) is a key enzyme for the desulfation of steroid sulfates, converting them into their biologically active forms. Notably, X-linked ichthyosis (XLI), a genetic disorder characterized by hyperkeratinization, arises as a direct result of STS deficiency. Keratinocyte differentiation is essential for proper keratinization. In this study, gene ontology analysis from STS-deficient mice revealed enhanced differentiation and upregulation of calcium-related signaling. Calcium plays a key role in regulating keratinocyte differentiation, with STS-deficient cells showing a marked increase in intracellular calcium influx. Additionally, these cells significantly upregulated calcium-sensing receptors (CasR), leading to elevated tyrosine phosphorylation, increased differentiation signaling, and the upregulation of early differentiation markers, including keratin 1 and keratin 10, as seen in HaCaT cells and mouse primary keratinocytes. Furthermore, STS inhibitors enhanced the expression of E-cadherin and late differentiation markers such as involucrin and loricrin. Due to increased calcium sensitivity, STS-deficient cells treated with calcium exhibited a significant upregulation of differentiation markers and reduced sensitivity to calcium chelation. Collectively, our findings demonstrate that reduced STS expression and inhibition of its activity enhance calcium responsiveness, induce CasR expression, and amplify calcium signaling, thereby promoting keratinocyte differentiation. These findings offer valuable insights into the mechanisms underlying STS deficiency-induced hyperkeratinization.
proteins
2026-01-15 | Early Neonatal presentation of X-linked Ichthyosis – A case report
X-linked ichthyosis (XLI) is an inherited disorder of keratinisation caused by a deficiency of the enzyme steroid sulfatase (STS), leading to accumulation of cholesterol sulfate in the stratum corneum and resulting in retention hyperkeratosis. Affected males typically present in the neonatal period with dark brown, polygonal scales over the trunk, neck, and extensor surfaces, with relative sparing of flexures, face, palms, and soles. Extracutaneous manifestations such as cryptorchidism or corneal opacities may be seen, and larger STS deletions can be associated with neurodevelopmental features. We report a male neonate born at 28 weeks of gestation. The infant developed skin scaling in the second week of life, which gradually darkened and peeled, primarily over the forehead and upper limbs. Supportive care with emollients and moisturisers was initiated. Genetic testing confirmed STS deletion consistent with XLI. The baby was discharged on day 46 of life and remains under follow-up for monitoring associated issues. Management of XLI is mainly symptomatic, with emphasis on skin hydration, gentle exfoliation, and avoidance of irritants, along with genetic counselling. Emerging therapies such as enzyme replacement and gene therapy are under investigation. Early recognition and confirmation allow timely care, anticipation of complications, and reassurance for families.
2020-12-23 | Ichthyoses in everyday practice: management of a rare group of diseases.
Ichthyoses comprise a heterogeneous group of hereditary disorders of keratinization characterized by a highly varied clinical picture. A distinction is made between common hereditary ichthyoses (ichthyosis vulgaris and X-linked ichthyosis), which usually manifest themselves in the first year of life, and rare, sometimes severe congenital ichthyoses. Patients with very mild symptoms often do not even realize they have ichthyosis. The diagnosis is usually based on clinical evaluation. Molecular genetic testing as well as histological and electron microscopic studies may aid in confirming the diagnosis. Mapping a family tree is also diagnostically useful. Besides skin manifestations, important aspects of the clinical examination and history include disease onset, presence of a collodion membrane at birth as well as the presence of hair anomalies and extracutaneous signs and symptoms. Rigorous hydration of the skin (several times a day) and balneotherapy are the mainstay of ichthyosis treatment. For patients with severe disease, systemic acitretin treatment should be considered on a case-by-case basis. While ichthyoses are generally limited to the skin, there are syndromic forms that may affect other organs and that require interdisciplinarity cooperation. Although ichthyoses remain incurable, they can be managed well with symptomatic treatment. However, such treatment is frequently time consuming and expensive. In the future, novel therapeutic approaches might include enzyme replacement and gene therapies as well as antiinflammatory drugs.
2017-06-01 | Transgenic overexpression of steroid sulfatase alleviates cholestasis
Sulfotransferase (SULT)-mediated sulfation and steroid sulfatase (STS)-mediated desulfation represent two critical mechanisms that regulate the chemical and functional homeostasis of endogenous and exogenous molecules. STS catalyzes the hydrolysis of steroid sulfates to form hydroxysteroids. Oxygenated cholesterol derivative oxysterols are known to be endogenous ligands of the liver X receptor (LXR), a nuclear receptor with anti-cholestasis activity, whereas the sulfated oxysterols antagonize LXR signaling. The conversion of sulfated oxysterols to their non-sulfated counterparts is catalyzed by STS. The aim of this study is to determine whether STS can alleviate cholestasis by increasing the activity of LXR. Liver-specific STS transgenic mice were created and subject to the lithocholic acid (LCA)-induced model of cholestasis. Transgenic overexpression of STS in the liver promoted bile acid elimination and alleviated LCA-induced cholestasis. The protective effect of the STS transgene was associated with the activation of LXR and induction of LXR target genes, likely because of the increased conversion of the antagonistic oxysterol sulfates to the agonistic oxysterols. STS has a novel function in controlling the homeostasis of bile acids by regulating endogenous LXR ligands.
2013-02-15 | Functional Cardiac Lipolysis in Mice Critically Depends on Comparative Gene Identification-58
Efficient catabolism of cellular triacylglycerol (TG) stores requires the TG hydrolytic activity of adipose triglyceride lipase (ATGL). The presence of comparative gene identification-58 (CGI-58) strongly increased ATGL-mediated TG catabolism in cell culture experiments. Mutations in the genes coding for ATGL or CGI-58 in humans cause neutral lipid storage disease characterized by TG accumulation in multiple tissues. ATGL gene mutations cause a severe phenotype especially in cardiac muscle leading to cardiomyopathy that can be lethal. In contrast, CGI-58 gene mutations provoke severe ichthyosis and hepatosteatosis in humans and mice, whereas the role of CGI-58 in muscle energy metabolism is less understood. Here we show that mice lacking CGI-58 exclusively in muscle (CGI-58KOM) developed severe cardiac steatosis and cardiomyopathy linked to impaired TG catabolism and mitochondrial fatty acid oxidation. The marked increase in ATGL protein levels in cardiac muscle of CGI-58KOM mice was unable to compensate the lack of CGI-58. The addition of recombinant CGI-58 to cardiac lysates of CGI-58KOM mice completely reconstituted TG hydrolytic activities. In skeletal muscle, the lack of CGI-58 similarly provoked TG accumulation. The addition of recombinant CGI-58 increased TG hydrolytic activities in control and CGI-58KOM tissue lysates, elucidating the limiting role of CGI-58 in skeletal muscle TG catabolism. Finally, muscle CGI-58 deficiency affected whole body energy homeostasis, which is caused by impaired muscle TG catabolism and increased cardiac glucose uptake. In summary, this study demonstrates that functional muscle lipolysis depends on both CGI-58 and ATGL. Efficient catabolism of cellular triacylglycerol (TG) stores requires the TG hydrolytic activity of adipose triglyceride lipase (ATGL). The presence of comparative gene identification-58 (CGI-58) strongly increased ATGL-mediated TG catabolism in cell culture experiments. Mutations in the genes coding for ATGL or CGI-58 in humans cause neutral lipid storage disease characterized by TG accumulation in multiple tissues. ATGL gene mutations cause a severe phenotype especially in cardiac muscle leading to cardiomyopathy that can be lethal. In contrast, CGI-58 gene mutations provoke severe ichthyosis and hepatosteatosis in humans and mice, whereas the role of CGI-58 in muscle energy metabolism is less understood. Here we show that mice lacking CGI-58 exclusively in muscle (CGI-58KOM) developed severe cardiac steatosis and cardiomyopathy linked to impaired TG catabolism and mitochondrial fatty acid oxidation. The marked increase in ATGL protein levels in cardiac muscle of CGI-58KOM mice was unable to compensate the lack of CGI-58. The addition of recombinant CGI-58 to cardiac lysates of CGI-58KOM mice completely reconstituted TG hydrolytic activities. In skeletal muscle, the lack of CGI-58 similarly provoked TG accumulation. The addition of recombinant CGI-58 increased TG hydrolytic activities in control and CGI-58KOM tissue lysates, elucidating the limiting role of CGI-58 in skeletal muscle TG catabolism. Finally, muscle CGI-58 deficiency affected whole body energy homeostasis, which is caused by impaired muscle TG catabolism and increased cardiac glucose uptake. In summary, this study demonstrates that functional muscle lipolysis depends on both CGI-58 and ATGL.
2000-02-01 | Dry skin, moisturization and corneodesmolysis
The process leading to the loss of corneocytes form the skin surface is termed desquamation. In healthy skin it is an orderly and essentially invisible process whereby individual or small groups of corneocytes detach from neighbouring cells to be lost to the environment and replaced by younger cells from the deeper layers. Desquamation is carefully controlled to ensure that corneum cohesion and integrity, and hence tissue thickness, is maintained. The most important components of the corneocytes contributing towards intercellular cohesion are the corneodesmosomes and lipids. Corneodesmosomes are proteinaceous complexes which effectively rivet corneocytes together. The intercellular lipids, primarily responsible for the water barrier, also provide part of the extracellular cement. In addition, the shape of the corneocyte itself plays a role in stratum corneum cohesion. Through interdigitation along their peripheral edges, adjacent corneocytes become physically locked together, a process which reinforces the integrity of the tissue. For effective desquamation to occur corneodesmosomes must be degraded: a process catalysed by serine proteases present within the intercellular space and facilitated by subtle changes in lipid composition and phase behaviour. Ultimately, it is the availability of free water which controls corneodesmolysis. In healthy skin this proteolytic process leaves relatively few corneodesmosomes intact in the most superficial layers. By contrast, in chronic and acute dry skin conditions, corneodesmosomal degradation and hence the final stages of desquamation are perturbed, leading to the characteristic formation of visible, powdery flakes on the skin surface. The inability to degrade these structures ultimately reflects a decreased hydrolytic activity of the desquamatory enzymes, either through reduced synthesis of the enzymes, inherent loss of activity, leaching from the surface layers of the corneum or changes in the surrounding lipid-rich microenvironment, which may indirectly reduce enzyme functionality. Increased understanding of the desquamation process is providing new insights into the mode of action of current moisturizing ingredients and is offering opportunities to develop novel therapies for preventing and correcting dry skin.
antibodies
2024-06-04 | Advancements in Ichthyosis Treatment in Pediatric Patients: Evaluating the Impact of Immune System Inhibitors Targeting TNF-alpha, IL-17A, IL-4, and IL-12
Lamellar, X-linked recessive, and Vulgaris ichthyosis represent rare genetic variants distinguished by abundant dry surface scales. The etiology of childhood ichthyosis involves a combination of acquired and inherited factors. Children with Ichthyosis have a Th17-dominant immune profile, similar to psoriasis, with a correlation between ichthyosis severity, erythema, Trans Epidermal Water Loss (TEWL), and immunological markers. In order to examine the safety and effectiveness of immune system inhibitors that target TNF-alpha, IL-17A, IL-4, and IL-12 in the treatment of pediatric Ichthyosis, a retrospective research study was conducted on 30 pediatric patients aged 6-12 years at tertiary care pediatric dermatology hospitals in UAE, for a time duration of 5 months. IL-17-A is a key cytokine of Ichthyosis, and its specific suppression is considered necessary in contrast to other cytokines. Consequently, the choice of treatment was dictated by elements unique to the condition and the intensity of symptoms, focusing on using Secukinumab as an IL-17-A inhibitor. The findings showed that, following five months of treatment, patients receiving secukinumab showed positive outcomes, with their ichthyosis area severity index score declining by 45 to 50%. Additionally, the proinflammatory rate of cytokines was significantly lower in this group of patients compared to the placebo-treated control group. The safety and Efficacy of Secukinumab compared to Ixekizumab and Brodalumab vs placebo were examined using t-tests, with statistical significance determined at P< 0.05. The present research study concludes that Secukinumab effectively enhances skin texture and reduces scaling severity in Ichthyosis, suggesting clinical relevance. The findings underscore Secukinumab’s potential as a beneficial agent for various ichthyosis types, such as lamellar, X-linked, and vulgaris. The study’s comparison with placebo and other IL-17A inhibitors like Ixekizumab and Brodalumab provides valuable insights into Secukinumab’s Efficacy and potential clinical uses.
2022-11-18 | 305 Overlaps between inflammatory dermatoses and ichthyoses: need for novel therapeutic approaches
Ichthyoses form a heterogeneous group of well-defined inherited skin diseases. However, the comorbidity of these cornification disorders needs to be further investigated, as psoriasiform skin lesions and/or atopic manifestations may be observed in many affected individuals. We recruited 64 patients with ichthyoses, 29 psoriasis and 37 atopic dermatitis (AD) patients, assessed the disease severity by the Ichthyosis Area Severity Index (IASI; 0-48) and pruritus characteristics by the Neuroderm Questionnaire. Further, we performed immunohistochemical stainings of CCL27, Nos2, filaggrin, β-defensin-2 and CD1a on 15 skin samples of ichthyoses and compared them to psoriasis and AD. In ichthyosis the median disease severity was 8 with highest scores in Netherton syndrome (NTS). Generalized pruritus occurred in 84% of patients with a median intensity of 3 on the numeric rating scale (0-10). 13% described neuropathic itch qualities and 15 patients showed an impaired quality of life due to itch. Of note, almost 50% with systemic therapy still described moderate pruritus. In AD pruritus was significantly higher than in the group of psoriasis and ichthyosis (p ≤ 0,01). Staining of CCL27 and Nos2 revealed a psoriasis-like phenotype in more than 50% of ichthyosis patients. Filaggrin deficiency was not only observed in ichthyosis vulgaris (IV), but also in congenital ichthyoses and X-linked ichthyosis. ß-defensin-2 was present in some samples, and there were two patients (IV and XLI) with high levels of CD1a. Atopic diathesis was not only prevalent in IV and NTS, but among all subtypes. We conclude that immunological characterization of ichthyoses according to a psoriasiform or atopic diathese pattern could improve treatment of the disease. Novel targeted therapies may be subject of future clinical studies in ichthyosis to improve itch, skin inflammation and probably scaling.
2016-05-01 | 395 Disease severity and cutaneous inflammation in ichthyosis are linked to Th17 pathway activation
The ichthyoses are rare, disfiguring, sometimes debilitating disorders featuring generalized scaling, erythema, and epidermal barrier impairment. Despite genetic advances, pathogenesis-based therapy is largely lacking given limited insight into molecular pathobiology. To determine if erythema in ichthyosis results from inflammation and correlates with clinical and barrier disease characteristics, we used immunohistochemistry and RT-PCR from biopsied skin of 21 genotyped ichthyosis patients (congenital ichthyosiform erythroderma, lamellar ichthyosis, epidermolytic hyperkeratosis, and Netherton syndrome) and compared them with healthy controls and atopic dermatitis (AD) and psoriasis patients. Clinical measures included transepidermal water loss, pruritus, and a severity scoring for ichthyosis (IASI) that integrates erythema (IASI-E) and scaling (IASI-S). Ichthyosis samples were characterized by increased epidermal hyperplasia (by thickness and K16 expression) and T-cell and dendritic-cells infiltrates, comparable to psoriasis and AD samples. We observed large increases of general inflammatory (IL-2), innate (IL-1β), and Th1/IFN (IFNγ) markers in ichthyosis, as in psoriasis or AD. Expression of Th2 markers (IL-13, IL-31) in ichthyoses was similar to controls. Most notable in ichthyotic skin, however, was significant induction of the Th17/IL-23 pathway (IL-17A, IL-23p40/p19, IL-19, CXCL1, PI3; p<0.05), similar to psoriasis. High correlations were found between IASI and its IASI-E component and IL-17A (r=0.74, p<0.001) or related markers. IASI-S was associated with barrier measures (TEWL, thickness, filaggrin, loricrin). Our data link ichthyosis fingerprinting to Th17/IL-23 polarization, similar to psoriasis, and raise the possibility of IL-17-targeting strategies for the ichthyoses.
oligonucleotides
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.
2024-02-20 | Unraveling the molecular mechanisms of cell migration impairment and apoptosis associated with steroid sulfatase deficiency: Implications for X-linked ichthyosis.
Steroid sulfatase (STS) deficiency is responsible for X-linked ichthyosis (XLI), a genetic disorder characterized by rough and dry skin caused by excessive keratinization. The impaired keratinization process leads to reduced cell mobility and increased apoptosis, which can cause an excessive buildup of the stratum corneum. In this study, we investigated the mechanisms underlying XLI and found that STS deficiency reduces cell mobility and increases apoptosis in human keratinocyte HaCaT cells. To explore these mechanisms further, RNA-sequencing was conducted on skin tissues from STS transgenic and knockout mice. Our RNA-seq results revealed that STS deficiency plays a critical role in regulating multiple signaling pathways associated with cell mobility and apoptosis, such as Wnt/β signaling and the Hippo signaling pathway. Knockdown of the STS gene using shRNA in HaCaT cells led to an upregulation of E-cadherin expression and suppression of key factors involved in epithelial-mesenchymal transition (EMT), such as N-cadherin and vimentin. Inhibition of EMT involved the Hippo signaling pathway and reduction of HIF-1α. Interestingly, inhibiting STS with shRNA increased mitochondrial respiration levels, as demonstrated by the extracellular flux oxygen consumption rate. Additionally, we observed a significant increase in ROS production in partial STS knockout cells compared to control cells. Our study demonstrated that the excessive generation of ROS caused by STS deficiency induces the expression of Bax and Bak, leading to the release of cytochrome c and subsequent cell death. Consequently, STS deficiency impairs cell mobility and promotes apoptosis, offering insights into the pathophysiological processes and potential therapeutic targets for XLI.
2020-08-12 | The Role of MicroRNAs in Epidermal Barrier
MicroRNAs (miRNAs), which mostly cause target gene silencing via transcriptional repression and degradation of target mRNAs, regulate a plethora of cellular activities, such as cell growth, differentiation, development, and apoptosis. In the case of skin keratinocytes, the role of miRNA in epidermal barrier integrity has been identified. Based on the impact of key genetic and environmental factors on the integrity and maintenance of skin barrier, the association of miRNAs within epidermal cell differentiation and proliferation, cell–cell adhesion, and skin lipids is reviewed. The critical role of miRNAs in the epidermal barrier extends the use of miRNAs for control of relevant skin diseases such as atopic dermatitis, ichthyoses, and psoriasis via miRNA-based technologies. Most of the relevant miRNAs have been associated with keratinocyte differentiation and proliferation. Few studies have investigated the association of miRNAs with structural proteins of corneocytes and cornified envelopes, cell–cell adhesion, and skin lipids. Further studies investigating the association between regulatory and structural components of epidermal barrier and miRNAs are needed to elucidate the role of miRNAs in epidermal barrier integrity and their clinical implications.
small molecules
2026-07-02 | Central precocious puberty as the initial manifestation of multisystem involvement caused by de novo heterozygous KMT2B mutation and STS hemizygous deletion: a case report.
Pathogenic loss-of-function variants in the KMT2B gene cause a rare autosomal dominant disorder with two major phenotypes: KMT2B-related dystonia (DYT-KMT2B) and KMT2B-related neurodevelopmental disorder (KMT2B-NDD). Central precocious puberty (CPP) has been documented as a comorbidity in patients with DYT-KMT2B, but has not been reported as the primary clinical manifestation of the disorder in patients without dystonia. Deletions or pathogenic variants in the STS gene cause X-linked ichthyosis (XLI). Concurrent KMT2B and STS alterations have not been well characterised, and GnRH analogue therapy for CPP in KMT2B-related disorders has not been previously described. An 8-year-10-month-old male presented with a 1-2-year history of progressive increase in penile length and girth. Physical examination revealed distinctive craniofacial dysmorphism, classic ichthyotic scaling, pubertal changes consistent with precocious puberty, and normal muscle tone without dystonic features. Biochemical testing confirmed markedly elevated serum total testosterone, a positive gonadotropin-releasing hormone (GnRH) stimulation test consistent with CPP, and bone age advanced by 1.2 years relative to chronological age. Neurocognitive assessment identified mild intellectual disability. Family-based whole-exome sequencing and copy number variation (CNV) analysis identified a de novo heterozygous pathogenic nonsense variant in KMT2B (NM_014727.3: c.4213del, p.Leu1405Ter) and a hemizygous pathogenic full-coding deletion of STS. The patient was treated with leuprorelin acetate for CPP and topical emollients for XLI. At 3-month follow-up, physical signs of puberty remained stable. GnRHa stimulation test showed indicating but incomplete suppression of the hypothalamic-pituitary-gonadal axis. The ichthyotic skin lesions improved markedly with topical therapy. The leuprorelin acetate dose was subsequently increased. The patient is continuing on the current regimen with close monitoring. Precocious puberty has been reported in eleven patients with KMT2B-related dystonia. This case documents the co-occurrence of a KMT2B-related disorder and XLI in a patient, and provides documentation of GnRH analogue therapy and structured endocrine follow-up for CPP in this population. KMT2B haploinsufficiency may contribute to premature activation of the hypothalamic-pituitary-gonadal axis through disruption of ERα-mediated transcriptional regulation and altered epigenetic programming at key hypothalamic developmental genes. Clinically, children with KMT2B-related disorders should undergo comprehensive endocrine assessment to facilitate early diagnosis and timely intervention.
2026-01-01 | The Use of Methylsulfonylmethane‐Containing Products in Dermatology: An Evidence‐Based Systematic Review of Safety and Efficacy
Background Methylsulfonylmethane (MSM) is a biologically active sulfur compound that has been implicated in structural protein synthesis and anti‐inflammatory signaling pathways. We conducted a systematic review to evaluate the efficacy and safety of MSM in skin care products and explore the underlying mechanism of action. Methods This review followed PRISMA guidelines and was registered on PROSPERO (CRD420251274679). PubMed, Embase, ClinicalTrials.gov, Cochrane Library, and Ovid/MEDLINE were searched from inception through December 23, 2025. Eligible studies evaluated topical or oral MSM for dermatologic conditions in human participants. Risk of bias was assessed using the Cochrane Risk of Bias 2.0 tool for randomized control trials and the Newcastle–Ottawa Scale for nonrandomized studies. Results Of the 228 records identified, seven studies ( n = 416) met the inclusion criteria: six randomized controlled trials and one case report, in adults with acne vulgaris, erythematous‐telangiectatic rosacea, nail psoriasis, skin aging, and X‐linked ichthyosis. MSM‐containing interventions (both topical and oral) were associated with statistically significant improvements in clinical severity and skin‐related outcomes, including inflammatory lesion counts, erythema, nail severity scores, and measures of skin hydration, elasticity, firmness, texture, and dermal thickness. Reported adverse events were mild and transient, with no serious adverse events or treatment‐related withdrawals. Conclusions The most reliable evidence supports oral MSM for photoaging, moderate support for acne, erythematous‐telangiectatic rosacea, and nail psoriasis, and weakest evidence for X‐linked ichthyosis. Importantly, studies lasting up to 24 weeks did not identify any serious safety concerns.
2025-04-04 | Syndromic epidermal differentiation disorders: a new classification toward pathogenesis-based therapy.
Since the 2010 classification of ichthyoses, our understanding of hereditary epidermal differentiation disorders (EDDs) has markedly increased, allowing for consideration of new therapeutic targets based on disease pathogenesis. A new gene- and protein product function-based classification focuses on shared mechanisms of disease pathogenesis, with the possibility that grouped disorders may respond similarly to new therapeutics. These EDDs have been subdivided into syndromic (sEDD), nonsyndromic with features limited to skin and appendages, and predominantly palmoplantar skin involvement (nonsyndromic and syndromic). sEDDs have clinically important extracutaneous features related to the gene alteration. Often, recognition based on skin manifestations facilitates early gene-based diagnosis, discussion of prognosis, genetic counselling and the initiation of therapy. All sEDDs are rare; the most common are STS-sEDD (formerly known as X-linked ichthyosis) and SPINK5-sEDD (formerly known as Netherton syndrome). Given the rarity, frequent association with early demise and variable clinical features of sEDDs, the natural history of the diseases with advancing age and genotype-phenotype relationships are poorly defined. Of the 51 sEDDs, associated neurological (n = 36; 71%) and/or ophthalmological (n = 25; 49%) findings are most common, and 39% (n = 20) have associated hair abnormalities. The widespread use of topical lovastatin for cholesterol synthesis-related sEDDs represents the prototype of pathogenesis-based therapy. This concept of upstream inhibition to prevent metabolite accumulation and supplementation with the pathway end product potentially applies to other sEDDs, such as those affecting ceramide synthesis and transport. Topical or systemically administered inhibition of activated pathways is another potential approach, exemplified by the emerging treatment of SPINK5-sEDD with kallikrein inhibitors. Many sEDDs may be amenable to gene editing or the introduction of functional cDNA. However, even systemic treatments targeting cutaneous diseases may not address extracutaneous manifestations that arise during embryological development.
2025-03-22 | Dysregulation of STS in keratinocytes promotes calcium signaling and differentiation.
Steroid sulfatase (STS) is a key enzyme for the desulfation of steroid sulfates, converting them into their biologically active forms. Notably, X-linked ichthyosis (XLI), a genetic disorder characterized by hyperkeratinization, arises as a direct result of STS deficiency. Keratinocyte differentiation is essential for proper keratinization. In this study, gene ontology analysis from STS-deficient mice revealed enhanced differentiation and upregulation of calcium-related signaling. Calcium plays a key role in regulating keratinocyte differentiation, with STS-deficient cells showing a marked increase in intracellular calcium influx. Additionally, these cells significantly upregulated calcium-sensing receptors (CasR), leading to elevated tyrosine phosphorylation, increased differentiation signaling, and the upregulation of early differentiation markers, including keratin 1 and keratin 10, as seen in HaCaT cells and mouse primary keratinocytes. Furthermore, STS inhibitors enhanced the expression of E-cadherin and terminal differentiation markers such as involucrin and loricrin. Due to increased calcium sensitivity, STS-deficient cells treated with calcium exhibited a significant upregulation of differentiation markers and reduced sensitivity to calcium chelation. Collectively, our findings demonstrate that reduced STS expression and inhibition of its activity enhance calcium responsiveness, induce CasR expression, and amplify calcium signaling, thereby promoting keratinocyte differentiation. These findings offer valuable insights into the mechanisms underlying STS deficiency-induced hyperkeratinization.
2024-12-12 | Dysregulation of STS in keratinocytes promotes calcium signaling and hyperkeratinization: Insights into the mechanisms underlying X-linked ichthyosis
Steroid sulfatase (STS) is a key enzyme for the desulfation of steroid sulfates, converting them into their biologically active forms. Notably, X-linked ichthyosis (XLI), a genetic disorder characterized by hyperkeratinization, arises as a direct result of STS deficiency. Keratinocyte differentiation is essential for proper keratinization. In this study, gene ontology analysis from STS-deficient mice revealed enhanced differentiation and upregulation of calcium-related signaling. Calcium plays a key role in regulating keratinocyte differentiation, with STS-deficient cells showing a marked increase in intracellular calcium influx. Additionally, these cells significantly upregulated calcium-sensing receptors (CasR), leading to elevated tyrosine phosphorylation, increased differentiation signaling, and the upregulation of early differentiation markers, including keratin 1 and keratin 10, as seen in HaCaT cells and mouse primary keratinocytes. Furthermore, STS inhibitors enhanced the expression of E-cadherin and late differentiation markers such as involucrin and loricrin. Due to increased calcium sensitivity, STS-deficient cells treated with calcium exhibited a significant upregulation of differentiation markers and reduced sensitivity to calcium chelation. Collectively, our findings demonstrate that reduced STS expression and inhibition of its activity enhance calcium responsiveness, induce CasR expression, and amplify calcium signaling, thereby promoting keratinocyte differentiation. These findings offer valuable insights into the mechanisms underlying STS deficiency-induced hyperkeratinization.
proteins
2026-01-15 | Early Neonatal presentation of X-linked Ichthyosis – A case report
X-linked ichthyosis (XLI) is an inherited disorder of keratinisation caused by a deficiency of the enzyme steroid sulfatase (STS), leading to accumulation of cholesterol sulfate in the stratum corneum and resulting in retention hyperkeratosis. Affected males typically present in the neonatal period with dark brown, polygonal scales over the trunk, neck, and extensor surfaces, with relative sparing of flexures, face, palms, and soles. Extracutaneous manifestations such as cryptorchidism or corneal opacities may be seen, and larger STS deletions can be associated with neurodevelopmental features. We report a male neonate born at 28 weeks of gestation. The infant developed skin scaling in the second week of life, which gradually darkened and peeled, primarily over the forehead and upper limbs. Supportive care with emollients and moisturisers was initiated. Genetic testing confirmed STS deletion consistent with XLI. The baby was discharged on day 46 of life and remains under follow-up for monitoring associated issues. Management of XLI is mainly symptomatic, with emphasis on skin hydration, gentle exfoliation, and avoidance of irritants, along with genetic counselling. Emerging therapies such as enzyme replacement and gene therapy are under investigation. Early recognition and confirmation allow timely care, anticipation of complications, and reassurance for families.
2020-12-23 | Ichthyoses in everyday practice: management of a rare group of diseases.
Ichthyoses comprise a heterogeneous group of hereditary disorders of keratinization characterized by a highly varied clinical picture. A distinction is made between common hereditary ichthyoses (ichthyosis vulgaris and X-linked ichthyosis), which usually manifest themselves in the first year of life, and rare, sometimes severe congenital ichthyoses. Patients with very mild symptoms often do not even realize they have ichthyosis. The diagnosis is usually based on clinical evaluation. Molecular genetic testing as well as histological and electron microscopic studies may aid in confirming the diagnosis. Mapping a family tree is also diagnostically useful. Besides skin manifestations, important aspects of the clinical examination and history include disease onset, presence of a collodion membrane at birth as well as the presence of hair anomalies and extracutaneous signs and symptoms. Rigorous hydration of the skin (several times a day) and balneotherapy are the mainstay of ichthyosis treatment. For patients with severe disease, systemic acitretin treatment should be considered on a case-by-case basis. While ichthyoses are generally limited to the skin, there are syndromic forms that may affect other organs and that require interdisciplinarity cooperation. Although ichthyoses remain incurable, they can be managed well with symptomatic treatment. However, such treatment is frequently time consuming and expensive. In the future, novel therapeutic approaches might include enzyme replacement and gene therapies as well as antiinflammatory drugs.
2017-06-01 | Transgenic overexpression of steroid sulfatase alleviates cholestasis
Sulfotransferase (SULT)-mediated sulfation and steroid sulfatase (STS)-mediated desulfation represent two critical mechanisms that regulate the chemical and functional homeostasis of endogenous and exogenous molecules. STS catalyzes the hydrolysis of steroid sulfates to form hydroxysteroids. Oxygenated cholesterol derivative oxysterols are known to be endogenous ligands of the liver X receptor (LXR), a nuclear receptor with anti-cholestasis activity, whereas the sulfated oxysterols antagonize LXR signaling. The conversion of sulfated oxysterols to their non-sulfated counterparts is catalyzed by STS. The aim of this study is to determine whether STS can alleviate cholestasis by increasing the activity of LXR. Liver-specific STS transgenic mice were created and subject to the lithocholic acid (LCA)-induced model of cholestasis. Transgenic overexpression of STS in the liver promoted bile acid elimination and alleviated LCA-induced cholestasis. The protective effect of the STS transgene was associated with the activation of LXR and induction of LXR target genes, likely because of the increased conversion of the antagonistic oxysterol sulfates to the agonistic oxysterols. STS has a novel function in controlling the homeostasis of bile acids by regulating endogenous LXR ligands.
2013-02-15 | Functional Cardiac Lipolysis in Mice Critically Depends on Comparative Gene Identification-58
Efficient catabolism of cellular triacylglycerol (TG) stores requires the TG hydrolytic activity of adipose triglyceride lipase (ATGL). The presence of comparative gene identification-58 (CGI-58) strongly increased ATGL-mediated TG catabolism in cell culture experiments. Mutations in the genes coding for ATGL or CGI-58 in humans cause neutral lipid storage disease characterized by TG accumulation in multiple tissues. ATGL gene mutations cause a severe phenotype especially in cardiac muscle leading to cardiomyopathy that can be lethal. In contrast, CGI-58 gene mutations provoke severe ichthyosis and hepatosteatosis in humans and mice, whereas the role of CGI-58 in muscle energy metabolism is less understood. Here we show that mice lacking CGI-58 exclusively in muscle (CGI-58KOM) developed severe cardiac steatosis and cardiomyopathy linked to impaired TG catabolism and mitochondrial fatty acid oxidation. The marked increase in ATGL protein levels in cardiac muscle of CGI-58KOM mice was unable to compensate the lack of CGI-58. The addition of recombinant CGI-58 to cardiac lysates of CGI-58KOM mice completely reconstituted TG hydrolytic activities. In skeletal muscle, the lack of CGI-58 similarly provoked TG accumulation. The addition of recombinant CGI-58 increased TG hydrolytic activities in control and CGI-58KOM tissue lysates, elucidating the limiting role of CGI-58 in skeletal muscle TG catabolism. Finally, muscle CGI-58 deficiency affected whole body energy homeostasis, which is caused by impaired muscle TG catabolism and increased cardiac glucose uptake. In summary, this study demonstrates that functional muscle lipolysis depends on both CGI-58 and ATGL. Efficient catabolism of cellular triacylglycerol (TG) stores requires the TG hydrolytic activity of adipose triglyceride lipase (ATGL). The presence of comparative gene identification-58 (CGI-58) strongly increased ATGL-mediated TG catabolism in cell culture experiments. Mutations in the genes coding for ATGL or CGI-58 in humans cause neutral lipid storage disease characterized by TG accumulation in multiple tissues. ATGL gene mutations cause a severe phenotype especially in cardiac muscle leading to cardiomyopathy that can be lethal. In contrast, CGI-58 gene mutations provoke severe ichthyosis and hepatosteatosis in humans and mice, whereas the role of CGI-58 in muscle energy metabolism is less understood. Here we show that mice lacking CGI-58 exclusively in muscle (CGI-58KOM) developed severe cardiac steatosis and cardiomyopathy linked to impaired TG catabolism and mitochondrial fatty acid oxidation. The marked increase in ATGL protein levels in cardiac muscle of CGI-58KOM mice was unable to compensate the lack of CGI-58. The addition of recombinant CGI-58 to cardiac lysates of CGI-58KOM mice completely reconstituted TG hydrolytic activities. In skeletal muscle, the lack of CGI-58 similarly provoked TG accumulation. The addition of recombinant CGI-58 increased TG hydrolytic activities in control and CGI-58KOM tissue lysates, elucidating the limiting role of CGI-58 in skeletal muscle TG catabolism. Finally, muscle CGI-58 deficiency affected whole body energy homeostasis, which is caused by impaired muscle TG catabolism and increased cardiac glucose uptake. In summary, this study demonstrates that functional muscle lipolysis depends on both CGI-58 and ATGL.
2000-02-01 | Dry skin, moisturization and corneodesmolysis
The process leading to the loss of corneocytes form the skin surface is termed desquamation. In healthy skin it is an orderly and essentially invisible process whereby individual or small groups of corneocytes detach from neighbouring cells to be lost to the environment and replaced by younger cells from the deeper layers. Desquamation is carefully controlled to ensure that corneum cohesion and integrity, and hence tissue thickness, is maintained. The most important components of the corneocytes contributing towards intercellular cohesion are the corneodesmosomes and lipids. Corneodesmosomes are proteinaceous complexes which effectively rivet corneocytes together. The intercellular lipids, primarily responsible for the water barrier, also provide part of the extracellular cement. In addition, the shape of the corneocyte itself plays a role in stratum corneum cohesion. Through interdigitation along their peripheral edges, adjacent corneocytes become physically locked together, a process which reinforces the integrity of the tissue. For effective desquamation to occur corneodesmosomes must be degraded: a process catalysed by serine proteases present within the intercellular space and facilitated by subtle changes in lipid composition and phase behaviour. Ultimately, it is the availability of free water which controls corneodesmolysis. In healthy skin this proteolytic process leaves relatively few corneodesmosomes intact in the most superficial layers. By contrast, in chronic and acute dry skin conditions, corneodesmosomal degradation and hence the final stages of desquamation are perturbed, leading to the characteristic formation of visible, powdery flakes on the skin surface. The inability to degrade these structures ultimately reflects a decreased hydrolytic activity of the desquamatory enzymes, either through reduced synthesis of the enzymes, inherent loss of activity, leaching from the surface layers of the corneum or changes in the surrounding lipid-rich microenvironment, which may indirectly reduce enzyme functionality. Increased understanding of the desquamation process is providing new insights into the mode of action of current moisturizing ingredients and is offering opportunities to develop novel therapies for preventing and correcting dry skin.
antibodies
2024-06-04 | Advancements in Ichthyosis Treatment in Pediatric Patients: Evaluating the Impact of Immune System Inhibitors Targeting TNF-alpha, IL-17A, IL-4, and IL-12
Lamellar, X-linked recessive, and Vulgaris ichthyosis represent rare genetic variants distinguished by abundant dry surface scales. The etiology of childhood ichthyosis involves a combination of acquired and inherited factors. Children with Ichthyosis have a Th17-dominant immune profile, similar to psoriasis, with a correlation between ichthyosis severity, erythema, Trans Epidermal Water Loss (TEWL), and immunological markers. In order to examine the safety and effectiveness of immune system inhibitors that target TNF-alpha, IL-17A, IL-4, and IL-12 in the treatment of pediatric Ichthyosis, a retrospective research study was conducted on 30 pediatric patients aged 6-12 years at tertiary care pediatric dermatology hospitals in UAE, for a time duration of 5 months. IL-17-A is a key cytokine of Ichthyosis, and its specific suppression is considered necessary in contrast to other cytokines. Consequently, the choice of treatment was dictated by elements unique to the condition and the intensity of symptoms, focusing on using Secukinumab as an IL-17-A inhibitor. The findings showed that, following five months of treatment, patients receiving secukinumab showed positive outcomes, with their ichthyosis area severity index score declining by 45 to 50%. Additionally, the proinflammatory rate of cytokines was significantly lower in this group of patients compared to the placebo-treated control group. The safety and Efficacy of Secukinumab compared to Ixekizumab and Brodalumab vs placebo were examined using t-tests, with statistical significance determined at P< 0.05. The present research study concludes that Secukinumab effectively enhances skin texture and reduces scaling severity in Ichthyosis, suggesting clinical relevance. The findings underscore Secukinumab’s potential as a beneficial agent for various ichthyosis types, such as lamellar, X-linked, and vulgaris. The study’s comparison with placebo and other IL-17A inhibitors like Ixekizumab and Brodalumab provides valuable insights into Secukinumab’s Efficacy and potential clinical uses.
2022-11-18 | 305 Overlaps between inflammatory dermatoses and ichthyoses: need for novel therapeutic approaches
Ichthyoses form a heterogeneous group of well-defined inherited skin diseases. However, the comorbidity of these cornification disorders needs to be further investigated, as psoriasiform skin lesions and/or atopic manifestations may be observed in many affected individuals. We recruited 64 patients with ichthyoses, 29 psoriasis and 37 atopic dermatitis (AD) patients, assessed the disease severity by the Ichthyosis Area Severity Index (IASI; 0-48) and pruritus characteristics by the Neuroderm Questionnaire. Further, we performed immunohistochemical stainings of CCL27, Nos2, filaggrin, β-defensin-2 and CD1a on 15 skin samples of ichthyoses and compared them to psoriasis and AD. In ichthyosis the median disease severity was 8 with highest scores in Netherton syndrome (NTS). Generalized pruritus occurred in 84% of patients with a median intensity of 3 on the numeric rating scale (0-10). 13% described neuropathic itch qualities and 15 patients showed an impaired quality of life due to itch. Of note, almost 50% with systemic therapy still described moderate pruritus. In AD pruritus was significantly higher than in the group of psoriasis and ichthyosis (p ≤ 0,01). Staining of CCL27 and Nos2 revealed a psoriasis-like phenotype in more than 50% of ichthyosis patients. Filaggrin deficiency was not only observed in ichthyosis vulgaris (IV), but also in congenital ichthyoses and X-linked ichthyosis. ß-defensin-2 was present in some samples, and there were two patients (IV and XLI) with high levels of CD1a. Atopic diathesis was not only prevalent in IV and NTS, but among all subtypes. We conclude that immunological characterization of ichthyoses according to a psoriasiform or atopic diathese pattern could improve treatment of the disease. Novel targeted therapies may be subject of future clinical studies in ichthyosis to improve itch, skin inflammation and probably scaling.
2016-05-01 | 395 Disease severity and cutaneous inflammation in ichthyosis are linked to Th17 pathway activation
The ichthyoses are rare, disfiguring, sometimes debilitating disorders featuring generalized scaling, erythema, and epidermal barrier impairment. Despite genetic advances, pathogenesis-based therapy is largely lacking given limited insight into molecular pathobiology. To determine if erythema in ichthyosis results from inflammation and correlates with clinical and barrier disease characteristics, we used immunohistochemistry and RT-PCR from biopsied skin of 21 genotyped ichthyosis patients (congenital ichthyosiform erythroderma, lamellar ichthyosis, epidermolytic hyperkeratosis, and Netherton syndrome) and compared them with healthy controls and atopic dermatitis (AD) and psoriasis patients. Clinical measures included transepidermal water loss, pruritus, and a severity scoring for ichthyosis (IASI) that integrates erythema (IASI-E) and scaling (IASI-S). Ichthyosis samples were characterized by increased epidermal hyperplasia (by thickness and K16 expression) and T-cell and dendritic-cells infiltrates, comparable to psoriasis and AD samples. We observed large increases of general inflammatory (IL-2), innate (IL-1β), and Th1/IFN (IFNγ) markers in ichthyosis, as in psoriasis or AD. Expression of Th2 markers (IL-13, IL-31) in ichthyoses was similar to controls. Most notable in ichthyotic skin, however, was significant induction of the Th17/IL-23 pathway (IL-17A, IL-23p40/p19, IL-19, CXCL1, PI3; p<0.05), similar to psoriasis. High correlations were found between IASI and its IASI-E component and IL-17A (r=0.74, p<0.001) or related markers. IASI-S was associated with barrier measures (TEWL, thickness, filaggrin, loricrin). Our data link ichthyosis fingerprinting to Th17/IL-23 polarization, similar to psoriasis, and raise the possibility of IL-17-targeting strategies for the ichthyoses.
oligonucleotides
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.
2024-02-20 | Unraveling the molecular mechanisms of cell migration impairment and apoptosis associated with steroid sulfatase deficiency: Implications for X-linked ichthyosis.
Steroid sulfatase (STS) deficiency is responsible for X-linked ichthyosis (XLI), a genetic disorder characterized by rough and dry skin caused by excessive keratinization. The impaired keratinization process leads to reduced cell mobility and increased apoptosis, which can cause an excessive buildup of the stratum corneum. In this study, we investigated the mechanisms underlying XLI and found that STS deficiency reduces cell mobility and increases apoptosis in human keratinocyte HaCaT cells. To explore these mechanisms further, RNA-sequencing was conducted on skin tissues from STS transgenic and knockout mice. Our RNA-seq results revealed that STS deficiency plays a critical role in regulating multiple signaling pathways associated with cell mobility and apoptosis, such as Wnt/β signaling and the Hippo signaling pathway. Knockdown of the STS gene using shRNA in HaCaT cells led to an upregulation of E-cadherin expression and suppression of key factors involved in epithelial-mesenchymal transition (EMT), such as N-cadherin and vimentin. Inhibition of EMT involved the Hippo signaling pathway and reduction of HIF-1α. Interestingly, inhibiting STS with shRNA increased mitochondrial respiration levels, as demonstrated by the extracellular flux oxygen consumption rate. Additionally, we observed a significant increase in ROS production in partial STS knockout cells compared to control cells. Our study demonstrated that the excessive generation of ROS caused by STS deficiency induces the expression of Bax and Bak, leading to the release of cytochrome c and subsequent cell death. Consequently, STS deficiency impairs cell mobility and promotes apoptosis, offering insights into the pathophysiological processes and potential therapeutic targets for XLI.
2020-08-12 | The Role of MicroRNAs in Epidermal Barrier
MicroRNAs (miRNAs), which mostly cause target gene silencing via transcriptional repression and degradation of target mRNAs, regulate a plethora of cellular activities, such as cell growth, differentiation, development, and apoptosis. In the case of skin keratinocytes, the role of miRNA in epidermal barrier integrity has been identified. Based on the impact of key genetic and environmental factors on the integrity and maintenance of skin barrier, the association of miRNAs within epidermal cell differentiation and proliferation, cell–cell adhesion, and skin lipids is reviewed. The critical role of miRNAs in the epidermal barrier extends the use of miRNAs for control of relevant skin diseases such as atopic dermatitis, ichthyoses, and psoriasis via miRNA-based technologies. Most of the relevant miRNAs have been associated with keratinocyte differentiation and proliferation. Few studies have investigated the association of miRNAs with structural proteins of corneocytes and cornified envelopes, cell–cell adhesion, and skin lipids. Further studies investigating the association between regulatory and structural components of epidermal barrier and miRNAs are needed to elucidate the role of miRNAs in epidermal barrier integrity and their clinical implications.
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Drug Discovery Landscape
2 orphan drug designations for Recessive X-linked ichthyosis.
2 orphan drug designations for Recessive X-linked ichthyosis.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Isotretinoin | small molecules | EMA | 2023-02-15 | — | Granzer Regulatory Consulting & Services GmbH |
Talarozole | small molecules | EMA | 2012-07-04 | — | [INACTIVE] Stiefel Laboratories (Maidenhead) Limited |
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