RARE DISEASE
Keratinopathic ichthyosis
Keratinopathic ichthyosis
Keratinopathic ichthyosis
Synonyms: KPI
Synonyms: KPI
Synonyms: KPI
Drug discovery
1
drug
With orphan designation
Overview
Keratinopathic ichthyosis comprises rare genetic disorders caused by mutations in KRT1, KRT10, or KRT2 genes, disrupting keratinocyte integrity. Clinical features include congenital blistering, erythroderma, and hyperkeratosis evolving into scales, with phenotypic variations such as epidermolytic ichthyosis (EI) and superficial EI. Palmoplantar keratoderma is common in KRT1 mutations. Complications include infections, pruritus, and mobility limitations [1][2][12][17].
Categories: rare genetic diseases, rare skin diseases
Research Papers
9 drug discovery papers about Keratinopathic ichthyosis, with 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
9 drug discovery papers about Keratinopathic ichthyosis, with 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2023-09-22 | Clinical and genetic findings in 13 Chinese children with keratinopathic ichthyosis.
Keratinopathic ichthyosis (KPI) represents a group of predominantly autosomal dominant genodermatoses resulting from mutations in the KRT1, KRT2, or KRT10 genes. In KPI, the relationship between genotype and phenotype is complex. To analyze the clinical manifestations and gene mutations in Chinese patients with KPI. Clinical data were collected from 13 children diagnosed with KPI, and peripheral blood DNA samples were extracted from both the patients and their parents Next-generation sequencing was performed using a congenital ichthyosis multi-gene panel, and the selected variants in the patients and their parents were further validated using the Sanger sequencing method. Genetic analysis identified missense mutations in either KRT1 or KRT10 in ten patients exhibiting varying degrees of severity and distinct features of epidermolytic ichthyosis. A missense hotspot mutation in KRT2 was identified in one patient with superficial epidermolytic ichthyosis. Additionally, two truncation mutations in KRT10 were detected, leading to the development of generalized ichthyosiform erythroderma. Ear malformation and ectropion at birth, scalp involvement, and palmoplantar hyperkeratosis were observed as early signs of ichthyosis with confetti. We analyzed the genotype-phenotype correlations in KPI, revealing that the types and locations of different mutations are associated with distinct phenotypic characteristics. Oral acitretin could be considered a treatment option for severe patients at an appropriate dosage and timing.
2023-03-20 | A Case of Epidermolytic Ichthyosis with Massive Hyperkeratosis Successfully Treated with Systemic Etretinate
A 2-day-old female infant was referred to our department because of diffuse erythema, blistering, and denuded skin over the body.Her skin had decreased blistering, however, diffuse erythema with scaling became more prominent with age.Histopathology showed marked orthohyperkeratosis and acanthosis accompanied by granular degeneration.Mutational analysis for KRT10 revealed a previously reported variant, c.467G>A (p.Arg156His) in the heterozygous state.Taken together, the diagnosis of Epidermolytic Ichthyosis (EI) caused by a KRT10 variant was confirmed.Oral retinoids dramatically decreased the hyperkeratosis.Among reported cases of EI caused by mutations in KRT10, the most frequent mutation is Arg156His.Most patients with EI reported in the literature with mutations at Arg156 have a severe phenotype.This arginine residue and the surrounding residues are conserved in all type I keratins throughout evolution.These findings suggest that the arginine residue is structurally critical to the formation of the keratin filament network.In patients with EI, epidermal barrier function is decreased, indicating that the phenotype of EI can result from not only aberrant keratinization but also mutational skin barrier defects.Etretinate is a retinoid that encourages desquamation and can induce prompt keratinization.It has been reported that retinoid therapy is much more effective in patients with KRT10 mutations compared to those with KRT1 mutations.In addition, EI patients with more extensive involvement benefit more from retinoids than those with mild or limited involvement.Therefore, retinoid should be considered as the first therapeutic option for severe EI and EI caused by KRT10 mutations.
2022-12-01 | 273 Serum interleukin-18 as a disease-specific marker of epidermolytic ichthyosis: a potential therapeutic target
Epidermolytic ichthyosis (EI) is a major form of congenital ichthyosis and characterized by erythroderma, marked scales, bulla, and erosions at birth. EI is recently classified as keratinopathic ichthyoses and caused mainly by heterozygous mutations in the KRT1 or KRT10 genes, encoding keratin (K) 1 or K10, respectively. No effective treatment strategy for EI has been established yet. To investigate disease-specific markers and novel therapeutic targets in EI, we examined serum samples for 9 patients with congenital ichthyoses including five EI patients, one ichthyosis with confetti patient, one Netherton syndrome patient, and two autosomal recessive congenital ichthyosis patients. Firstly, multiplex bead-based cytokine assays were performed in serum samples for congenital ichthyoses patients and healthy controls. Several inflammatory cytokines were elevated in serum for EI patients and we focused on interleukin(IL)-18 which was markedly elevated in EI patients. ELISA analysis also revealed serum IL-18 significantly increased in EI patients (3675.5±1869.7 pg/mL, mean±SEM) compared with healthy controls and other types of ichthyosis patients (226.7±40.9 pg/mL, p<0.001). Further, to investigate whether mutant K1 promotes IL-18 production in keratinocytes, we generated cDNA constructs harboring wild-type or mutant KRT1 and performed in vitro experiments. HaCaT cells expressing mutant K1 showed NLRP3 aggregated in the cytoplasm, suggesting NLRP3 inflammasome activation and its downstream caspase-1-mediated IL-18 activation. Our results might suggest a novel pathogenic hypothesis for EI in which mutant keratins cause NLRP3 inflammasome activation and a novel treatment option using IL-18 blockade.
2022-01-11 | Analysis of the structure and function of the epidermal barrier in patients with ichthyoses—clinical and electron microscopical investigations
Ichthyoses are pathogenetically characterized by a pronounced disorder of the epidermal barrier. Clinically, hyperkeratosis, severe scaling and erythroderma are present on the entire integument. The time-consuming therapy includes daily baths and the application of skin care products to restore the epidermal barrier.To enhance the knowledge about the structure and function of the epidermal barrier in ichthyoses, we conducted clinical, biophysical and electron microscopical measurements on 46 patients with ichthyoses, including autosomal recessive ichthyoses, keratinopathic ichthyoses, X-chromosomal-recessive ichthyosis and Netherton syndrome.The patients displayed a significantly decreased skin hydration along with unexpectedly low transepidermal waterloss values. Electron microscopical examinations demonstrated a severe occlusion of the epidermis by lipid remnants of skin care products in the stratum corneum. We found decreased intercellular lipid lamellae and an increased undulation of the corneocyte membrane of all ichthyoses, mostly pronounced in Netherton syndrome. The lipid profiles of ichthyoses showed decreased esterified Ω-hydroxy-sphingosine (EOS) ceramide levels.The results demonstrate the extent of the epidermal barrier disruption in ichthyoses. In combination with the knowledge about pathogenetic causes, individually improved therapeutic options can be derived from our results. In the future, the analyses of the organization of intercellular lipid lamellae and corneocyte membrane undulation will enable improved investigations of the epidermal barrier in ichthyoses and may be used to study and evaluate possible effects of topical skin preparations.
2018-07-23 | Cryptotanshinone from Salvia miltiorrhiza Roots Reduces Cytokeratin CK1/10 Expression in Keratinocytes by Activation of Peptidyl-prolyl-cis-trans-isomerase FKBP1A
Abstract Cryptotanshinone (CTS) (1 µM) from the roots of Salvia miltiorrhiza exerts a strong influence on the terminal differentiation of human keratinocytes (HaCaT cell line, primary natural human keratinocytes) and downregulates the expression of differentiation-specific cytokeratins CK1 and CK10 on protein and gene level. Other differentiation specific proteins as involucrin, filaggrin, loricrin, and transglutaminase were not affected to a higher extent. CTS (1 µM) did not influence the cell viability and the proliferation of keratinocytes. Using a combination of drug affinity response target stability assay in combination with a proteomic approach and multivariate statistics for target elucidation, peptidyl-prolyl-cis-trans-isomerase FKBP1A (known target of inhibitors such as tacrolimus or rapamycin) was addressed as potential molecular target of CTS. The interaction of CTS with FKBP1A was additionally shown by thermal shift and enzymatic activity assays. Interestingly, CTS served as an activator of FKBP1A, which led to a reduced activity of the TGFβ receptor pathway and therefore to a diminished CK1 and CK10 expression. The combination of the FKBP1A activator CTS with the inhibitor tacrolimus neutralized the effects of both compounds. From these data, a potential dermatological use of CTS and CTS-containing plant extracts (e.g., hydroalcoholic extract from the roots of S. miltiorrhiza) for keratinopathic ichthyosis, a disease characterized by overexpression of CK1 and CK10, is discussed. This study displays an experimental strategy for combining phytochemical aspects on active natural products with systematic identification of molecular targets on gene, protein, and cell level.
2023-09-22 | Clinical and genetic findings in 13 Chinese children with keratinopathic ichthyosis.
Keratinopathic ichthyosis (KPI) represents a group of predominantly autosomal dominant genodermatoses resulting from mutations in the KRT1, KRT2, or KRT10 genes. In KPI, the relationship between genotype and phenotype is complex. To analyze the clinical manifestations and gene mutations in Chinese patients with KPI. Clinical data were collected from 13 children diagnosed with KPI, and peripheral blood DNA samples were extracted from both the patients and their parents Next-generation sequencing was performed using a congenital ichthyosis multi-gene panel, and the selected variants in the patients and their parents were further validated using the Sanger sequencing method. Genetic analysis identified missense mutations in either KRT1 or KRT10 in ten patients exhibiting varying degrees of severity and distinct features of epidermolytic ichthyosis. A missense hotspot mutation in KRT2 was identified in one patient with superficial epidermolytic ichthyosis. Additionally, two truncation mutations in KRT10 were detected, leading to the development of generalized ichthyosiform erythroderma. Ear malformation and ectropion at birth, scalp involvement, and palmoplantar hyperkeratosis were observed as early signs of ichthyosis with confetti. We analyzed the genotype-phenotype correlations in KPI, revealing that the types and locations of different mutations are associated with distinct phenotypic characteristics. Oral acitretin could be considered a treatment option for severe patients at an appropriate dosage and timing.
2023-03-20 | A Case of Epidermolytic Ichthyosis with Massive Hyperkeratosis Successfully Treated with Systemic Etretinate
A 2-day-old female infant was referred to our department because of diffuse erythema, blistering, and denuded skin over the body.Her skin had decreased blistering, however, diffuse erythema with scaling became more prominent with age.Histopathology showed marked orthohyperkeratosis and acanthosis accompanied by granular degeneration.Mutational analysis for KRT10 revealed a previously reported variant, c.467G>A (p.Arg156His) in the heterozygous state.Taken together, the diagnosis of Epidermolytic Ichthyosis (EI) caused by a KRT10 variant was confirmed.Oral retinoids dramatically decreased the hyperkeratosis.Among reported cases of EI caused by mutations in KRT10, the most frequent mutation is Arg156His.Most patients with EI reported in the literature with mutations at Arg156 have a severe phenotype.This arginine residue and the surrounding residues are conserved in all type I keratins throughout evolution.These findings suggest that the arginine residue is structurally critical to the formation of the keratin filament network.In patients with EI, epidermal barrier function is decreased, indicating that the phenotype of EI can result from not only aberrant keratinization but also mutational skin barrier defects.Etretinate is a retinoid that encourages desquamation and can induce prompt keratinization.It has been reported that retinoid therapy is much more effective in patients with KRT10 mutations compared to those with KRT1 mutations.In addition, EI patients with more extensive involvement benefit more from retinoids than those with mild or limited involvement.Therefore, retinoid should be considered as the first therapeutic option for severe EI and EI caused by KRT10 mutations.
2022-12-01 | 273 Serum interleukin-18 as a disease-specific marker of epidermolytic ichthyosis: a potential therapeutic target
Epidermolytic ichthyosis (EI) is a major form of congenital ichthyosis and characterized by erythroderma, marked scales, bulla, and erosions at birth. EI is recently classified as keratinopathic ichthyoses and caused mainly by heterozygous mutations in the KRT1 or KRT10 genes, encoding keratin (K) 1 or K10, respectively. No effective treatment strategy for EI has been established yet. To investigate disease-specific markers and novel therapeutic targets in EI, we examined serum samples for 9 patients with congenital ichthyoses including five EI patients, one ichthyosis with confetti patient, one Netherton syndrome patient, and two autosomal recessive congenital ichthyosis patients. Firstly, multiplex bead-based cytokine assays were performed in serum samples for congenital ichthyoses patients and healthy controls. Several inflammatory cytokines were elevated in serum for EI patients and we focused on interleukin(IL)-18 which was markedly elevated in EI patients. ELISA analysis also revealed serum IL-18 significantly increased in EI patients (3675.5±1869.7 pg/mL, mean±SEM) compared with healthy controls and other types of ichthyosis patients (226.7±40.9 pg/mL, p<0.001). Further, to investigate whether mutant K1 promotes IL-18 production in keratinocytes, we generated cDNA constructs harboring wild-type or mutant KRT1 and performed in vitro experiments. HaCaT cells expressing mutant K1 showed NLRP3 aggregated in the cytoplasm, suggesting NLRP3 inflammasome activation and its downstream caspase-1-mediated IL-18 activation. Our results might suggest a novel pathogenic hypothesis for EI in which mutant keratins cause NLRP3 inflammasome activation and a novel treatment option using IL-18 blockade.
2022-01-11 | Analysis of the structure and function of the epidermal barrier in patients with ichthyoses—clinical and electron microscopical investigations
Ichthyoses are pathogenetically characterized by a pronounced disorder of the epidermal barrier. Clinically, hyperkeratosis, severe scaling and erythroderma are present on the entire integument. The time-consuming therapy includes daily baths and the application of skin care products to restore the epidermal barrier.To enhance the knowledge about the structure and function of the epidermal barrier in ichthyoses, we conducted clinical, biophysical and electron microscopical measurements on 46 patients with ichthyoses, including autosomal recessive ichthyoses, keratinopathic ichthyoses, X-chromosomal-recessive ichthyosis and Netherton syndrome.The patients displayed a significantly decreased skin hydration along with unexpectedly low transepidermal waterloss values. Electron microscopical examinations demonstrated a severe occlusion of the epidermis by lipid remnants of skin care products in the stratum corneum. We found decreased intercellular lipid lamellae and an increased undulation of the corneocyte membrane of all ichthyoses, mostly pronounced in Netherton syndrome. The lipid profiles of ichthyoses showed decreased esterified Ω-hydroxy-sphingosine (EOS) ceramide levels.The results demonstrate the extent of the epidermal barrier disruption in ichthyoses. In combination with the knowledge about pathogenetic causes, individually improved therapeutic options can be derived from our results. In the future, the analyses of the organization of intercellular lipid lamellae and corneocyte membrane undulation will enable improved investigations of the epidermal barrier in ichthyoses and may be used to study and evaluate possible effects of topical skin preparations.
2018-07-23 | Cryptotanshinone from Salvia miltiorrhiza Roots Reduces Cytokeratin CK1/10 Expression in Keratinocytes by Activation of Peptidyl-prolyl-cis-trans-isomerase FKBP1A
Abstract Cryptotanshinone (CTS) (1 µM) from the roots of Salvia miltiorrhiza exerts a strong influence on the terminal differentiation of human keratinocytes (HaCaT cell line, primary natural human keratinocytes) and downregulates the expression of differentiation-specific cytokeratins CK1 and CK10 on protein and gene level. Other differentiation specific proteins as involucrin, filaggrin, loricrin, and transglutaminase were not affected to a higher extent. CTS (1 µM) did not influence the cell viability and the proliferation of keratinocytes. Using a combination of drug affinity response target stability assay in combination with a proteomic approach and multivariate statistics for target elucidation, peptidyl-prolyl-cis-trans-isomerase FKBP1A (known target of inhibitors such as tacrolimus or rapamycin) was addressed as potential molecular target of CTS. The interaction of CTS with FKBP1A was additionally shown by thermal shift and enzymatic activity assays. Interestingly, CTS served as an activator of FKBP1A, which led to a reduced activity of the TGFβ receptor pathway and therefore to a diminished CK1 and CK10 expression. The combination of the FKBP1A activator CTS with the inhibitor tacrolimus neutralized the effects of both compounds. From these data, a potential dermatological use of CTS and CTS-containing plant extracts (e.g., hydroalcoholic extract from the roots of S. miltiorrhiza) for keratinopathic ichthyosis, a disease characterized by overexpression of CK1 and CK10, is discussed. This study displays an experimental strategy for combining phytochemical aspects on active natural products with systematic identification of molecular targets on gene, protein, and cell level.
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Drug Discovery Landscape
1 orphan drug designation for Keratinopathic ichthyosis.
1 orphan drug designation for Keratinopathic ichthyosis.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Talarozole | small molecules | EMA | 2012-07-04 | — | [INACTIVE] Stiefel Laboratories (Maidenhead) Limited |
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