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:
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.
2026-01-15 | 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.
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.
2025-12-22 | 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
Abstract 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.
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.
2026-01-15 | 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.
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.
2025-12-22 | 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
Abstract 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.
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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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