先天性魚鱗癬

Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of inherited cornification disorders caused by defects in epidermal barrier formation. Mutations in CYP4F22 are an uncommon cause of ARCI and are associated with variable phenotypes including lamellar ichthyosis (LI) and congenital ichthyosiform erythroderma (CIE). This is a report of a genetically confirmed case of CYP4F22-related ARCI in a child born to consanguineous parents who presented with collodion membrane at birth followed by persistent ichthyosiform scaling and palmoplantar keratoderma. Genetic analysis identified a homozygous pathogenic CYP4F22 variant, c.1303C>T p.(His435Tyr). In addition to cutaneous findings, the patient had Hirschsprung disease managed surgically during infancy and was followed by pediatric nephrology for Bartter-like manifestations associated with hypokalemia and bilateral renal stones. This case highlights the importance of recognizing phenotypic heterogeneity of CYP4F22-associated ARCI and describes unusual extracutaneous manifestations in association with this rare genodermatosis.

INTRODUCTION AND IMPORTANCE: X-linked ichthyosis (XLI) is a genetic condition characterized by scaly skin due to steroid sulfatase (STS) deficiency, often associated with additional neurodevelopmental issues. CASE PRESENTATION: A 10-year-old male child was admitted to the dermatology department. The child had been born prematurely at 26 weeks' gestation with a low birth weight of 1.6 kg. He presented with seizures characterized by abnormal upper-limb movements and was diagnosed with congenital ichthyosis. The child exhibited delayed language and motor development, learning difficulties, microcephaly, and dry, scaly skin, which he habitually peeled and ingested. Genetic analysis (single-nucleotide polymorphism and combined comparative genomic hybridization) revealed a 1.65 Mb deletion on chromosome Xp22.31 affecting the STS gene and other adjacent genes. The patient had low STS enzyme activity (3.5 nmol/hour/protein) in adipose tissue. Neuroimaging showed no structural abnormalities, though an electroencephalogram indicated mild slowing. CLINICAL DISCUSSION: Given the established association between STS deletions and neurodevelopmental as well as psychiatric comorbidities, early recognition of emerging psychiatric features is essential. Given the established association between STS deletions and neurodevelopmental as well as psychiatric comorbidities, early recognition of emerging psychiatric manifestations is essential. Management should follow evidence-based recommendations for first-episode or early psychotic symptoms, emphasizing careful assessment, individualized pharmacological treatment when indicated, and multidisciplinary psychosocial support. Such an approach may improve clinical stabilization while avoiding premature diagnostic labeling. CONCLUSION: This case highlights the importance of early genetic diagnosis and personalized treatment approaches, integrating dermatological, neurological, and psychiatric care to optimize outcomes in XLI.

Cholesterol plays a critical role in maintaining normal physiological functions, and it is particularly important in skin tissue. Dysregulation of cholesterol metabolism can lead to a spectrum of skin disorders, including ichthyosis, porokeratosis, keratosis follicularis spinulosa decalvans and related diseases. While the pathogenesis of certain genodermatoses of keratinization has been clearly linked to abnormal cholesterol metabolism, known genetic mutations account for only a subset of cases, suggesting additional cholesterol-linked modifiers, suggesting a potential involvement of cholesterol-related pathways. This review summarizes recent advances in understanding genodermatoses of keratinization associated with disrupted cholesterol metabolism and discusses their underlying molecular mechanisms. A better understanding of cholesterol dysregulation may facilitate the identification of novel diagnostic biomarkers and therapeutic targets, providing new opportunities for precision management of inherited keratinization disorders.

Orai1, the pore-forming subunit of the calcium (Ca2+) release-activated Ca2+ (CRAC) channel, plays a central role in store-operated Ca2+ entry (SOCE) in animal cells and thereby serves as a key regulator of intracellular Ca2+ homeostasis. Disruption of this tightly controlled process is associated with a wide spectrum of human diseases. Dysfunction can result from a multitude of remodeling mechanisms, including altered protein expression (up- or downregulation), assembly remodeling, or mutations. We focus in particular on Orai1 mutations, which have been linked to severe combined immunodeficiency (SCID) as a result of channel loss-of-function (LoF), as well as to disorders like tubular aggregate myopathy (TAM) and Stormorken syndrome (STRMK) arising from gain-of-function (GoF) alterations. These mutation-induced functional defects can be attributed to a wide variety of disruptions in the complex activation cascade of the Orai1 channel. Under physiological conditions, Orai1 activation involves all four transmembrane (TM) domains and follows a sophisticated interaction mechanism that ensures accurate signal transmission from the protein periphery toward its central Ca2+-conducting pore. In this Review, we compile all currently known disease-associated Orai1 mutations, delineate the mechanisms by which they interfere with the activation cascade, and discuss their pathological relevance. Their widespread distribution across all the domains of this Ca2+ channel highlights that malfunctions at virtually any point along the Orai1 TM domain interfaces can profoundly impair its activation mechanism, ultimately leading to severe diseases.

Background/Objectives: Congenital ichthyoses (CI) are inherited disorders of keratinization characterized by epidermal barrier dysfunction, abnormal desquamation, and variable degrees of inflammation. Increasing evidence suggests a role for IL-23/Th17-mediated immune dysregulation in some CI subtypes, providing a rationale for targeted biologic therapies. Secukinumab, an anti-IL-17A monoclonal antibody, has emerged as a potential therapeutic option, although real-world evidence remains limited. This study evaluated the effectiveness of secukinumab in adult patients with severe CI. Methods: We performed a retrospective monocentric case series including eight adult patients with severe congenital ichthyosis treated with secukinumab for at least six months and followed for up to 56 months. Clinical outcomes included Investigator Global Assessment (IGA) scores for erythema, scaling, scalp involvement, and palmoplantar hyperkeratosis, together with pruritus assessed by Numeric Rating Scale (NRS). Results: Erythema and scaling showed most of their improvement during the first six months of treatment, after which mean clinical scores remained relatively stable throughout follow-up. At the last available assessment, improvement rates were 100% for erythema, 87.5% for trunk and limb scaling, 100% for scalp scaling, and 75% for palmoplantar hyperkeratosis. Hyperkeratosis showed a less pronounced response than inflammatory manifestations. Pruritus improved within the first 3-4 months of treatment and was sustained over time, with mean NRS scores decreasing from 6.5 at baseline to below 4 within 3-4 months. No discontinuations due to adverse events or lack of efficacy were recorded. Conclusions: Secukinumab was associated with clinically meaningful improvements in inflammatory manifestations of CI, particularly erythema and pruritus, while showing a more limited effect on hyperkeratotic features. These findings support the potential role of IL-17 inhibition in selected CI phenotypes.