We report the case of a 4-year-old boy diagnosed with keratitis-ichthyosis-deafness (KID) syndrome with long-term follow-up, including multiple surgical and nonsurgical treatments. Genetic testing revealed a missense GJB2 mutation (p.Asp50Asn). His ocular condition deteriorated to the point that, at 37 years of age, he required bilateral keratoprosthesis (KPro) implantation, resulting in best-corrected visual acuity of 20/25 in the right eye and 20/40 in the left eye. Our findings suggest that more advanced cases of KID syndrome may benefit from treatment options that rely less on ocular surface stability, such as KPro implantation, whereas therapies that treat the ocular surface may be preferred in early-stage disease.

Protein-bound ceramides are a specialized subclass of ceramides that are essential for skin barrier function, and their defective formation leads to severe skin disorder ichthyosis. Despite their biological importance, the precise molecular structures of protein-bound ceramides have remained incompletely defined, largely due to the technical challenges arising from their unique covalent linkage between lipid and protein components with highly distinct physicochemical properties. We investigated whether epoxy-ketone (EpK)-type protein-bound ceramides present in mouse epidermis are conserved in human skin. Mass spectrometric analyses of epoxy-enone (EpE) acylceramides reversibly released from EpK-type protein-bound ceramides revealed only low levels in human stratum corneum. Instead, much higher amounts of dihydroxy-enone (DiHE) acylceramides were detected, indicating that dihydroxy-ketone (DiHK)-type protein-bound ceramides are predominant in human skin. In contrast, DiHK-type protein-bound ceramides were present in mouse epidermis at much lower levels. DiHE acylceramides appeared as two chromatographically distinct peaks, which likely correspond to putative stereoisomers with (9R,10S) and (9R,10R) configurations. Age-dependent increases in the (9R,10S) form in mouse epidermis closely paralleled changes in the expression levels of the epoxide hydrolase Ephx3, suggesting a role for EPHX3 in the conversion of epoxy-type ceramides to dihydroxy-type ceramides through epoxide ring opening. Together, these findings reveal molecular diversity in protein-bound ceramides and a fundamental difference between human and mouse epidermal lipid architectural organization.

Repetin (RPTN) is a member of the fusion S100 protein family encoded within the epidermal differentiation complex. Although genetic studies have revealed that RPTN is a susceptibility gene for atopic dermatitis (AD), its biological function remains poorly understood. In this study, we investigated the role of RPTN in epidermal homeostasis and inflammatory skin diseases. We examined RPTN expression in normal skin, inflammatory skin diseases, and differentiated normal human keratinocytes (NHKs). Functional analyses were performed using RPTN knockdown (KD) NHK and three-dimensional (3D) skin-equivalent models. Epidermal barrier function was assessed using a lucifer yellow permeability assay, and cytokine-mediated regulation of RPTN expression was evaluated using 3D atopic dermatitis (AD) and psoriasis models. RPTN was primarily expressed in the granular layer of the normal epidermis and increased with keratinocyte differentiation. In the 3D skin-equivalent model, RPTN deficiency impaired epidermal barrier function and induced the expression of differentiation-related genes, including FLG, IVL, TGM1, CLDN1, KLK7, ALOX12, and TCHHL1. Notably, RPTN knockdown significantly increased IL-25 expression. RPTN expression was elevated in chronic atopic dermatitis (AD) lesions and in hypergranular epithelia of psoriasis vulgaris, lichen planus, and epidermolytic ichthyosis. In a 3D AD model, IL-4 and IL-13 significantly induced RPTN expression. These findings indicate that RPTN contributes to maintaining epidermal barrier homeostasis and suggest that it may be associated with regulating inflammatory responses.

Acute myeloid leukemia may occur in patients with xeroderma pigmentosum at a younger age and can be associated with complex cytogenetics and poor treatment response, highlighting the importance of regular hematologic monitoring.

Background: Congenital ichthyoses are a clinically and genetically heterogeneous group of Mendelian disorders of cornification. According to the 2025 classification, non-syndromic epidermal differentiation disorders (nEDDs) are categorized based on the biological function of the causative gene products. Variants in TGM1 cause a transglutaminase-related nEDD (TGM1-nEDD), typically corresponding to the traditional phenotype of lamellar ichthyosis (LI), whereas biallelic variants in CYP4F22 cause a lipid-metabolism-related nEDD (CYP4F22-nEDD), formerly classified as ARCI type 5. The latter form is characterized by impaired acylceramide synthesis and epidermal barrier dysfunction. Although CYP4F22-nEDD usually follows a persistent course, considerable phenotypic variability has been reported, including milder forms and self-improving collodion ichthyosis. Methods and Results: We report two unrelated Italian neonates with congenital ichthyosis, investigated by targeted next-generation sequencing (NGS). Patient 1 presented with a phenotype consistent with LI and carried compound heterozygous TGM1 variants: the known pathogenic c.1147G>A p.(Val383Met) variant, and the novel c.860C>T p.(Thr287Ile) variant, classified as likely pathogenic according to the American College of Medical Genetics and Genomics (ACMG) criteria. Patient 2 presented as a collodion baby and carried two heterozygous CYP4F22 variants: the known pathogenic nonsense variant c.1084C>T p.(Arg362Ter), and the previously unreported in-frame deletion c.543_545del p.(Ile181del), currently classified as a variant of uncertain significance (VUS). Because parental segregation analysis was unavailable, the allelic phase of the CYP4F22 variants could not be established, and molecular confirmation of autosomal recessive inheritance was not possible. Both patients showed marked clinical improvement during follow-up with topical emollient therapy alone. In Patient 2, the clinical course was consistent with a self-improving collodion ichthyosis phenotype. A structured literature review was performed to contextualize the clinical and molecular findings. Conclusions: These cases illustrate the clinical and genetic heterogeneity of nEDDs, and confirm the value of NGS in the management of neonates with congenital ichthyosis. The principal novelty of this report lies in the identification of previously unreported TGM1 and CYP4F22 sequence variants. While functional validation is lacking, integration of clinical and genetic findings with literature evidence may assist interpretation of rare variants and support genetic counselling.

Harlequin ichthyosis (HI) is a rare epidermal differentiation disorder characterized by thick hyperkeratotic plates, fissuring, and high neonatal morbidity. Long-term management remains challenging. We report two children with genetically confirmed HI who demonstrated meaningful improvement in pruritus, erythema, scaling, and overall well-being following dupilumab therapy, suggesting a potential role for IL-4/IL-13 blockade as an adjunct or alternative treatment in HI.

Extremely rare cases show co-occurrence of Sjogren-Larsson syndrome (SLS) and central precocious puberty (CPP), and our understanding of it is still limited. In this case report, we reported a 9-year-old boy (weight: 20 kg; height: 120 cm) showing SLS and CPP simultaneously. The patient presented to our hospital with testicle enlargement and presence of pubic hair. SLS was diagnosed based on the presence of ichthyosis and intelligent disability, together with genetic confirmation by next-generation sequencing, which identified two pathogenic variants (c.608_609del and c.1157A>G) in the ALDH3A2 gene. The diagnosis of CPP was established based on mildly advanced bone age, ultrasonographic evidence of pubertal development, and elevated basal gonadotropin and testosterone levels. The patient subsequently received triptorelin acetate (3.75mg) for treating CPP, while merely moisturization and rehabilitation was used for treating SLS. In the follow-up, he showed growth delay, with a body height of 120 cm at age 8.5 years old and 123.5 cm at 9.5 years old.

Nucleotide excision repair (NER) is a conserved genome maintenance pathway that removes bulky, helix-distorting DNA lesions, including ultraviolet-induced photoproducts and chemically induced adducts. By restoring DNA integrity, NER preserves transcriptional continuity and replicative fitness, thereby limiting mutagenesis, replication stress, and cell death. Inherited defects in NER genes cause rare disorders such as xeroderma pigmentosum (XP), Cockayne syndrome (CS), and trichothiodystrophy (TTD), classically associated with photosensitivity, neurodevelopmental impairment, growth failure, and, in some subtypes, marked cancer predisposition. Traditionally, clinical attention has focused on dermatologic and neurologic manifestations, whereas immune dysfunction has been regarded as peripheral or secondary. Recent clinical and immunological studies indicate that immune abnormalities may represent an underrecognized component of selected NER disorders. Reported findings include impaired vaccine responses, hypogammaglobulinemia, IgG subclass deficiency, altered B cell differentiation, CD4 lymphopenia, restricted T cell receptor repertoires, and defective dendritic cell maturation. These abnormalities are not evenly distributed across the NER spectrum and appear more prominent in selected molecular subgroups. In particular, disorders affecting transcription-associated NER functions, including TFIIH-linked conditions, may combine impaired DNA repair with reduced transcriptional capacity, thereby increasing immune-cell vulnerability during activation. By contrast, many repair-dominant XP subtypes seem to retain largely preserved baseline immune function, although clinically relevant abnormalities may become apparent during infection, vaccination, or other immune challenges. In this Mini Review, we summarize clinical evidence for immune dysfunction in NER disorders, interpret it in the context of global genome and transcription-coupled NER, and discuss implications for immunological assessment and inborn errors of immunity-oriented classification.