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Background/Objectives: Staphylococcal scalded skin syndrome (SSSS) is a toxin-mediated skin disorder caused by Staphylococcus aureus (S. aureus), mainly affecting young children. This study aimed to describe the epidemiology, clinical features, microbiology, and management of pediatric SSSS and to explore factors associated with culture positivity, antimicrobial resistance, and complications. Methods: Retrospective cohort study of children hospitalized with SSSS at the major tertiary pediatric hospital in Greece, from January 2009 to December 2019. Exploratory association testing and parsimonious logistic regression were performed. Results: Overall, 51 children with a mean (±SD) age 2.5 ± 2 years were identified. Prior to diagnosis, 70.6% (36/51) of children had not received any antibiotic treatment. S. aureus was isolated from cultures in 43.1% (22/51) of cases. Carriage of S. aureus was detected in 34.0% (16/47) of children and 37.0% (10/27) of parents. Antibiotic resistance (%) for S. aureus was penicillin 95.5%, oxacillin 4.5%, erythromycin 4.5%, clindamycin 9.1%, mupirocin 40.9%, and fusidic acid 18.2%. Annual incidence of SSSS was estimated at 0.00–0.32/1000 hospitalizations from 2009 to 2016, but increased after 2017, reaching the highest incidence in 2019 (1.05/1000 hospitalizations); 50.7% of cases occurred in 2018–2019 (p < 0.001). During this period, resistance to oxacillin (MRSA strains) did not change (p = 0.53), whereas resistance to mupirocin increased over time, from 0% in 2009–2014 to 34.6% in 2018–2019 (p = 0.05). Penicillin was excluded from the composite drug-resistance outcome. Child nasal S. aureus carriage was independently associated with positive S. aureus culture (adjusted odds ratio [aOR] 4.18, 95% CI 1.14–15.27; p = 0.031) and with non-penicillin antibiotic resistance (aOR 25.68, 95% CI 2.64–249.50; p = 0.005). Elevated inflammatory markers were independently associated with complications (aOR 13.66, 95% CI 1.47–126.64; p = 0.021). Regarding treatment, clindamycin was the first-line agent in 58.8% (30/51) and was used as monotherapy in 49.0% (25/51). Conclusions: A notable increase in the incidence of SSSS was detected after 2017. Oxacillin resistance remained stable, but mupirocin resistance increased. Child nasal S. aureus carriage was associated with culture positivity and clinically relevant non-penicillin antibiotic resistance. Continuous surveillance is necessary as regional resistance patterns should guide therapy.

Marinesco–Sjögren syndrome (MSS) is a rare autosomal recessive neuromuscular disorder marked by ataxia, muscle weakness, cataracts, and often intellectual and skeletal abnormalities. It is commonly caused by loss-of-function variants in the SIL1 gene, which impair binding immunoglobulin protein (BiP) function, leading to protein misfolding and activation of the unfolded protein response. In a 2-year-old patient with typical MSS symptoms, we identified a previously unreported c.1024G>A (p.E342K) variant in SIL1 via whole-exome sequencing. The pathogenicity of this Sil1 variant was supported by evidence of structural changes revealed through in silico predictions, circular dichroism, and native gel electrophoresis. Patient-derived fibroblasts exhibited reduced Sil1 protein levels, likely due to misfolding and degradation, which was partially rescued by proteasome inhibition. Proteomics revealed a profile similar to known MSS cases and a distinctive MSS transcriptional signature. Ultrastructural analysis confirmed typical MSS features, such as autophagic vacuoles and lipid droplets. Although the p.E342K phenotype appears milder than the reference pathogenic variant R111X, our findings support the reclassification of this novel variant as pathogenic, in accordance with the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) 2015 guidelines and the refinements proposed by the Clinical Genome Resource Sequence Variant Interpretation (ClinGen SVI) recommendations. Furthermore, the overall evidence also provides important insights into the genotype–phenotype correlation and the underlying pathogenic mechanism of the p.E342K variant.

Background Inherited ichthyoses or Mendelian disorders of cornification (MeDOC) are clinically heterogeneous disorders with high unmet therapeutic needs, which are characterized by skin hyperkeratosis and scaling. Some MeDOC types are associated with defects of the epidermal lipid metabolism, resulting in perturbed barrier permeability and subsequent epidermal hyperplasia, hyperkeratosis and inflammation. An example is the CHILD (congenital hemidysplasia with ichthyosiform nevus and limb defects) syndrome, an X-linked dominant multisystem MeDOC caused by mutations in the NSDHL (NAD(P)H steroid dehydrogenase-like protein) gene, which is involved in the distal cholesterol biosynthetic pathway. The skin manifestations of the CHILD syndrome have been attributed to two major mechanisms: deficiency of cholesterol, probably influencing the proper corneocyte membrane formation, and toxic accumulation of aberrant steroid precursors. Methods Here we addressed the efficacy of an ointment containing cholesterol and simvastatin, an agent inhibiting endogenous cholesterol synthesis in a compassionate-use treatment of three patients with CHILD syndrome. To test the specificity of this therapeutic approach, we applied the same topical treatment to two patients with other types of MeDOC with disturbed skin lipid metabolism. Results The therapy with simvastatin and cholesterol was highly effective and well-tolerated by the CHILD syndrome patients; only lesions in the body folds represented a therapeutic challenge. No improvement was noted in the patients with other types of MeDOC. Conclusions This therapy is inexpensive and accessible to every patient with CHILD syndrome, because both simvastatin and cholesterol are available worldwide. Our data provide initial evidence of the specificity of the therapeutic effect of the simvastatin-cholesterol ointment in CHILD syndrome in comparison to other types of MeDOC.

Netherton syndrome (NS) is a severe skin disease caused by loss-of-function mutations in SPINK5 (serine protease inhibitor Kazal-type 5) encoding the serine protease inhibitor LEKTI (lympho-epithelial Kazal type-related inhibitor). Here, we disclose new SPINK5 defects in 12 patients, who presented a clinical triad suggestive of NS with variations in inter- and intra-familial disease expression. We identified a new and frequent synonymous mutation c.891C>T (p.Cys297Cys) in exon 11 of the 12 NS patients. This mutation disrupts an exonic splicing enhancer sequence and causes out-of-frame skipping of exon 11. Haplotype analysis indicates that this mutation is a founder mutation in Greece. Two other new deep intronic mutations, c.283-12T>A in intron 4 and c.1820+53G>A in intron 19, induced partial intronic sequence retention. A new nonsense c.2557C>T (p.Arg853X) mutation was also identified. All mutations led to a premature termination codon resulting in no detectable LEKTI on skin sections. Two patients with deep intronic mutations showed residual LEKTI fragments in cultured keratinocytes. These fragments retained some functional activity, and could therefore, together with other determinants, contribute to modulate the disease phenotype. This new founder mutation, the most frequent mutation described in European populations so far, and these unusual intronic mutations, widen the clinical and molecular spectrum of NS and offer new diagnostic perspectives for NS patients.