C1Q labels a highly aggressive macrophage-like leukemia population indicating extramedullary infiltration and relapse.

Extramedullary infiltration (EMI) is a concomitant manifestation that may indicate poor outcome of acute myeloid leukemia (AML). The underlying mechanism remains poorly understood and therapeutic options are limited. Here, we employed single-cell RNA sequencing on bone marrow (BM) and EMI samples from a patient with AML presenting pervasive leukemia cutis. A complement C1Q+ macrophage-like leukemia subset, which was enriched within cutis and existed in BM before EMI manifestations, was identified and further verified in multiple patients with AML. Genomic and transcriptional profiling disclosed mutation and gene expression signatures of patients with EMI that expressed high levels of C1Q. RNA sequencing and quantitative proteomic analysis revealed expression dynamics of C1Q from primary to relapse. Univariate and multivariate analysis demonstrated adverse prognosis significance of C1Q expression. Mechanistically, C1Q expression, which was modulated by transcription factor MAF BZIP transcription factor B, endowed leukemia cells with tissue infiltration ability, which could establish prominent cutaneous or gastrointestinal EMI nodules in patient-derived xenograft and cell line-derived xenograft models. Fibroblasts attracted migration of the C1Q+ leukemia cells through C1Q-globular C1Q receptor recognition and subsequent stimulation of transforming growth factor ß1. This cell-to-cell communication also contributed to survival of C1Q+ leukemia cells under chemotherapy stress. Thus, C1Q served as a marker for AML with adverse prognosis, orchestrating cancer infiltration pathways through communicating with fibroblasts and represents a compelling therapeutic target for EMI.

Genotype and phenotype correlations in 441 patients with epidermolysis bullosa from China.

BACKGROUND: Epidermolysis bullosa (EB) is a heterogeneous group of rare and incurable genetic blistering disorders. OBJECTIVES: The objective was to analyse the genotype-phenotype correlation in EB among Chinese individuals. METHODS: Next-generation sequencing and Sanger sequencing were performed to genetically confirm clinically diagnosed EB. Reverse transcription-PCR and splice-site analysis were used to evaluate the consequences of splicing mutations. RESULTS: A total of 441 cases (413 families) across 11 genes were included. EB simplex (EBS), junctional EB (JEB), dystrophic EB (DEB), Kindler EB, simplex and junctional compound EB accounted for 23.4%, 12.7%, 61.5%, 1.1% and 0.2%, respectively. In 16 probands with presumptive recessive EB, failed to find the second allele, COL7A1 (10), COL17A1 (4), LAMB3 (1) and ITGB4 (1). De novo mutations are common in dominant EB (63.8% in EBS, 27.5% in DEB) but extremely rare in recessive DEB (RDEB; 0.74%). Mosaicism is more common than presumed, with 5.4% of dominant EBS. In JEB, only 45.0% of patients with biallelic premature termination codon (PTC) mutations in laminin 332 genes died within 24 months, with a longer average survival age of 11.1 months. In JEB, unusual phenotypes are frequently observed, notably urinary tract involvement, duodenal atresia and EB nevi. In RDEB, 48.8% of cases with biallelic PTC mutations in COL7A1 exhibited a relatively mild phenotype; they are likely to develop a severe phenotype at 0-4 years old, and the PTC mutations position closer to the N-terminal, leading to earlier onset. Glycine substitution mutations in DEB have complex genotypic and phenotypic heterogeneity. The rare subtype, dominant and recessive compound DEB, consists of 1.8% of the total DEB. CONCLUSIONS: This study reveals the general rules governing genotype-phenotype correlations, rare phenotypes and complex genotypes. Collectively, mutation analysis in different forms of EB provides the basis for improved subclassification with accurate genetic counselling and for prenatal diagnosis.

Intravenous immunoglobulin therapy in children with severe atopic dermatitis.

Children with severe atopic dermatitis (AD) can benefit from intravenous immunoglobulin (IVIG) therapy. This study aimed to identify the efficacy and safety of IVIG therapy in children with severe AD. Twenty pediatric AD patients were enrolled in this study. Patients with an Investigator's Global Assessment score of 0 or 1 or a reduction of 2 points after treatment were defined as high-responders (HRs), otherwise, they were defined as low-responders (LRs). Twelve patients (60%) achieved an excellent treatment response after 2 months, while eight (40%) had a low response. The Scoring Atopic Dermatitis index had improved significantly at 2 months post-treatment compared with baseline (p < 0.001). Baseline total serum IgE levels and eosinophil counts were elevated in all subjects and decreased significantly at 2 months post-treatment (p = 0.004 and 0.021, respectively). Baseline IgE levels were significantly higher in the HR group compared with the LR group (p = 0.020). The treatment was well tolerated. Fever was the most common adverse event and occurred in five patients (25%). In conclusion, IVIG could be a safe and effective therapy for children with severe AD and may be more effective in patients with higher IgE levels. Further studies are needed to investigate the different therapeutic responses in patients with different AD phenotypes.

Successful treatment with baricitinib of linear morphea following the lines of Blaschko mimicking lichen striatus.

Linear morphea, also known as linear scleroderma, is a localized form of scleroderma characterized by the presence of lesions that follow a linear distribution pattern. Apart from the typical inflammation and fibrosis of the skin, the linear subtype of morphea often affects underlying structures such as muscles and bones, which can lead to functional limitations. Lichen striatus, a linear inflammatory skin condition, primarily affects children aged 5 to 15 years. Interestingly, both diseases can exhibit lesions that follow the lines of Blaschko. Here we report a case with linear morphea following the lines of Blaschko mimicking lichen striatus in a 4-year-old child. This unique case represents the first documented instance of linear morphea exhibiting a precise Blaschko pattern and being successfully treated with baricitinib. The patient received oral baricitinib at a daily dosage of 2 mg for a duration of 1 year, resulting in remarkable improvement. The majority of the lesions softened, and there was no significant disease progression or occurrence of adverse events throughout the treatment period. Recognizing linear morphea at an early stage is of utmost importance in ensuring effective treatment and preventing disfiguring sequelae. Patients suspected of lichen striatus should also be closely followed and linear morphea should be excluded during the follow-up. The recent breakthrough in the application and the safety of baricitinib in scleroderma is also reviewed.

Transglutaminase 3 regulates cutaneous squamous carcinoma differentiation and inhibits progression via PI3K-AKT signaling pathway-mediated Keratin 14 degradation.

Cutaneous squamous carcinoma is the second most common epithelial malignancy, associated with significant morbidity, mortality, and economic burden. However, the mechanisms underlying cSCC remain poorly understood. In this study, we identified TGM3 as a novel cSCC tumor suppressor that acts via the PI3K-AKT axis. RT-qPCR, IHC and western blotting were employed to assess TGM3 levels. TGM3-overexpression/knockdown cSCC cell lines were utilized to detect TGM3's impact on epithelial differentiation as well as tumor cell proliferation, migration, and invasion in vitro. Additionally, subcutaneous xenograft tumor models were employed to examine the effect of TGM3 knockdown on tumor growth in vivo. Finally, molecular and biochemical approaches were employed to gain insight into the tumor-suppressing mechanisms of TGM3. TGM3 expression was increased in well-differentiated cSCC tumors, whereas it was decreased in poor-differentiated cSCC tumors. Loss of TGM3 is associated with poor differentiation and a high recurrence rate in patients with cSCC. TGM3 exhibited tumor-suppressing activity by regulating cell proliferation, migration, and invasion both in vitro and in vivo. As a novel cSCC tumor differentiation marker, TGM3 expression was positively correlated with cell differentiation. In addition, our results demonstrated an interaction between TGM3 and KRT14 that aids in the degradation of KRT14. TGM3 deficiency disrupts keratinocytes differentiation, and ultimately leads to tumorigenesis. Furthermore, RNA-sequence analysis revealed that loss of TGM3 enhanced EMT via the PI3K-AKT signaling pathway. Deguelin, a PI3K-AKT inhibitor, blocked cSCC tumor growth induced by TGM3 knockdown in vivo. Taken together, TGM3 inhibits cSCC tumor growth via PI3K-AKT signaling, which could also serve as a tumor differentiation marker and a potential therapeutic target for cSCC. Proposed model depicted the mechanism by which TGM3 suppress cSCC development. TGM3 reduces the phosphorylation level of AKT and degrades KRT14. In the epithelial cell layer, TGM3 exhibits a characteristic pattern of increasing expression from bottom to top, while KRT14 and pAKT are the opposite. Loss of TGM3 leads to reduced degradation of KRT14 and activation of pAKT, disrupting keratinocyte differentiation, and eventually resulting in the occurrence of low-differentiated cSCC.

Successfully treated with siltuximab and prednisone in a 7-year-old girl with DOCK8-deficiency presenting as recurrent wart-like lesions: a case report.

Dedicator of cytokinesis 8 (DOCK8) deficiency represents a primary immunodeficiency with a wide range of clinical symptoms, including recurrent infections, atopy, and increased malignancy risk. This study presents a case of a 6-year-old girl with DOCK8 deficiency, characterized by severe, treatment-resistant herpetic infections who was successfully treated with siltuximab and glucocorticoids. The successful use of siltuximab in achieving remission highlights the pivotal role of interleukin-6 (IL-6) in DOCK8 deficiency pathogenesis and suggests that IL-6 modulation can be critical in managing DOCK8 deficiency-related viral infections, which may inform future therapeutic strategies for DOCK8 deficiency and similar immunodeficiencies.

Identifying immuno-related diagnostic genes and immune infiltration signatures for periodontitis and alopecia areata.

BACKGROUND: Although there have been indications that periodontitis (PD) may be susceptible to alopecia areata (AA), the underlying mechanism of its pathogenesis remains poorly understood. The objective of our study is to conduct further research into the occurrence of this complication. METHODS: The gene expression omnibus (GEO) database was the source of acquisition for both PD and AA datasets. Various methods, including the differentially expressed genes (DEGs) analysis, functional enrichment analysis, protein-protein interaction (PPI) network construction, Cytohubba algorithms, and RandomForest algorithms, were utilized to identify candidate hub immuno-related genes (IRGs) for diagnosing AA with PD. The diagnostic efficacy was assessed by constructing receiver operating characteristic (ROC) curves. To further deepen our understanding, immune cell infiltration, flow cytometry assay, and immunofluorescence techniques were employed to uncover immune cell dysregulation in PD and AA. RESULTS: 899 and 803 DEGs were detected in AA and PD, respectively, with an intersection of 150 common DEGs enriched in immune regulation. Further analysis of the junction of shared DEGs and IRGs was analyzed using the PPI network, Mcode, and Cytohubba algorithms. Three hub genes (CTSS, IL2RG, and ITGAL) were subsequently selected by Cytohubba and RandomForest algorithms and were found to be promising candidate hub genes with high diagnostic values (AUC ranging from 0.776 to 0.909) for diagnosing AA with PD. Additionally, various dysregulated immune cells were observed, with mast cells potentially serving as markers for AA and plasma for PD. CONCLUSION: Three candidate hub IRGs (CTSS, IL2RG, and ITGAL) were identified with considerable diagnostic values. Besides, mast cells could serve as markers for AA, while plasma may indicate PD. Our research has the potential to identify shared diagnostic candidate genes and immune cells for AA and PD patients.

Coexistence of Subcutaneous Panniculitis-Like T-Cell Lymphoma and Dermatomyositis in a 12-Year-Old Boy.

Subcutaneous panniculitis-like T-cell lymphoma (SPTL) is an extremely rare, indolent skin malignancy that can be difficult to distinguish from autoimmune disease-associated panniculitides. Here, we describe a 12-year-old boy who was diagnosed at age 7 years with dermatomyositis with classical manifestations, including poikiloderma, Gottron's sign, and symmetric muscle weakness. Recently, the boy presented multiple subcutaneous nodules and fever. Histopathological examination and immunohistochemical staining revealed coexistence of SPTL. To our knowledge, this is the first case of dermatomyositis accompanied with SPTL. This case alert clinical physicians of the possibility of SPTL should be considered when a patient with dermatomyositis has new lesions presenting as nodules and unknown fever.

Successful treatment with secukinumab of psoriasis-like dermatitis in a patient with holocarboxylase synthetase deficiency.

Holocarboxylase synthetase deficiency (HSD) is a rare autosomal recessive disorder of biotin metabolism. Typical manifestations include irreversible metabolic disorders and erythroderma-like dermatitis. Most patients respond well to biotin supplementation. Psoriasis-like phenotype associated with this disease has been rarely reported in the literature and experiences with the use of biologics in patients with HSD are still lacking. We reported a rare case of recurrent psoriasis-like skin lesions in a 6-year-old child with HSD. The patient did not respond to initial therapy with high-dose oral biotin. Immunofluorescence staining showed an increased number of interleukin (IL)-17A+ cells in his skin lesions. Based on this finding, the patient was successfully treated with human anti-IL-17A monoclonal antibody (secukinumab). He did not report any side effects and remained healthy during the 2-year follow-up. We provide a comprehensive review of the reported cases of HSD with psoriasis-like dermatitis to date. The psoriasis-like phenotype of HSD is controversial in treatment and IL-17A inhibitor is an alternative therapeutic option.

Facial Balamuthia mandrillaris infection with neurological involvement in an immunocompetent child.

Cutaneous infection by Balamuthia mandrillaris is a rare condition that is sometimes complicated by life-threatening CNS involvement. It often evades timely diagnosis due to its rarity and non-specific clinical manifestations. Patients can be either immunocompetent or immunocompromised. It is probably transmitted via inhalation or inoculation through broken skin, and then spreads to the brain and other organs through haematogenous spread. It is important for clinicians to be aware of this disease because rapid diagnosis and subsequent therapy has, in some cases, been associated with survival. In this Grand Round, we report the case of a 7-year-old boy who presented with large, chronic plaques on his face. Several biopsies showed non-specific granulomatous inflammation. The patient deteriorated rapidly and died within 1 month of displaying abnormal symptoms in the CNS. Immunohistochemical staining of skin tissue identified B mandrillaris as the infectious agent. The diagnosis was confirmed with PCR, which detected B mandrillaris DNA in formalin-fixed skin tissue sections. B mandrillaris infection should be considered in the differential diagnosis of patients with chronic granulomatous lesions. We also reviewed the epidemiology, B mandrillaris in nature and in the laboratory, clinical manifestations, histopathology, diagnosis, and treatment of infection.

Netherton syndrome caused by compound heterozygous mutation, c.80A>G mutation in SPINK5 and large-sized genomic deletion mutation, and successful treatment of intravenous immunoglobulin.

BACKGROUND: Netherton syndrome (NS) is an autosomal recessive disorder due to mutations in the SPINK5 gene. Here, we report the first case of NS caused by a large genomic deletion. METHODS: We present the clinical data of a 3-year-old Chinese boy who was initially misdiagnosed with severe atopic dermatitis. Subsequently, the patient presented with typical ichthyosis linearis circumflexa and had representative hair shaft of trichorrhexis invaginate, which alerted the physician of the high possibility of NS. A genomic DNA sample was extracted from peripheral blood and whole-exome sequencing (WES) was performed. Sanger sequencing and quantitative real-time polymerase chain reaction (qRT-PCR) were performed to verify the mutation and genomic deletion, respectively, in the pedigree. RESULTS: WES revealed compound heterozygous mutations in SPINK5, including a c.80A>G mutation and a ~275 Kb-sized genomic deletion (chr5:147443576-147719312). The c.80A>G mutation was verified by Sanger sequencing in the pedigree. The father had the same heterozygous mutation; however, the mutation was absent in the proband's mother. The qRT-PCR results identified a large deletion (chr5:147444834-147445034) in SPINK5 in the proband and his mother. The eruptions improved remarkably after intravenous immunoglobulin (IVIG) therapy. CONCLUSIONS: This is the first observation of NS caused by a large deletion. Our findings have important implications for mutation screening and genetic counseling in NS. Our report also verifies and supports the safety and efficacy of IVIG therapy in patients with NS.