暂无摘要。

BACKGROUND: Kawasaki disease (KD) is a systemic vasculitis accompanied by many systemic physiological and biochemical changes. Elucidating its molecular mechanisms is crucial for diagnosing and developing effective treatments. NLR Family CARD Domain Containing 4 (NLRC4) encodes the key components of inflammasomes that function as pattern recognition receptors. The purpose of this study was to investigate the potential of NLRC4 methylation as a biomarker for KD.
METHODS: In this study, pyrosequencing was utilized to analyze NLRC4 promoter methylation in blood samples from 44 children with initial complete KD and 51 matched healthy controls. Methylation at five CpG sites within the NLRC4 promoter region was evaluated.
RESULTS: Compared to controls, NLRC4 methylation significantly decreased in KD patients (CpG1: p = 2.93E-06; CpG2: p = 2.35E-05; CpG3: p = 6.46E-06; CpG4: p = 2.47E-06; CpG5: p = 1.26E-05; average methylation: p = 5.42E-06). These changes were significantly reversed after intravenous immunoglobulin (IVIG) treatment. ROC curve analysis demonstrated remarkable diagnostic capability of mean NLRC4 gene methylation for KD (areas under ROC curve = 0.844, sensitivity = 0.75, p = 9.61E-06, 95% confidence intervals were 0.762-0.926 for mean NLRC4 methylation). In addition, NLRC4 promoter methylation was shown to be significantly negatively correlated with the levels of central granulocyte percentage, age, mean haemoglobin quantity and mean erythrocyte volume. Besides, NLRC4 promoter methylation was positively correlated with lymphocyte percentage, lymphocyte absolute value.
CONCLUSIONS: Our work revealed the role of peripheral NLRC4 hypomethylation in KD pathogenesis and IVIG treatment response, could potentially serve as a treatment monitoring biomarker, although its precise functions remain to be elucidated.

暂无摘要。

Exophiala dermatitidis is a relatively common environmental black yeast with a worldwide distribution that rarely causes fungal infection. Here, we report a case of a 6-year-old girl with central nervous system (CNS) encephalitis caused by E. dermatitidis and Angiostrongylus cantonensis. E. dermatitidis was identified by both cerebrospinal fluid culture and metagenomic next-generation sequencing (mNGS). Angiostrongylus cantonensis infection was confirmed by an enzyme linked immunosorbent assay (ELISA). Whole exome sequencing showed that this previously healthy girl carried a homozygous CARD9 mutation for c.820dupG (p.D274Gfs*61) that underlies invasive fungal and parasite infections. We chose glucocortieoid pulse therapy and anti-infective therapy based on the initial results of laboratory examination and cranial MRI images. With the aggravation of the disease and the evidence of the subsequent etiologic test, the combination of antifungal antiparasitic treatments (voriconazole, fluorocytosine and amphotericin B) were actively used. Unfortunately, the girl finally died due to severe systemic infection. mNGS performs a potential value for diagnosing rare CNS infections, and autosomal recessive CARD9 deficiency should be considered in patient with fatal invasive fungal infections.

BACKGROUND: Acute generalized exanthematous pustulosis (AGEP) is a serious adverse skin reaction characterized by the rapid appearance of densely distributed, small, sterile pustules with erythema. However, its pathogenesis is not fully understood. Hydroxychloroquine is widely used for the treatment of autoimmune diseases. Some patients presenting with AGEP have IL36RN and CARD14 gene mutations. Our report describes a patient with rheumatoid arthritis and AGEP associated with hydroxychloroquine and a newly discovered CARD14 gene mutation.
METHODS: A 28-year-old woman with rheumatoid arthritis, treated with leflunomide therapy without marked relief of joint pain, developed multiple rashes with pruritis covering the body 5 days after switching to hydroxychloroquine treatment.
METHODS: Based on the patient\'s history, symptoms, and histopathological findings, AGEP was diagnosed.
METHODS: Whole-exome sequencing and Sanger validation revealed no mutations in the IL36RN gene; however, a CARD14 gene mutation was present. The patient was treated using ketotifen fumarate tablets, dexamethasone sodium phosphate, calcium gluconate injection, methylprednisolone injection, vitamins C and B12, hydrocortisone butyrate cream, Reed acne cream, potassium chloride tablets, and pantoprazole enteric-coated capsules.
RESULTS: The rash improved after 15 days.
UNASSIGNED: There has been little basic research on AGEP-related genetics, and the CARD14 mutation may underlie several pustular rashes, including AGEP and generalized pustular psoriasis. Follow-up studies and further accumulation of patient data are required.

Deep dermatophytosis is an invasive and sometimes life-threatening fungal infection mainly reported in immunocompromised patients. However, a caspase recruitment domain-containing protein 9 (CARD9) deficiency has recently been reported to cause deep dermatophytosis. Herein, we report the first Japanese case of deep dermatophytosis associated with CARD9 deficiency. An 80-year-old Japanese man with tinea corporis presented with subcutaneous nodules on his left sole. Histopathological findings revealed marked epithelioid cell granulomas with filamentous fungal structures in the deep dermis and subcutis, and the patient was diagnosed with deep dermatophytosis. Despite antifungal therapy, the subcutaneous nodule on his left sole gradually enlarged, his left calcaneal bone was invaded, and the patient finally underwent amputation of his left leg. Genetic analysis revealed a homozygous CARD9 c.586 A > G (p. Lys196Glu) variant, suggesting a CARD9 deficiency. Here, we discuss the clinical features of CARD9 deficiency-associated deep dermatophytosis with a case report and review of the literature.

患儿　男，12岁8月龄，因“间断头痛2个月，呕吐10 d”于2021年1月6日入住西安市儿童医院神经外科。结合病史、体格检查、实验室检查、宏基因组二代测序、影像学检查，诊断为白色念珠菌致感染性脑脊髓炎，基因检测结果发现患儿携带CARD9基因NM—052813.5：c.1118G>C（p.R373P）和c.951G>A（p.R317R）复合杂合变异，其中p.R373P可致常染色体隐性遗传的家族性念珠菌2型感染。经两性霉素B静脉点滴及鞘内注射，联合伏立康唑、氟胞嘧啶口服，共治疗4.3个月，好转出院。.

Cold agglutinin disease (CAD) is a rare cold autoimmune haemolytic anaemia (cAIHA) caused by IgM antibodies recognizing I antigens on erythrocytes. cAIHA is now mainly classified into two types: primary CAD and cold agglutinin syndrome (CAS). CAS develops in association with the underlying disease, which is most commonly malignant lymphoma. Recent studies have identified gene mutations in CARD11 and KMT2D in a high proportion of patients with CAD, which has led to recognition of CAD as an indolent lymphoproliferative disorder. We herein report a case of cAIHA without lymphocytosis or lymphadenopathy in whom bone marrow was infiltrated by a small population of clonal lymphocytes (6.8%) expressing cell surface markers consistent with chronic lymphocytic leukaemia (CLL). Whole-exome sequencing of bone marrow mononuclear cells revealed mutations in the CARD11 and KMT2D genes. This patient also had somatic hypermutation with overrepresentation of IGHV4-34, which is prevalent in CLL harbouring the KMT2D mutation. These observations suggest that CAS caused by early-phase CLL could be misinterpreted as primary CAD.

BACKGROUND: A number of recalcitrant phaeohyphomycosis cases with a life-threatening prognosis have been observed in CARD9-deficient patients, but little is known about the long-term management strategies that are effective for such intractable individuals.
OBJECTIVE: To study the genetic and immunological mechanisms underlying recalcitrant phaeohyphomycosis and to share our clinical experiences regarding its treatment.
METHODS: Ten CARD9-deficient patients with recalcitrant phaeohyphomycosis admitted to our centre in the past two decades were followed-up, and their clinical presentations, laboratory findings, treatment and prognoses were analysed; one of them was a novel case of recalcitrant phaeohyphomycosis harbouring CARD9 mutations. Innate and adaptive immunological responses of patient-derived peripheral blood mononuclear cells were evaluated using ELISA and flow cytometry.
RESULTS: We identified a total of seven CARD9 mutations in the ten analysed patients. Moreover, patient-derived cells exhibited a significant impairment of innate and adaptive immune responses upon fungus-specific stimulation. All the patients experienced recurrence and exacerbation; four of them died, two exhibited continued disease progress with unsatisfactory therapeutic efficacy, three showed obvious improvement under maintenance therapy, and only one achieved a clinical cure.
CONCLUSIONS: Our study highlighted that otherwise healthy patients diagnosed with early-onset, unexplained and recalcitrant phaeohyphomycosis should be analysed for CARD9 mutations and immune deficiency. Thereafter, the length and choice of management remain challengeable and must be adjusted based on the clinical presentations and responses of patients over their lifetimes. Although continued posaconazole treatment may be the promising first-line therapy at present, novel strategies are worth exploring.

Dermatophytosis is the most common type of superficial fungal infection caused by dermatophytes. Occasionally, the fungus invades deep into the dermis or other tissues, causing deep dermatophytosis. Deep dermatophytosis is often associated with Caspase Recruitment Domain-containing protein 9 (CARD9) deficiency in patients. Here, we report the first case of deep dermatophytosis with a rare mycosis fungoides manifestation caused by T. tonsurans in a patient with a novel mutation in exon 4 of CARD9. The condition presented with heterozygous K196E mutation, which leads to deficiency of innate and adaptive immune responses in the patient, and caused intractable severe lesions. The patient received treatment with multiple antifungal drugs and was ultimately alleviated by posaconazole. These findings extend the pathogen spectrum of deep dermatophytosis linked with CARD9 deficiency and enriched their phenotypic spectrum.