Dominant-negative NFKBIA mutation promotes IL-1ß production causing hepatic disease with severe immunodeficiency.

Although IKK-ß has previously been shown as a negative regulator of IL-1ß secretion in mice, this role has not been proven in humans. Genetic studies of NF-κB signaling in humans with inherited diseases of the immune system have not demonstrated the relevance of the NF-κB pathway in suppressing IL-1ß expression. Here, we report an infant with a clinical pathology comprising neutrophil-mediated autoinflammation and recurrent bacterial infections. Whole-exome sequencing revealed a de novo heterozygous missense mutation of NFKBIA, resulting in a L34P IκBα variant that severely repressed NF-κB activation and downstream cytokine production. Paradoxically, IL-1ß secretion was elevated in the patient's stimulated leukocytes, in her induced pluripotent stem cell-derived macrophages, and in murine bone marrow-derived macrophages containing the L34P mutation. The patient's hypersecretion of IL-1ß correlated with activated neutrophilia and liver fibrosis with neutrophil accumulation. Hematopoietic stem cell transplantation reversed neutrophilia, restored a resting state in neutrophils, and normalized IL-1ß release from stimulated leukocytes. Additional therapeutic blockade of IL-1 ameliorated liver damage, while decreasing neutrophil activation and associated IL-1ß secretion. Our studies reveal a previously unrecognized role of human IκBα as an essential regulator of canonical NF-κB signaling in the prevention of neutrophil-dependent autoinflammatory diseases. These findings also highlight the therapeutic potential of IL-1 inhibitors in treating complications arising from systemic NF-κB inhibition.

Drug reaction with eosinophilia and systemic symptoms in a cohort of Asian children.

BACKGROUND/OBJECTIVES: Drug reaction with eosinophilia and systemic symptoms (DRESS) is rare but potentially fatal in children. Fever and rash, which are salient features of DRESS, may mimic other commonly encountered pediatric conditions. We profiled the DRESS cases in a tertiary children's hospital in Singapore. METHODS: The medical records of all pediatric DRESS patients diagnosed from 2006 to 2016. Data on epidemiology, inciting drugs, clinical, pathologic manifestations, and treatment were assessed. RESULTS: Ten patients aged 4-16 years old were diagnosed with DRESS within the 10-year period. Drugs implicated were antibiotics, such as trimethoprim-sulfamethoxazole, and anticonvulsants, such as carbamazepine, phenobarbitone, and levetiracetam. All patients had fever and pruritic exanthems. Desquamation, purpura, and oral mucositis were also observed. Lymphadenopathy, hepatomegaly, and facial edema occurred frequently. There was liver involvement in all cases, but none progressed to liver failure. Seven patients had eosinophilia, and nine had atypical lymphocytosis. Other laboratory abnormalities included low hemoglobin, thrombocytosis, and prolonged coagulation times. All patients received systemic corticosteroids of varying durations and dosages. Systemic steroids were weaned after 19 days to 4 months. Disease resolution, with liver enzyme levels returning to normal, occurred within 28-90 days. One patient developed TSH-receptor-antibody-positive hyperthyroidism 6 months after the onset of DRESS, while another patient developed chronic urticaria 4 months after resolution of DRESS. CONCLUSION: Early recognition of DRESS is important to ensure that the inciting drug is discontinued, and supportive treatment started expediently. Liver involvement was very common but responded well to systemic steroids.

Vulvar basal cell carcinoma: clinical features and treatment outcomes from a tertiary care centre.

We retrospectively reviewed the clinical features, management and outcomes of patients diagnosed with basal cell carcinoma (BCC) of the vulva at the Gynaecological Cancer Centre, KK Women's and Children's Hospital, Singapore, between 1 January 2000 and 28 February 2014. Patients with vulvar BCC were identified from the cancer registry, and their medical records reviewed and analysed. A total of 11 patients with vulvar BCC were identified. Mean age at diagnosis was 63 (range 30-85) years. Ethnically, ten patients were Chinese and one was Malay. Average time from onset of symptoms to diagnosis was 13.8 (range 2-60) months. The most common presenting symptoms were lump and pruritus. All patients were managed surgically. Recurrence was noted in only one patient. Vulvar BCC, although rare, has an excellent prognosis when managed appropriately. Histological diagnosis of all persistent papules, plaques and pigmented lesions is important for early diagnosis.

Epstein-Barr virus positive diffuse large B-cell lymphoma presenting with vaginal sloughing and ulcerated skin nodule.

Malignant lymphomas presenting in the female genital tract are extremely rare. We report a case of Epstein-Barr virus associated diffuse large B-cell lymphoma of the genital tract and skin in a 60-year-old woman on long-term azathioprine.