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.

Effects of Cast Immobilisation on Skin Barrier Function.

INTRODUCTION: Cast immobilisation remains the mainstay of treatment for various fractures in paediatric patients, yet patients commonly complain of skin irritation and discomfort. This study aimed to perform a qualitative and quantitative evaluation of the effects of cast immobilisation on the skin of children and adolescents. MATERIALS AND METHODS: Patients aged 6-17 years of age with a fracture treated in a fiberglass short-arm or short-leg cast were recruited. Transepidermal water loss (TEWL), stratum corneum (SC) hydration, hair density and presence of any skin signs were assessed before and after cast. Patients were required to complete a weekly questionnaire to rate itch, malodour, warmth, and dampness of the skin under the cast. RESULTS: A total of 60 subjects completed the study. Thirty-six patients received a short-arm cast; 24 received a short-leg cast. Upon cast removal, TEWL was significantly increased on the volar surface of the arms and legs (P <0.05), and the dorsal surface of the arm (P <0.05). Likewise, SC hydration was significantly increased at most sites (P <0.05), except the volar surface of the leg (P = 0.513). There was no change in hair density. Throughout the duration of casting, there was an increase in itch and malodour scores. CONCLUSION: Moderate but significant changes in TEWL, SC hydration and subjective symptoms were observed during the duration of cast immobilisation, demonstrating that cast immobilisation for up to 4 weeks exerts moderate adverse impact on patients' skin. Further studies to explore the use of better materials for cast immobilisation to improve skin barrier function and overall patient satisfaction are warranted.

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.

Effect of atopic dermatitis on quality of life and its psychosocial impact in Asian adolescents.

BACKGROUND/OBJECTIVES: Atopic dermatitis (AD) is a common condition affecting up to 20% of the paediatric population in Singapore. It is often associated with significant psychosocial morbidity and can affect patients' quality of life (QOL) tremendously. This study investigated the varying lifestyle impacts, and psychosocial domains most affected by AD in adolescent children in Singapore. METHODS: A prospective study evaluating the impact of AD on the QOL of adolescents was conducted over a 6-month period from July to December 2014. Adolescents aged 11-16 years with varying eczema severity were recruited. Eczema severity was determined by using the eczema area and severity index (EASI) scores. Lifestyle impact of AD was evaluated using patient-reported children's dermatology life quality index (CDLQI) scores. Statistical analysis was performed using an analysis of one-way variance and Student's t-test. RESULTS: A total of 50 patients were enrolled and divided into three groups: mild (<10.3), moderate (10.3-20.9) and severe (>20.9) eczema based on EASI scores. Patients with mild and moderate eczema had lower CDLQI scores. Adolescents were most affected by the disruption that their symptoms had on their leisure and physical activities and sleep as a result of itch and scratching, respectively. CONCLUSION: Chronic sufferers of severe eczema experience poorer QOL than those with mild or moderate eczema. They also experience significant psychosocial impact as a consequence of their condition.

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.

Guidelines for the Management of Atopic Dermatitis in Singapore.

INTRODUCTION: Atopic dermatitis is a common, chronic pruritic condition affecting both children and adults, which has a negative impact on the quality of life. These guidelines were developed by an expert workgroup appointed by the Dermatological Society of Singapore, to provide doctors with information to assist in the management of their patients with atopic dermatitis. The workgroup members are experienced dermatologists with interest and expertise in eczemas. MATERIALS AND METHODS: Workgroup members arrived at a consensus on the topics to be included. Relevant studies from the literature were assessed for best evidence, supplemented by the collective experience of the workgroup. RESULTS: For mild atopic dermatitis, emollients, mild potency topical steroids and topical calcineurin inhibitors are recommended. For moderate-to-severe atopic dermatitis, the use of emollients, moderate-to-potent topical steroids, topical calcineurin inhibitors, wet dressings, antimicrobials for secondary skin infection, phototherapy, and systemic therapy (e.g. prednisolone, cyclosporine, azathioprine or methotrexate) may be warranted. Patients with moderate-to-severe atopic dermatitis should be managed in conjunction with a dermatologist. CONCLUSION: Good outcomes can be achieved with an individualised therapeutic approach combined with adequate patient and parental education.

Elderly Hospitalised Patients-The Impact of Itch and its Prevalence.

INTRODUCTION: Pruritus in elderly patients can have a significant impact on the quality of life but may be underestimated and poorly addressed by healthcare professionals. MATERIALS AND METHODS: From March to May 2010, a structured interview questionnaire including the Dermatology Life Quality Index (DLQI) was administered to all patients admitted to the geriatric ward in Changi General Hospital, Singapore, except for those with cognitive impairment. RESULTS: A total of 194 patients were enrolled in the study; 94 patients (48.5%) were experiencing itch at the point of the interview; mean DLQI score for patients with itch was 6.7; 35.1% of patients experienced sleep disruption whilst 30.9% reported impairment of concentration levels as a consequence of their itch. Of the patients who had informed their doctor about the problem, 73.7% felt that doctors had not adequately addressed the cause of the itch. Among patients who reported itch, the DLQI score correlates with the severity of pruritus with a regression coefficient of 0.2737 (P <0.001); 9.6% of patients with itch were independent with their activities of daily living compared to 21% of patients who did not experience itch. CONCLUSION: Almost half of the subjects in our study experienced itch and a third of them reported impairment of quality of life. Patients who were independent of their activities of daily living were also less likely to experience itch. This study highlights the importance of increasing awareness of pruritus among physicians as pruritus can have adverse consequences on patients' quality of life when left unaddressed.