Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris.

Ichthyosis vulgaris (OMIM 146700) is the most common inherited disorder of keratinization and one of the most frequent single-gene disorders in humans. The most widely cited incidence figure is 1 in 250 based on a survey of 6,051 healthy English schoolchildren. We have identified homozygous or compound heterozygous mutations R501X and 2282del4 in the gene encoding filaggrin (FLG) as the cause of moderate or severe ichthyosis vulgaris in 15 kindreds. In addition, these mutations are semidominant; heterozygotes show a very mild phenotype with incomplete penetrance. The mutations show a combined allele frequency of approximately 4% in populations of European ancestry, explaining the high incidence of ichthyosis vulgaris. Profilaggrin is the major protein of keratohyalin granules in the epidermis. During terminal differentiation, it is cleaved into multiple filaggrin peptides that aggregate keratin filaments. The resultant matrix is cross-linked to form a major component of the cornified cell envelope. We find that loss or reduction of this major structural protein leads to varying degrees of impaired keratinization.

Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis.

Atopic disease, including atopic dermatitis (eczema), allergy and asthma, has increased in frequency in recent decades and now affects approximately 20% of the population in the developed world. Twin and family studies have shown that predisposition to atopic disease is highly heritable. Although most genetic studies have focused on immunological mechanisms, a primary epithelial barrier defect has been anticipated. Filaggrin is a key protein that facilitates terminal differentiation of the epidermis and formation of the skin barrier. Here we show that two independent loss-of-function genetic variants (R510X and 2282del4) in the gene encoding filaggrin (FLG) are very strong predisposing factors for atopic dermatitis. These variants are carried by approximately 9% of people of European origin. These variants also show highly significant association with asthma occurring in the context of atopic dermatitis. This work establishes a key role for impaired skin barrier function in the development of atopic disease.

Successful Management of Neutropenic Sepsis Is Key to Better Survival of Patients With Blood Cancer in Sri Lanka: Real-World Data From the Resource-Limited Setting.

PURPOSE: Sepsis is the main cause of nonrelapse mortality, and there are no published data on applicability of supportive care protocols from high-income countries such as Sri Lanka. The aim of the study was to investigate management and mortality of neutropenic episodes among Hemato-Oncology patients. MATERIALS AND METHODS: Retrospective analysis of clinical characteristics, management, morbidity, and mortality of neutropenic Hemato-Oncology patients presented to the Lanka Hospital Blood Cancer Centre from January 1, 2019 to December 31, 2019 was performed. RESULTS: A total of 169 neutropenic episodes were identified; 115 (68%) of such episodes were related to chemotherapy. Acute leukemia, lymphoproliferative disorders, and plasma cell disorders accounted for 23%, 69%, and 8% of patients, respectively. The median age of patients who had sepsis was 56 years, whereas that of those who had no sepsis was 53 years (P = .49). The median time to neutropenia was 9 days for those in the sepsis group compared with 8 days in the group that had no sepsis (0.64). The median neutrophil count in the group that had sepsis was 0.06, whereas it was 0.69 in the group that had no sepsis (P ≤ .05). The median time to commencement of antibiotics was 20 minutes. CONCLUSION: To our knowledge, this is the only documented study related to outcome and successful applicability of western supportive care protocols to Sri Lankan patients with neutropenia. In this study, we have shown that neutropenic sepsis can be successfully managed in the setting of limited resources with service development, following guidelines and staff training.

Response and Survival Estimates of Patients With Plasma Cell Myeloma in a Resource-Constrained Setting Using Protocols From High-Income Countries: A Single-Center Experience From Sri Lanka.

PURPOSE: There is a significant disparity in global cancer care and outcome between countries. Progress in the treatment of symptomatic plasma cell myeloma (PCM) in high-income countries is not seen in low- and middle-income countries. MATERIALS AND METHODS: This is was a retrospective cohort study of all patients diagnosed with PCM between May 1, 2013, and September 30, 2021, at the first hemato-oncology center in Sri Lanka. We aimed to provide data on clinicopathologic characteristics, response, and survival estimates. RESULTS: A total of 79 patients with PCM received first-line therapy during the study period. The median age was 64 years, and approximately one third (33%) of patients were older than 70 years. There were 42 (53%) males and 37 females. Hypercalcemia, renal impairment, anemia, and bone disease were detected in 36.7%, 38%, 72.1%, and 81%, respectively. Thirty-nine, 34, and six patients received a combination of cyclophosphamide, thalidomide, and dexamethasone; bortezomib, thalidomide, and dexamethasone; and other treatments, respectively. The overall response rate (≥ partial response) was approximately 97% for both cyclophosphamide, thalidomide, and dexamethasone and bortezomib, thalidomide, and dexamethasone. Twenty-three (29%) of these patients died during the study period, but only 14 (18%) died due to PCM or associated sepsis. After a median follow-up of 40.6 months (range, 35.2-59.07 months), the median overall survival was 84.2 months (95% CI, 60.87 to not available). The 5-year estimated overall survival was 65%. CONCLUSION: To our knowledge, this is the only well-characterized study on long-term survival of patients with PCM in Sri Lanka. We have shown that it is possible to successfully apply Western treatment and supportive care protocols to the local population. These published data will help to benchmark and improve the treatment and develop blood cancer care in the local setting.

Applicability of protocols from high-income countries in a resource limited setting; real world data of histopathology, clinical features and long-term outcome of Hodgkin Lymphoma in Sri Lanka.

Background:: There is a significant disparity in global cancer care and out-come between countries. We aimed to provide data on characteristics, average cost of treatment and survival estimates in patients with Hodgkin Lymphoma in Sri Lanka. Methods: All patients diagnosed with Hodgkin Lymphoma between 01.05.2013 and 01.10.2020 were included in the analysis. Findings: Classical Hodgkin Lymphoma(cHL) diagnosed in 85%; 68% presented with B symptoms and 61% had advanced stage of disease. Treatment was discontinued by 23% either before or just after starting treatment of whom 72% percent were females. The complete response (CR) rate of patients who continued treatment was 86% while the estimated five-year survival rate is 92%. Seventeen percent of these patients died but only two percent due to Hodgkin Lymphoma or associated treatment in the group which continued treatment compared to 45% in the group who defaulted treatment (p-value 0.0002). Five-year survival rate of patients who defaulted treatment was 50% while patients who continued treatment have an estimated five-year survival rate of 90%. Average cost of first line treatment was between US$ 2280 and US$ 7642. First treatment failure may incur substantially higher health care costs. Interpretation: This is the only well characterized study on long-term survival of patients with Hodgkin Lymphoma in Sri Lanka. We have shown that it is possible to successfully apply western treatment and supportive care protocols to the local population. This published data will help to bench mark and improve the treatment and develop blood cancer care in the local setting.

Blood cancer care in a resource limited setting during the Covid-19 outbreak; a single center experience from Sri Lanka.

BACKGROUND: The Covid-19 pandemic has caused significant morbidity and mortality among patients with cancer. Most countries employed measures to prevent spread of Covid-19 infection which include shielding, quarantine, lockdown, travel restrictions, physical distancing and the use of personal protective equipment. This study was carried out to assess the change in patient attendance and the efficacy of newly implemented strategies to mitigate the impact of Covid-19 on services at the Lanka Hospital Blood Cancer Centre (LHBCC) in Colombo, Sri Lanka. METHODOLOGY: Telephone consultation, infection control, personal protective measures and emergency admission policy were implemented with the aim of having a Covid-19 free ward and to prevent cross-infections. This descriptive cross-sectional study was conducted with 1399 patient episodes (in-patient care or day-case review). We analysed patients treated as in-patient as well as day-case basis between 01st April 2020 and 31st December 2020. RESULTS: There were 977 day-case based episodes and 422 in-patient based episodes. There was a 14% drop in episode numbers compared to same period in 2019. There was no cross infection and no patients with Covid-19 related symptoms or positive test results entered the LHBCC during the study period. CONCLUSION: Services in blood cancer care were maintained to prevent late stage presentation and adverse outcome. Measures implemented to prevent Covid-19 were effective to allow continuation of treatment. This study highlights the importance of implementing strict protocols, clinical screening, use of appropriate personal protective equipment in delivering blood cancer care during the Covid-19 pandemic. This is the only documented study relating to outcome and successful applicability of measures to prevent spread of Covid-19 infection and maintaining services among blood cancer patients in Sri Lanka.

Trimethylaminuria (fish-odor syndrome): a case report.

BACKGROUND: Trimethylaminuria (fish-odor syndrome) is a rare metabolic disorder characterized by a body malodor similar to that of decaying fish. The condition results from mutations affecting the flavin-containing monooxygenase 3 (FMO3) gene. Affected individuals may exhibit a variety of psychosocial phenomena. A high index of suspicion for this disorder needs to be maintained when treating individuals presenting with a history of real or perceived body odor. Observation We evaluated a 41-year-old man who presented with a long medical history of a fishy body odor. Results from biochemical investigations confirmed a diagnosis of primary trimethylaminuria, and results of molecular genetic studies revealed homozygosity for a mutation on exon 4 of the FMO3 gene, FMO3/P153L (c.458C --> T). The patient found that information he subsequently obtained about his condition on the Internet and discussion with friends and family members to be the most useful therapeutic approach. CONCLUSIONS: Trimethylaminuria is a rare metabolic disorder. Psychological accompaniments are recognized as major sources of distress to affected individuals. We discuss the features of this syndrome and highlight the importance of counseling and support in the treatment of such patients.