SUM M A R YWe performed genetic and immunohistochemical studies in a sister and brother with autosomal recessive neonatal inflammatory skin and bowel lesions. The girl died suddenly at 12 years of age from parvovirus B19-associated myocarditis; her brother had mild cardiomyopathy. We identified a loss-of-function mutation in ADAM17, which encodes a disintegrin and metalloproteinase 17 (also called tumor necrosis factor α [TNF-α]-converting enzyme, or TACE), as the probable cause of this syndrome. Peripheral-blood mononuclear cells (PBMCs) obtained from the brother at 17 years of age showed high levels of lipopolysaccharide-induced production of interleukin-1β and interleukin-6 but impaired release of TNF-α. Despite repeated skin infections, this young man has led a relatively normal life. (Funded by Barts and the London Charity and the European Commission Seventh Framework Programme.) I nflammatory disorders of the skin and gut, including eczema, psoriasis, and celiac disease, have been linked to changes in barrier function and immune responses, by means of genetic and functional studies. Large casecontrol studies combined with genomewide association studies have identified common genetic risk factors, with low penetrance, for a plethora of human disorders. Such studies have also identified numerous single-nucleotide polymorphisms (SNPs) in genes linked to the regulation of immunity and inflammation affecting epithelial tissues. 1,2High-throughput sequence technology can be used to identify rare but penetrant disease-associated mutations in affected members of families with mendelian conditions. [3][4][5][6] We combined this technology with SNP-homozygosity mapping and targeted sequence capture to identify likely causative genes in a syndrome of neonatal-onset inflammatory skin and bowel disease in two siblings. C A SE R EP OR TTwo of three children born to consanguineous parents (first cousins) of Lebanese origin had the same clinical features involving the skin, hair, and gut. The skin lesions developed on the second day of life, with diarrhea developing in the first week of life. The affected girl died at 12 years of age from fulminant parvovirus B19-associatedThe New England Journal of Medicine Downloaded from nejm.org at MAX DELBRUECK CENTRUM FOR MOLECULAR MED on April 2, 2014. For personal use only. No other uses without permission.

Objective: The question of whether depression is associated with worse survival in people with cancer remains unanswered because of methodological criticism of the published research on the topic. We aimed to study the association in a large methodologically robust study. Methods: We analyzed data on 20,582 patients with breast, colorectal, gynecological, lung, and prostate cancers who had attended cancer outpatient clinics in Scotland, United Kingdom. Patients had completed two-stage screening for major depression as part of their cancer care. These data on depression status were linked to demographic, cancer, and subsequent mortality data from national databases. We estimated the association of major depression with survival for each cancer using Cox regression. We adjusted for potential confounders and interactions between potentially time-varying confounders and the interval between cancer diagnosis and depression screening, and used multiple imputation for missing depression and confounder data. We pooled the cancer-specific results using fixed-effects meta-analysis. Results: Major depression was associated with worse survival for all cancers, with similar adjusted hazard ratios (HRs): breast cancer (