Multiple intestinal atresia (MIA) is a rare cause of bowel obstruction that is sometimes associated with a combined immunodeficiency (CID), leading to increased susceptibility to infections. The factors underlying this rare disease are poorly understood. We characterized the immunological and intestinal features of 6 unrelated MIA-CID patients. All patients displayed a profound, generalized lymphocytopenia, with few lymphocytes present in the lymph nodes. The thymus was hypoplastic and exhibited an abnormal distribution of epithelial cells. Patients also had profound disruption of the epithelial barrier along the entire gastrointestinal tract. Using linkage analysis and whole-exome sequencing, we identified 10 mutations in tetratricopeptide repeat domain-7A (TTC7A), all of which potentially abrogate TTC7A expression. Intestinal organoid cultures from patient biopsies displayed an inversion of apicobasal polarity of the epithelial cells that was normalized by pharmacological inhibition of Rho kinase. Our data indicate that TTC7A deficiency results in increased Rho kinase activity, which disrupts polarity, growth, and differentiation of intestinal epithelial cells, and which impairs immune cell homeostasis, thereby promoting MIA-CID development.

Correspondence n engl j med 375;5 nejm.org August 4, 2016 Human Coronavirus OC43 Associated with Fatal EncephalitisTo the Editor: Encephalitis is a serious neurologic syndrome characterized by brain inflammation that may be fatal. Although the majority of cases are caused by viruses, the identification of a causal organism can be difficult. Encephalopathy that affects patients with immunodeficiency is particularly challenging to diagnose, since the clinical presentation may be atypical and the differential diagnosis may include unusual pathogens or a noninfective cause. Deep sequencing of clinical samples has the potential to identify the pathogens associated with encephalitis, particularly in cases in which traditional techniques have not identified the candidate causative pathogen. 1Here we report the use of deep sequencing of a brain biopsy sample obtained from an 11-monthold boy with severe combined immunodeficiency who had symptoms of viral encephalitis with negative results on conventional diagnostic polymerase-chain-reaction (PCR) assay. The boy's family provided written informed consent.The boy underwent unconditioned cord-blood transplantation, which resulted in T-cell engraftment. Nonetheless, his condition continued to deteriorate, and he died 1.5 months after receiving the transplant. RNA sequencing of a brain biopsy sample obtained 2 months after the onset of symptoms showed the presence of human coronavirus OC43 (HCoV-OC43), which was sub- sequently confirmed on real-time PCR (threshold cycle, 24) and brain immunohistochemical analysis (Fig. 1). Full details on the case history, library preparation, bioinformatics analysis, species identification as reported by the profiling method metaMix, 2 PCR confirmation, immunohistochemical analysis, and phylogenetic and variant analyses are provided in the Supplementary Appendix, available with the full text of this letter at NEJM.org.The human betacoronaviruses, including HCoV-OC43, are predominantly associated with respiratory tract infections. The group includes viruses that cause the severe acute respiratory syndrome and the Middle East respiratory syndrome. HCoV-OC43 is generally associated with mild upper respiratory tract infections, although it has been shown to have neuroinvasive properties. In vivo studies in mice have shown that HCoV-OC43 can infect neurons and cause encephalitis.3 The virus has also been shown to cause persistent infections in human neural-cell lines. 4 A single report identified HCoV-OC43 RNA in the cerebrospinal fluid of a child with acute disseminated encephalomyelitis. 5 In the case we describe here, three independent methods were used to identify HCoV-OC43 in brain tissue of a child with acute encephalomyelitis.Deep sequencing of biopsy material provides an important tool for the diagnosis of unexplained encephalomyelitis, particularly in patients with immunodeficiency who have undergone stem-cell transplantation, when the differential diagnosis may include immune-mediated inflammation or drug toxicity. The identificatio...

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Elective cesarean section under spinal anesthesia for women infected with HIV-1 taking antiretroviral therapy was not associated with intraoperative or postoperative complications.

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