Monogenic forms of vasculitis are rare but increasingly recognized. Furthermore, genetic immunodeficiency is increasingly associated with inflammatory immune dysregulatory features, including vasculitis. This case report describes a child of non-consanguineous parents who presented with chronic digital vasculitis early in life, is of short stature, has facial dysmorphia, immunodeficiency (low serum IgA, high serum IgM), recurrent bacterial infections, lymphoproliferation, absence of detectable serum C1q, and low classical complement pathway activity. We identified a previously reported de novo heterozygous pathogenic splice mutation in PIK3R1 (c.1425 + 1G > A), resulting in the skipping of exon 11 of the p85α subunit of phosphatidylinositol 3-kinase and causing activated PI3Kδ syndrome type II (APDS2). This explained the phenotype, with the exception of digital vasculitis and C1q deficiency, which have never been described in association with APDS2. No mutations were identified in C1QA, B, or C, their promoter regions, or in any other complement component. Functional studies indicated normal monocytic C1q production and release, suggesting that the observed C1q deficiency was caused by peripheral consumption of C1q. Since C1q deficiency has never been associated with APDS2, we assessed C1q levels in two unrelated patients with genetically confirmed APDS2 and confirmed C1q deficiency in those two cases as well. This observation suggests C1q deficiency to be an inherent but previously unrecognized feature of APDS2. We speculate that the consumption of C1q is driven by increased apoptotic bodies derived from immune cellular senescence, combined with elevated IgM production (both inherent features of APDS2). Secondary C1q deficiency in APDS2 may further contribute to immunodeficiency and could also be associated with inflammatory immune dysregulatory phenotypes, such as the digital vasculitis observed in our case.

HistopathologyVolume 63, Issue 1 p. 142-143 Correspondence Assessment of MUC4 expression in primary bone tumours Roberto Tirabosco, Roberto Tirabosco Department of Histopathology, Royal National Orthopaedic Hospital, Middlesex, UKSearch for more papers by this authorFitim Berisha, Fitim Berisha Department of Histopathology, Royal National Orthopaedic Hospital, Middlesex, UKSearch for more papers by this authorHongtao Ye, Hongtao Ye Department of Histopathology, Royal National Orthopaedic Hospital, Middlesex, UKSearch for more papers by this authorDina Halai, Dina Halai Department of Histopathology, Royal National Orthopaedic Hospital, Middlesex, UKSearch for more papers by this authorM Fernanda Amary, M Fernanda Amary Department of Histopathology, Royal National Orthopaedic Hospital, Middlesex, UKSearch for more papers by this authorAdrienne M Flanagan, Adrienne M Flanagan Department of Histopathology, Royal National Orthopaedic Hospital, Middlesex, UK UCL Cancer Institute, London, UKSearch for more papers by this author Roberto Tirabosco, Roberto Tirabosco Department of Histopathology, Royal National Orthopaedic Hospital, Middlesex, UKSearch for more papers by this authorFitim Berisha, Fitim Berisha Department of Histopathology, Royal National Orthopaedic Hospital, Middlesex, UKSearch for more papers by this authorHongtao Ye, Hongtao Ye Department of Histopathology, Royal National Orthopaedic Hospital, Middlesex, UKSearch for more papers by this authorDina Halai, Dina Halai Department of Histopathology, Royal National Orthopaedic Hospital, Middlesex, UKSearch for more papers by this authorM Fernanda Amary, M Fernanda Amary Department of Histopathology, Royal National Orthopaedic Hospital, Middlesex, UKSearch for more papers by this authorAdrienne M Flanagan, Adrienne M Flanagan Department of Histopathology, Royal National Orthopaedic Hospital, Middlesex, UK UCL Cancer Institute, London, UKSearch for more papers by this author First published: 13 May 2013 https://doi.org/10.1111/his.12134Citations: 5Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article. References 1Doyle LA, Moller E, Dal Cin P et al. MUC4 is a highly sensitive and specific marker for low-grade fibromyxoid sarcoma. Am. J. Surg. Pathol. 2011; 35; 733– 741. 2Doyle LA, Wang WL, Dal Cin P et al. MUC4 is a sensitive and extremely useful marker for sclerosing epithelioid fibrosarcoma: association with FUS gene rearrangement. Am. J. Surg. Pathol. 2012; 36; 1444– 1451. 3Guillou L, Benhattar J, Gengler A et al. Translocation-positive low-grade fibromyxoid sarcoma: clinicopathologic and molecular analysis of a series expanding the morphologic spectrum and suggesting potential relationship to sclerosing epithelioid fibrosarcoma. Am. J. Surg. Pathol. 2007; 31; 1387– 1402. 4Rekhi B, Folpe AL, Deshmukh M et al. Sclerosing epithelioid fibrosarcoma – a report of two cases with cytogenetic analysis of FUS gene rearrangement by FISH technique. Pathol. Oncol. Res. 2011; 17; 145– 148. 5Wang WL, Evans HL, Meis JM et al. FUS rearrangements are rare in ‘pure’ sclerosing epithelioid fibrosarcoma. Mod. Pathol. 2012; 25; 846– 853. 6Graham RPD, Dry S, Li X et al. Ossifying fibromyxoid tumor of soft parts: a clinicopathologic, proteomic and genomic study. Am. J. Surg. Pathol. 2011; 35; 1615– 1625. Citing Literature Volume63, Issue1July 2013Pages 142-143 ReferencesRelatedInformation

Background: Neurofibromatosis type 1 is one of the most common familial diseases, the hallmark of which is the development of multiple neurofibromas. These are benign nerve sheath tumours, which can transform into malignant peripheral nerve sheath tumours (MPNST).Methods: The aim of this study was to identify differentially expressed microRNA (miRNA) in neurofibromas and MPNST obtained from patients with neurofibromatosis type 1 using microarray analysis. Differential expression was validated by reverse transcription quantitative-PCR, and functional studies were performed after transfection of miRNA oligonucleotide mimics into MPNST cells.Results: Sixteen miRNA were significantly differentially expressed in MPNST compared with NF, and of these fourteen were downregulated in MPNST: these included miR-30e*, miR-29c*, miR-29c, miR-340*, miR-30c, miR-139-5p, miR-195, miR-151-5p, miR-342-5p, miR-146a, miR-150, miR-223, let-7 a and let-7 g with a false discovery rate of q = 8.48E-03 for the least significant miRNA. In contrast, miR-210 and miR-339-5p were upregulated in MPNST compared with neurofibromas. Prediction softwares/algorithms identified a list of genes targeted by miR-29c including extracellular matrix genes and matrix metalloproteinase (MMP)-2, all of which are reported to be involved in cell migration and invasion. Functional studies in a MPNST cell line, sNF96.2, using a mimic of the mature miR-29c showed reduced invasion, whereas there was no change in proliferation. Zymography of the manipulated cells showed that MMP2 activity was also reduced when miR-29c expression was forced in sNF96.2.Conclusion: We provide evidence that reduction of miR-29c has a pivotal role in the progression of nerve sheath tumours and results by increasing the invasive/migratory properties of nerve sheath tumours.

Chordoma is a rare malignant tumour of bone, the molecular marker of which is the expression of the transcription factor T (also referred to as brachyury). Silencing of T induces growth arrest in chordoma cell lines; however its downstream genomic targets are unknown. In this thesis I have identified these targets with validation in human chordoma samples. This was achieved by using an integrated functional genomics approach involving shRNA-mediated brachyury knockdown, gene expression microarray, ChIP-seq experiments and bioinformatics analyses. The results show that T regulates a downstream network that involves key cell cycle related genes amongst other potential oncogenic programmes. This is the first documentation of genomic T targets in humans and provides a molecular insight into the pathogenesis of chordoma. In a separate but related piece of work, a genetic association study was conducted to determine the genetic susceptibility determinants in patients with sporadic chordomas. Whole-exome and Sanger sequencing of T exons revealed a strong risk association with the common non-synonymous SNP rs2305089 in chordoma. The degree of risk imparted by this variant is large and is an exceptional finding in cancer genetics. Overall the work presented in this thesis contributes to the evolving understanding of T’s role in the pathogenesis of this rare bone cancer.