A high-throughput amplicon screen for somatic UBA1 variants in Cytopenic and Giant Cell Arteritis cohorts

Somatic mutations in the gene encoding the major E1 ubiquitin ligase, UBA1, were recently identified as a cause of VEXAS, a late-onset acquired auto-inflammatory syndrome. Differential diagnoses for patients subsequently found to have VEXAS include relapsing polychondritis, Sweet’s syndrome, myelodysplastic syndrome (MDS), giant cell arteritis (GCA) and undifferentiated systemic autoinflammatory disease (uSAID). We therefore sought to screen DNA from individuals with a non-diagnostic cytopenia or GCA, for known VEXAS-associated mutations. To this end, we developed a multiplexed UBA1 amplicon sequencing assay, allowing quick screening of large cohorts while also providing sufficient sequencing depth to identify somatic mutations to an allele frequency <1%. Using this assay, we screened genomic DNA from 612 males diagnosed with GCA, and bone marrow DNA from 1,055 cases with an undiagnosed cytopenia. No GCA cases were found to have UBA1 mutations, however 4 different mutations in the cytopenic cohort were identified in 7 individuals. Furthermore, we describe a female case identified in the screen with a UBA1 mutation and all VEXAS-associated phenotypes, but without Monosomy X. Our study suggests that, despite the overlap in clinical features, VEXAS is rarely misdiagnosed as GCA, but identified in 1.0% of males with an undiagnosed cytopenia. The identification of a UBA1 variant in a female case adds further evidence that VEXAS should not be ruled out as a differential diagnosis in females with VEXAS-like symptoms.Key points-Mutations in UBA1 exon 3 have been associated with VEXAS syndrome-UBA1 exon 3 was screened in 1650 patients with cytopenia or GCA by amplicon sequencing.-6 males were identified from the non-diagnostic cytopenia cohort (1.0%) with UBA1 mutations.-A female with a somatic UBA1 mutation was identified without Monosomy X

Pioneering, prodigious and perspicacious: Grunya Efimovna Sukhareva’s life and contribution to conceptualising autism and schizophrenia

Grunya Efimovna Sukhareva’s seminal role in being the first to publish a clinical description of autistic traits in 1925, before both Kanner and Asperger, has been revealed relatively recently. Nevertheless, Sukhareva’s work is little known and largely unrecognised beyond Russia. Amidst calls for greater recognition of her pivotal contribution in the genesis of autism conceptualisation and categorisation, this article provides a biographical and historical background. Sukhareva’s wide-ranging psychiatric work is adumbrated and her pioneering efforts in conceptualising both schizophrenia and autism are elucidated. The article reflects on possible explanations for the belated and incomplete recognition of Sukhareva’s role. The current article indicates how Sukhareva’s work was ahead of its time in reflecting modern criteria for autism diagnoses and in its focus on female case studies. Sukhareva’s somewhat precarious position as a foremost psychiatrist condemned in the Stalinist years for being anti-Marxist is explicated. The article outlines further directions for academic research on Sukhareva’s work and contributions.

Hybrid Carcinoma of the Parotid Gland: An Extremely Rare Three Cases with an Immunohistochemical Analysis and a Review of the Literature

Salivary hybrid carcinoma (HC) is defined as when two or more kinds of carcinoma exist at the same location in a single mass. We reestimated and examined three cases of salivary gland HC. Case 1 involved a 76-year-old male. Case 2 involved a 74-year-old female. Case 3 involved a 66-year-old male. Histologically, case 1 involved a combination of salivary duct carcinoma (SDC) and squamous cell carcinoma (SqCC). Immunohistochemically, the former was positive for gross cystic disease fluid protein (GCDFP)-15 and androgen receptor (AR). Case 2 involved a combination of SqCC and neuroendocrine carcinoma. Immunohistochemically the latter was positive for synaptophysin and neural cell adhesion molecule (NCAM). Case 3 involved a combination of SDC and epithelial–myoepithelial carcinoma (EMC). Immunohistochemically, the former was positive for GCDFP-15 and AR, whereas the inner cells of the latter were positive for cytokeratin 7, and the outer cells of the latter were positive for actin. Because of the transitional zone between SDC and EMC, it was speculated that high-grade SDC arose from low-grade EMC.

Acute Pancreatitis with Large Infected Pseudo Pancreatic Cyst in a Post-Partum Female – Case Report

A frequent cause for patient presentation to the emergency department and the most serious gastrointestinal condition resulting in admission is acute pancreatitis. Pancreatitis is an inflammatory process within the pancreas. Although the disease is mostly mild, the mortality rate of severe forms may be up to 30 percent. Two of the following three criteria are required for diagnosis: epigastric abdominal pain, elevated lipase, and pancreatic inflammation on imaging.1 The occurrence of acute pancreatitis is approximately 1 in 1000 to 5000 births and is commonly seen in the last weeks of gestation or in post-partum period. Cholelithiasis, which accounts for more than 65 percent of cases, is the most common cause of acute pancreatitis in pregnancy.2 Pancreatic ascites results from persistent leakage of pancreatic secretions in the peritoneum from pancreatic duct injury. The extent of pancreatic ascites varies, depending on the site and degree of ductal damage and infection.3 The complications of acute or chronic pancreatitis are pancreatic pseudocysts. Initial diagnosis is mostly done by imaging. Endoscopic ultrasound with fine needle aspiration cytology (FNAC) has become the standard test to help differentiate pseudocyst from other cystic lesions of the pancreas. With supportive treatment, most pseudocysts resolve spontaneously. Poor predictors for the potential of pseudocyst resolution or complications are the size of the pseudocyst and the length of time the cyst has been present, but larger cysts in general are more likely to be symptomatic or cause complications.4 We report a case of young female presenting with jaundice and ascites two days post-partum, who was eventually diagnosed as a case of pancreatic ascites with large pancreatic pseudocyst.

A Turner syndrome case associated with dic(Y;22)

Background Constitutional telomeric associations are very rare events and the mechanism underlying their development is not well understood. Case presentation We here describe a female case of Turner syndrome with a 45,X,add(22)(p11.2)[25]/45,X[5]. We reconfirmed this karyotype by FISH analysis as 45,X,dic(Y;22)(p11.3;p11.2)[28]/45,X[2].ish dic(Y;22)(SRY+,DYZ1+). A possible mechanism underlying this mosaicism was a loss of dic(Y;22) followed by a monosomy rescue of chromosome 22. However, SNP microarray analysis revealed no loss of heterozygosity (LOH) in chromosome 22, although a mosaic pattern of LOH was clearly detectable at the pseudoautosomal regions of the sex chromosomes. Conclusions Our results suggest that the separation of the dicentric chromosome at the junction resulted in a loss of chromosome Y without a loss of chromosome 22, leading to this patient’s unique mosaicism. Although telomere signals were not detected by FISH at the junction, it is likely that the original dic(Y;22) chromosome was generated by unstable telomeric associations. We propose a novel “pulled apart” mechanism as the process underlying this mosaicism.