Human germline heterozygous gain-of-function STAT6 variants cause severe allergic disease.

STAT6 (signal transducer and activator of transcription 6) is a transcription factor that plays a central role in the pathophysiology of allergic inflammation. We have identified 16 patients from 10 families spanning three continents with a profound phenotype of early-life onset allergic immune dysregulation, widespread treatment-resistant atopic dermatitis, hypereosinophilia with esosinophilic gastrointestinal disease, asthma, elevated serum IgE, IgE-mediated food allergies, and anaphylaxis. The cases were either sporadic (seven kindreds) or followed an autosomal dominant inheritance pattern (three kindreds). All patients carried monoallelic rare variants in STAT6 and functional studies established their gain-of-function (GOF) phenotype with sustained STAT6 phosphorylation, increased STAT6 target gene expression, and TH2 skewing. Precision treatment with the anti-IL-4Rα antibody, dupilumab, was highly effective improving both clinical manifestations and immunological biomarkers. This study identifies heterozygous GOF variants in STAT6 as a novel autosomal dominant allergic disorder. We anticipate that our discovery of multiple kindreds with germline STAT6 GOF variants will facilitate the recognition of more affected individuals and the full definition of this new primary atopic disorder.

A 47-Year-Old Woman With Hemoptysis and a Lung Cyst.

CASE PRESENTATION: A 47-year-old woman was admitted to the hospital for an episode of hemoptysis. She coughed out small amount of clotted blood the morning of admission. She had no other symptoms on further review. Her medical history was unremarkable with the exception of an upper respiratory tract infection 9 months previously. She did not have any significant medical history or recent sick contacts. She was a lifelong nonsmoker and the mother of three teenaged children. She had irregular menses for the past 2 years, and her last menstrual period was 3 months ago. She reliably reported not engaging in any sexual contact for the past 2 years.

Rapid reduction of viruria and stabilization of allograft function by fusidic acid in a renal transplant recipient with JC virus-associated nephropathy.

JC virus (JCV)-associated nephropathy has been increasingly recognized as a cause of allograft dysfunction with graft loss in renal transplant recipients. Like many other opportunistic viral infections in transplant recipients, there are currently limited therapeutic options for this condition. Fusidic acid has previously been reported to exhibit antiviral activity against JCV in in vitro assays. We report the first in vivo study to document the rapid reduction of JC viruria and stabilization of allograft function by oral fusidic acid (fusidate sodium) in a deceased donor renal transplant recipient with JCV-associated nephropathy and acute allograft dysfunction which did not improve initially to surgical relief of hydronephrosis and reduction of immunosuppressants. Rapid reduction of JC viruria detected by quantitative PCR and stabilization of renal function were observed. Fusidic acid has several practical advantages in this clinical setting, including a low EC50 against JCV, high plasma C max, long half-life, availability of both oral and intravenous formulations, excellent oral bioavailability, good patient tolerability, and lack of serious drug interactions with other drugs taken by renal transplant recipients. Further mechanistic and clinical studies are necessary to evaluate this treatment option for JCV-associated nephropathy.

Fine needle aspiration cytology in follicular dendritic cell sarcoma: a report of two cases.

BACKGROUND: Since the first description of extranodalfollicular dendritic cell sarcoma in 1994, there has been a gradual increase in understanding of the morphologic features and clinical presentation of this tumor. However, difficulties persist in making cytologic diagnosis. CASES: Two cases of follicular dendritic cell sarcoma with fine needle aspiration cytology (FNAC) findings were reported. The first patient was a Chinese woman who presented with a right tonsillar mass, which was followed by right submandibular recurrence. The second patient was a Chinese man with known history of Castleman's disease of the nasopharynx complicated by follicular dendritic cell sarcoma, followed by tumor recurrence in cervical lymph nodes. FNAC of both recurrent cases showed isolated or syncytial sheets of tumor cells containing eosinophilic granular cytoplasm, ill-defined cell borders, round to oval nuclei, solitary round eosinophilic nucleoli and fine chromatin. CONCLUSION: The tumor cells in follicular dendritic cell sarcoma show cytologic features reminiscent of native follicular dendritic cells but with a greater than expected cell number and nuclear pleomorphism. These cells may be immunohistochemically inert for follicular dendritic cell markers CD21 and CD35. A presumptive diagnosis on the basis of cytologic examination is possible when paying attention to the subtle morphologic features.

Focal segmental glomerulosclerosis after membranous glomerulonephritis in remission: temporal diversity of glomerulopathy after bone marrow transplantation.

Heavy proteinuria after bone marrow transplantation (BMT) is rare. Pathology shows membranous glomerulonephritis (MGN) in most cases. After BMT, focal segmental glomerulosclerosis (FSGS) after resolution of MGN has not been reported. We describe a 13-year-old boy who had matched unrelated donor allogeneic BMT for relapsed acute lymphoblastic leukemia, complicated by chronic graft-versus-host disease. Nephrotic syndrome developed 1 year after BMT and renal biopsy revealed MGN. Immunosuppressive therapy achieved good clinical remission, and treatment was stopped after 15 months. He developed significant proteinuria 55 months later. The second renal biopsy showed FSGS without changes of MGN. This distinctive disease evolution gives inspiring implications. Complete morphological resolution of graft-versus-host disease-associated MGN, achieved in our case, has not been previously documented. Recurrent significant proteinuria after BMT is not necessarily due to previous renal lesion, and a repeat renal biopsy is indicated. The pathogenesis of MGN and FSGS are different, and different mechanisms of glomerular injury can interplay in a single patient after BMT. This case helps to expand our knowledge of the temporal morphological spectrum of renal lesions associated with BMT.

Sonographic features of lethal multiple pterygium syndrome at 14 weeks.

Lethal multiple pterygium syndrome is a rare inherited disorder. Previous reports suggest that the diagnosis may be based on prenatal sonographic demonstration of severe limb flexion, absence of fetal motion, and a large cystic hygroma in the second and third trimesters. We present the sonographic features and postmortem features of a fetus with lethal multiple pterygium syndrome at 13 weeks of gestation, which shows that the condition can possibly be diagnosed in the first trimester of pregnancy.

Granulomatous appendicitis progressing to Crohn's disease with bleeding complication.

Granulomatous appendicitis can be idiopathic or due to a number of specific causes. Idiopathic granulomatous appendicitis is regarded as a separate disease entity and usually has a benign course. We report on a case of granulomatous appendicitis, which progressed to fulminant Crohn's colitis shortly after appendicectomy. During the treatment with intravenous steroid, torrential gastro-intestinal bleeding developed and emergency subtotal colectomy had to be performed. The clinical and histological features of the case are presented and the literature on granulomatous appendicitis reviewed.