Seth Septer

Early-onset lymphoproliferation and autoimmunity caused by germline STAT3 gain-of-function mutations.

Germline loss-of-function mutations in the transcription factor signal transducer and activator of transcription 3 (STAT3) cause immunodeficiency, whereas somatic gain-of-function mutations in STAT3 are associated with large granular lymphocytic leukemic, myelodysplastic syndrome, and aplastic anemia. Recently, germline mutations in STAT3 have also been associated with autoimmune disease. Here, we report on 13 individuals from 10 families with lymphoproliferation and early-onset solid-organ autoimmunity associated with 9 different germline heterozygous mutations in STAT3. Patients exhibited a variety of clinical features, with most having lymphadenopathy, autoimmune cytopenias, multiorgan autoimmunity (lung, gastrointestinal, hepatic, and/or endocrine dysfunction), infections, and short stature. Functional analyses demonstrate that these mutations confer a gain-of-function in STAT3 leading to secondary defects in STAT5 and STAT1 phosphorylation and the regulatory T-cell compartment. Treatment targeting a cytokine pathway that signals through STAT3 led to clinical improvement in 1 patient, suggesting a potential therapeutic option for such patients. These results suggest that there is a broad range of autoimmunity caused by germline STAT3 gain-of-function mutations, and that hematologic autoimmunity is a major component of this newly described disorder. Some patients for this study were enrolled in a trial registered at www.clinicaltrials.gov as #NCT00001350.

Deregulation of Hippo kinase signalling in human hepatic malignancies.

Hepatocellular carcinoma (HCC), cholangiocarcinoma (CC) and hepatoblastoma (HB) are the main hepatic malignancies with limited treatment options and high mortality. Recent studies have implicated Hippo kinase pathway in cancer development, but detailed analysis of Hippo kinase signalling in human hepatic malignancies, especially CC and HB, is lacking.

Yes-associated protein is involved in proliferation and differentiation during postnatal liver development

It is known that the liver undergoes size increase and differentiation simultaneously during the postnatal period. Cells in the liver undergo a period of well-controlled proliferation to achieve the adult liver-to-body weight ratio. The postnatal liver growth is also accompanied by simultaneous hepatic differentiation. However, the mechanisms of liver size regulation and differentiation are not completely clear. Herein we report that yes-associated protein (Yap), the downstream effector of the Hippo Kinase signaling pathway, plays a role in liver size regulation and differentiation during the postnatal liver growth period. Postnatal liver growth was studied in C57BL/6 mice over a time course of postnatal days (PND) 0-30. Analysis of nuclear Yap by Western blot indicated peak Yap activation between PND15-20, which coincided with increased cyclin D1 expression and liver cell proliferation. Analysis of postnatal liver development in Yap(+/-) mice revealed a significant decrease in the liver-to-body weight ratio compared with Yap(+/+) mice at PND15 and -30. Yap(+/-) mice exhibited a significant decrease in postnatal liver cell proliferation, but no change in apoptosis was observed. Furthermore, global gene expression analysis of Yap(+/-) livers revealed a role of Yap in regulation of genes involved in bile acid metabolism, retinoic acid metabolism, ion transport, and extracellular matrix proteins. Taken together, these data indicate that Yap plays a role in both cell proliferation and possibly in hepatic differentiation during postnatal liver development.

Microbiome, Metabolome and Inflammatory Bowel Disease.

Inflammatory Bowel Disease (IBD) is a multifactorial disorder that conceptually occurs as a result of altered immune responses to commensal and/or pathogenic gut microbes in individuals most susceptible to the disease. During Crohn’s Disease (CD) or Ulcerative Colitis (UC), two components of the human IBD, distinct stages define the disease onset, severity, progression and remission. Epigenetic, environmental (microbiome, metabolome) and nutritional factors are important in IBD pathogenesis. While the dysbiotic microbiota has been proposed to play a role in disease pathogenesis, the data on IBD and diet are still less convincing. Nonetheless, studies are ongoing to examine the effect of pre/probiotics and/or FODMAP reduced diets on both the gut microbiome and its metabolome in an effort to define the healthy diet in patients with IBD. Knowledge of a unique metabolomic fingerprint in IBD could be useful for diagnosis, treatment and detection of disease pathogenesis.

Clinical outcome of pediatric collagenous gastritis: Case series and review of literature

Collagenous gastritis (CG) is characterized by patchy subepithelial collagen bands. Effective treatment and the clinical and histological outcome of CG in children are poorly defined. The aim of this study is to summarize the published literature on the clinical outcome and response to therapy of pediatric CG including two new cases. We performed a search in Pubmed, OVID for related terms; articles including management and clinical and/or endo-histologic follow up information were included and abstracted. Reported findings were pooled in a dedicated database including the corresponding data extracted from chart review in our patients with CG. Twenty-four patients were included (17 females) with a mean age of 11.7 years. The clinical presentation included iron deficiency anemia and dyspepsia. The reported duration of follow up (in 18 patients) ranged between 0.2-14 years. Despite most subjects presenting with anemia including one requiring blood transfusion, oral iron therapy was only documented in 12 patients. Other treatment modalities were antisecretory measures in 13 patients; proton pump inhibitors (12), or histamine-2 blockers (3), sucralfate (5), prednisolone (6), oral budesonide in 3 patients where one received it in fish oil and triple therapy (3). Three (13%) patients showed no clinical improvement despite therapy; conversely 19 out of 22 were reported with improved symptoms including 8 with complete symptom resolution. Spontaneous clinical resolution without antisecretory, anti-inflammatory or gastroprotective agents was noted in 5 patients (4 received only supplemental iron). Follow up endo-histopathologic data (17 patients) included persistent collagen band and stable Mononuclear cell infiltrate in 12 patients with histopathologic improvement in 5 patients. Neither collagen band thickness nor mononuclear cell infiltrate correlated with clinical course. Intestinal metaplasia and endocrine cell hyperplasia were reported (1) raising the concern of long term malignant transformation. In summary, CG in children is a chronic disease, typically with a variable clinical response and an indolent course that is distinct from the adult phenotype. Long term therapy usually included iron supplementation but cannot be standardized, given the chronicity of the disease, variability of response and potential for adverse events.

Esophageal polyps in pediatric patients undergoing routine diagnostic upper gastrointestinal endoscopy: a multicenter study.

Esophageal polyps are uncommon findings in pediatric patients, and reports have been limited to case reports. Esophageal polyps have been previously ascribed to esophagitis secondary to gastroesophageal reflux, medications, infections and recurrent vomiting. They have been associated with underlying conditions such as hiatal hernia, Barretts esophagus, eosinophilic esophagitis and Crohns disease. Presenting complaints of children with esophageal polyps have included vomiting, dysphagia, hematemesis and abdominal pain. The aim of this paper is to characterize the incidence, clinical presentation and progression, histologic subtypes and associated mucosal abnormalities in children with esophageal polyps. A retrospective multicenter study was performed at four institutions identifying diagnosis of esophageal polyps in pediatric patients (<21 years). Information was obtained from patient charts, endoscopy reports and histopathology reports. Specimens and slides were examined by experienced pediatric pathologists for all included cases. Esophageal polyps were identified in 13 patients (9 M) from 9438 esophagogastroduodenoscopies (0.14%). Mean age of subjects was 9.2 years. Vomiting was the most common indication for endoscopy. Polyp location was at the gastroesophageal junction in 7 of the 13 cases. Most polyps were inflammatory (n = 7). Esophagitis was noted in 69% of those with esophageal polyps. Repeat endoscopies in six patients at a mean interval of 8 months noted persistence of polyps in all six patients. This paper is the first to characterize esophageal polyps in pediatrics. These polyps are rare in children and often are associated with esophagitis. Presenting complaints seem to vary by age. Polyps did not consistently change with either time or acid suppression. The optimal management strategy has yet to be defined and likely depends on the underlying pathophysiologic process.

Effects of Whole Body Therapeutic Hypothermia on Gastrointestinal Morbidity and Feeding Tolerance in Infants with Hypoxic Ischemic Encephalopathy

Objective. This retrospective cohort study evaluated the effects of whole body therapeutic hypothermia (WBTH) on gastrointestinal (GI) morbidity and feeding tolerance in infants with moderate-to-severe hypoxic ischemic encephalopathy (HIE). Study Design. Infants ≥ 35 weeks gestational age and ≥1800 grams birth weight with moderate-to-severe HIE treated from 2000 to 2012 were compared. 68 patients had documented strictly defined criteria for WBTH: 32 historical control patients did not receive WBTH (non-WBTH) and 36 cohort patients received WBTH. Result. More of the non-WBTH group infants never initiated enteral feeds (28% versus 6%; P = 0.02), never reached full enteral feeds (38% versus 6%, P = 0.002), and never reached full oral feeds (56% versus 19%, P = 0.002). Survival analyses demonstrated that the WBTH group reached full enteral feeds (median time: 11 versus 9 days; P = 0.02) and full oral feeds (median time: 19 versus 10 days; P = 0.01) sooner. The non-WBTH group had higher combined outcomes of death and gastric tube placement (47% versus 11%; P = 0.001) and death and gavage feeds at discharge (44% versus 11%; P = 0.005). Conclusion. WBTH may have beneficial effects on GI morbidity and feeding tolerance for infants with moderate-to-severe HIE.

Present Standard in Pediatric Gastroenterology Fellowship Training in the Interpretation of Capsule Endoscopy.

ABSTRACT Consensuses on fellowship training in wireless capsule endoscopy (WCE) interpretation have been published for adult gastroenterology (GI) but not in pediatric GI training. A questionnaire has been sent to 64 pediatric and 45 adult GI fellowship programs to compare their present training approach. Adult GI programs reported having a formal GI capsule endoscopy module in 38% and required to attend hands-on course in 27% as compared with 4% and 8% in pediatric programs, respectively. A more formalized approach to WCE training may be required for credentialing pediatric trainees to be aligned with expectations in adult GI programs.

A Novel Variant in the STAT3 Gene Associated with Autoimmune Enteropathy in a Father–Son Duo

Autoimmune enteropathy (AIE) is a rare clinical condition characterized by intractable diarrhea of early childhood.¹ While AIE can feature both simple Mendelian inheritance or a complex multifactorial pattern, the pathogenesis remains unclear in many cases.² This is important for providing an accurate recurrence risk as affected individuals survive until adulthood and have children. Here, we describe a father and son with AIE who had clinically distinct courses. Exome sequencing has revealed a novel missense variant, c.2147C>T; (p.Thr716Met) in the signal transducer and activator of transcription 3 gene (STAT3) in both the father and son, consistent with autosomal dominant inheritance. STAT3 regulates immune reactions, and mutations in this gene have previously been associated with autoimmunity and Hyper IgE syndrome, but not AIE. Further studies are needed to assess the functional effect of this variant as it relates to the phenotype.

Increased YAP Activation Is Associated With Hepatic Cyst Epithelial Cell Proliferation in ARPKD/CHF

Autosomal recessive polycystic kidney disease/congenital hepatic fibrosis (ARPKD/CHF) is a rare but fatal genetic disease characterized by progressive cyst development in the kidneys and liver. Liver cysts arise from aberrantly proliferative cholangiocytes accompanied by pericystic fibrosis and inflammation. Yes-associated protein (YAP), the downstream effector of the Hippo signaling pathway, is implicated in human hepatic malignancies such as hepatocellular carcinoma, cholangiocarcinoma, and hepatoblastoma, but its role in hepatic cystogenesis in ARPKD/CHF is unknown. We studied the role of the YAP in hepatic cyst development using polycystic kidney (PCK) rats, an orthologous model of ARPKD, and in human ARPKD/CHF patients. The liver cyst wall epithelial cells (CWECs) in PCK rats were highly proliferative and exhibited expression of YAP. There was increased expression of YAP target genes, Ccnd1 (cyclin D1) and Ctgf (connective tissue growth factor), in PCK rat livers. Extensive expression of YAP and its target genes was also detected in human ARPKD/CHF liver samples. Finally, pharmacological inhibition of YAP activity with verteporfin and short hairpin (sh) RNA-mediated knockdown of YAP expression in isolated liver CWECs significantly reduced their proliferation. These data indicate that increased YAP activity, possibly through dysregulation of the Hippo signaling pathway, is associated with hepatic cyst growth in ARPKD/CHF.