Faculty Bibliography

OBJECTIVE:Familial dysautonomia (FD) is a rare inherited autosomal recessive disorder with abnormal somatosensory, enteric, and afferent autonomic neurons. We aimed to define the incidence of gastrointestinal bleeding and its associated risk factors in patients with FD. METHODS:In this retrospective case-control study, we identified all episodes of gastrointestinal bleeding in patients with FD, occurring over four decades (January 1980-December 2017), using the New York University FD registry. RESULTS:We identified 104 episodes of gastrointestinal bleeding occurring in 60 patients with FD. The estimated incidence rate of gastrointestinal bleeds in the FD population rate was 4.20 episodes per 1000 person-years. We compared the 60 cases with 94 age-matched controls. Bleeding in the upper gastrointestinal tract from gastric and duodenal ulcers occurred most frequently (64 bleeds, 75.6%). Patients were more likely to have a gastrostomy (G)-tube and a Nissen fundoplication [odds ratio (OR) 3.73, 95% confidence interval (CI) 1.303-13.565] than controls. The mean time from G-tube placement to first gastrointestinal bleed was 7.01 years. The mean time from Nissen fundoplication to bleed was 7.01 years. Cases and controls had similar frequency of intake of nonsteroidal antiinflammatory drugs (NSAID) and selective serotonin reuptake inhibitors (SSRI). CONCLUSION/CONCLUSIONS:The incidence of gastrointestinal bleeding in the pediatric FD population was estimated to be 4.20 per 1000 person-years, 21 times higher than in the general pediatric population (0.2 per 1000 person-years). Patients with FD with a G-tube and a Nissen fundoplication had a higher risk of a subsequent gastrointestinal bleeding.

Genetic analysis of human inborn errors of immunity has defined the contribution of specific cell populations and molecular pathways in the host defense against infection. The STAT family of transcription factors orchestrate hematopoietic cell differentiation. Patients with de novo activating mutations of STAT3 present with multiorgan autoimmunity, lymphoproliferation, and recurrent infections. We conducted a detailed characterization of the blood monocyte and dendritic cell (DC) subsets in patients with gain-of-function (GOF) mutations across the gene. We found a selective deficiency in circulating nonclassical CD16⁺ and intermediate CD16⁺CD14⁺ monocytes and a significant increase in the percentage of classical CD14⁺ monocytes. This suggests a role for STAT3 in the transition of classical CD14⁺ monocytes into the CD16⁺ nonclassical subset. Developmentally, ex vivo-isolated STAT3^GOF CD14⁺ monocytes fail to differentiate into CD1a⁺ monocyte-derived DCs. Moreover, patients with STAT3^GOF mutations display reduced circulating CD34⁺ hematopoietic progenitors and frequency of myeloid DCs. Specifically, we observed a reduction in the CD141⁺ DC population, with no difference in the frequencies of CD1c⁺ and plasmacytoid DCs. CD34⁺ hematopoietic progenitor cells from patients were found to differentiate into CD1c⁺ DCs, but failed to differentiate into CD141⁺ DCs indicating an intrinsic role for STAT3 in this process. STAT3^GOF-differentiated DCs produced lower amounts of CCL22 than healthy DCs, which could further explain some of the patient pathological phenotypes. Thus, our findings provide evidence that, in humans, STAT3 serves to regulate development and differentiation of nonclassical CD16⁺ monocytes and a subset of myeloid DCs.

The association of new onset Henoch-Schönlein purpura (HSP) and inflammatory bowel disease (IBD) has been reported in the setting of concomitant anti-TNF-ɑ treatment. We present two pediatric IBD cases who developed new onset HSP without such association. These cases add to the literature by suggesting an association between HSP and IBD in pediatric population. We discuss possible underlying pathophysiological mechanisms, suggesting some commonality with IgA nephropathy. Increased awareness for HSP in pediatric IBD patients regardless of anti-TNF- ɑ therapy involvement is important for timely recognition and appropriate multi-disciplinary management.

PURPOSE/OBJECTIVE:Familial dysautonomia (FD) is a rare hereditary sensory and autonomic neuropathy (HSAN-3) that is clinically characterized by impaired pain and temperature perception and abnormal autonomic function. Patients with FD have gastrointestinal dysmotility and report a range of gastrointestinal symptoms that have yet to be systematically evaluated. The aim of this study was to establish the frequency and severity of gastrointestinal symptoms in patients with FD. METHODS:The validated National Institutes of Health Patient-Reported Outcomes Measurement Information System (PROMIS) survey questionnaire, together with additional FD-specific questions, were distributed to 202 living patients with genetically confirmed FD who had been identified from the New York University FD Patient Registry or, when relevant, to their respective caretaker. As a comparison group, we used a general US adult population for whom PROMIS scores were available (N = 71,812). RESULTS:Of the 202 questionnaires distributed, 77 (38%) were returned, of which 53% were completed by the patient. Median age of the respondents was 25 years, and 44% were male. Gastrostomy tube was the sole nutrition route for 25% of the patients, while 53% were reliant on the gastrostomy tube only for liquid intake. The prevalence of gastrointestinal symptoms was significantly higher in each of the eight domains of PROMIS in patients with FD than in the controls. Gastrointestinal symptoms as measured by raw scores on the PROMIS scale were significantly less severe in the FD patient group than in the control population in all domains with the exception of the abdominal pain domain. The surveys completed by caregivers reported the same burden of symptoms as those completed only by patients. CONCLUSION/CONCLUSIONS:Gastrointestinal symptoms affect nearly all patients with FD. Gastrointestinal symptoms are more prevalent in adult patients with FD than in the average US adult population but are less severe in the former.

Gastrointestinal dysfunction in children with autism spectrum disorder (ASD) is common and associated with problem behaviors. This study describes the development of a brief, parent-report screen that relies minimally upon the child's ability to report or localize pain for identifying children with ASD at risk for one of three common gastrointestinal disorders (functional constipation, functional diarrhea, and gastroesophageal reflux disease). In a clinical sample of children with ASD, this 17-item screen identified children having one or more of these disorders with a sensitivity of 84%, specificity of 43%, and a positive predictive value of 67%. If found to be valid in an independent sample of children with ASD, the screen will be useful in both clinical practice and research.

BACKGROUND:Familial dysautonomia (Riley-Day syndrome, hereditary sensory autonomic neuropathy type-III) is a rare genetic disease caused by impaired development of sensory and afferent autonomic nerves. As a consequence, patients develop neurogenic dysphagia with frequent aspiration, chronic lung disease, and chemoreflex failure leading to severe sleep disordered breathing. The purpose of these guidelines is to provide recommendations for the diagnosis and treatment of respiratory disorders in familial dysautonomia. METHODS:We performed a systematic review to summarize the evidence related to our questions. When evidence was not sufficient, we used data from the New York University Familial Dysautonomia Patient Registry, a database containing ongoing prospective comprehensive clinical data from 670 cases. The evidence was summarized and discussed by a multidisciplinary panel of experts. Evidence-based and expert recommendations were then formulated, written, and graded using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system. RESULTS:Recommendations were formulated for or against specific diagnostic tests and clinical interventions. Diagnostic tests reviewed included radiological evaluation, dysphagia evaluation, gastroesophageal evaluation, bronchoscopy and bronchoalveolar lavage, pulmonary function tests, laryngoscopy and polysomnography. Clinical interventions and therapies reviewed included prevention and management of aspiration, airway mucus clearance and chest physical therapy, viral respiratory infections, precautions during high altitude or air-flight travel, non-invasive ventilation during sleep, antibiotic therapy, steroid therapy, oxygen therapy, gastrostomy tube placement, Nissen fundoplication surgery, scoliosis surgery, tracheostomy and lung lobectomy. CONCLUSIONS:Expert recommendations for the diagnosis and management of respiratory disease in patients with familial dysautonomia are provided. Frequent reassessment and updating will be needed.

Dietary exclusion of gluten containing products has become increasingly popular in the general population and currently about 30% of people in the United States are limiting gluten ingestion. While celiac disease (CD), wheat allergy (WA) and non-celiac gluten sensitivity (NCGS) constitute a spectrum of gluten related disorders that require exclusion of gluten from the diet, together these account for a relatively small percentage of those following a gluten free diet and the vast majority has no medical necessity for doing so. Differentiating between CD, WA and NCGS has important prognostic and therapeutic implications. Because of the protean manifestations of the gluten related disorders it is not possible to differentiate between them on clinical grounds alone. This clinical report will compare and contrast the manifestations of the gluten related disorders, emphasize the importance of differentiating between these conditions, discuss initial and subsequent tests needed to confirm the diagnosis and provide recommendations on treatment and follow up for each condition.

Celiac disease is a chronic immune-mediated condition that develops in genetically predisposed individuals. It is characterized by the presence of circulating auto-antibodies in addition to an enteropathy and at times, other extra-intestinal manifestations triggered by exposure to the gliadin fraction of gluten, a family of proteins found in wheat, barley, and rye. There seems to be a rise in reported adverse reactions to gluten, an entity currently termed non-celiac gluten (or perhaps more accurately, wheat) sensitivity, where neither the enteropathy nor the auto-antibodies are present. Celiac disease has protean extra-intestinal manifestations, and an accurate diagnosis should be sought in people suffering from seemingly unrelated complaints, such as fatigue, anorexia, delayed puberty, short stature, decreased bone density, unusual skin rashes, unexplained iron deficiency, and infertility. The presence of an enteropathy, in conjunction with the positive serology, is considered the diagnostic gold standard for making the diagnosis of celiac disease. It is important to stress that the elimination of gluten, even in asymptomatic patients, brings about health benefits, particularly in relation to bone health, as well as a decrease in the incidence of small bowel malignancy, especially lymphoma. Better understanding of the pathophysiology of celiac disease and the molecular mechanisms involved in antigen recognition and processing has provided the impetus for the development of pharmacologic agents that might block the recognition of gluten and its conversion to a toxic antigenic target. Inhibition of tight junction dysregulation could also prevent or minimize the damage triggered by gluten. Work on genetically modified wheat cultivars has progressed, and the possibility of a vaccine to block the immune mediated trigger is being actively investigated. Education and guidance by a knowledgeable nutritionist or registered dietitian can go a long way in minimizing the stress and facilitating the acceptance of the diet and the life-style changes that it represents.

The pulmonary involvement concurrent with gastrointestinal (GI) diseases is often clinically subtle. Radiological manifestations might lag behind the respiratory compromise, and only such specialized testing as high resolution computed tomography (HRCT), permeability studies with labelled proteins, or comprehensive pulmonary function tests (PFTs) may be sensitive enough to detect the evolving pathophysiology. Increasing recognition of specific entities, such as immune-mediated alveolitis, will allow implementation of therapies that can significantly improve a patient's prognosis