Dupilumab in adolescent eosinophilic esophagitis: Experience with fibrostenosis and EGID with esophageal involvement.

We evaluated patients aged 12-20 on dupilumab 300 mg weekly for treatment of eosinophilic esophagitis (EoE) who had ≥1 follow-up endoscopy at a tertiary care pediatric hospital (n = 18). Fifty percent had inflammatory EoE (n = 9), 22% had fibrostenotic EoE (n = 4), and 28% had non-EoE eosinophilic gastrointestinal disease (EGID) with esophageal involvement (n = 5). Ninety-four percent discontinued topical corticosteroids (TCS) 2-4 weeks after starting dupilumab. Eighty-nine percent of inflammatory EoE patients had histological response (<15 eosinophils/high-powered field) after an average of 19.1 weeks. One hundred percent of patients with fibrostenotic disease exhibited histological response after 16.8 weeks. Of patients with non-EoE EGID, 60% achieved esophageal histological response after an average of 40.1 weeks. In a small cohort, dupilumab was very effective for adolescent inflammatory and fibrostenotic EoE despite rapid weaning of TCS. Dupilumab was also somewhat effective for non-EoE EGID with esophageal involvement; however, a longer duration of therapy was required.

Hypereosinophilic Syndrome with Pulmonary Involvement in Ulcerative Colitis.

Reactive eosinophilia is associated with inflammatory bowel disease and is more common in patients with ulcerative colitis (UC) compared with Crohn's disease. The prevalence rate of peripheral blood eosinophilia in patients with inflammatory bowel disease has been described to be as high as 30%-40% of patients in a pediatric study. The coexistence of hypereosinophilic syndrome (HES) and UC is uncommon. We present a 15-year-old boy with UC associated with HES who presented with chest pain and shortness of breath. Laboratory evaluation showed marked eosinophilia. Alternative causes of eosinophilia including eosinophilic leukemia, infections, or drug-induced eosinophilic pneumonia were ruled out. The patient was ultimately diagnosed with HES responsive to mepolizumab.

Clinical utility of whole-genome DNA methylation profiling as a primary molecular diagnostic assay for central nervous system tumors-A prospective study and guidelines for clinical testing.

Background: Central nervous system (CNS) cancer is the 10th leading cause of cancer-associated deaths for adults, but the leading cause in pediatric patients and young adults. The variety and complexity of histologic subtypes can lead to diagnostic errors. DNA methylation is an epigenetic modification that provides a tumor type-specific signature that can be used for diagnosis. Methods: We performed a prospective study using DNA methylation analysis as a primary diagnostic method for 1921 brain tumors. All tumors received a pathology diagnosis and profiling by whole genome DNA methylation, followed by next-generation DNA and RNA sequencing. Results were stratified by concordance between DNA methylation and histopathology, establishing diagnostic utility. Results: Of the 1602 cases with a World Health Organization histologic diagnosis, DNA methylation identified a diagnostic mismatch in 225 cases (14%), 78 cases (5%) did not classify with any class, and in an additional 110 (7%) cases DNA methylation confirmed the diagnosis and provided prognostic information. Of 319 cases carrying 195 different descriptive histologic diagnoses, DNA methylation provided a definitive diagnosis in 273 (86%) cases, separated them into 55 methylation classes, and changed the grading in 58 (18%) cases. Conclusions: DNA methylation analysis is a robust method to diagnose primary CNS tumors, improving diagnostic accuracy, decreasing diagnostic errors and inconclusive diagnoses, and providing prognostic subclassification. This study provides a framework for inclusion of DNA methylation profiling as a primary molecular diagnostic test into professional guidelines for CNS tumors. The benefits include increased diagnostic accuracy, improved patient management, and refinements in clinical trial design.

Bone Marrow Suppression Associated With Celiac Disease in a 4-Year-Old Boy.

Celiac disease is an immune-mediated process against gluten, resulting in inflammation and villous atrophy of the duodenum. Symptoms of malabsorption characterize the classic presentation; however, abdominal pain, constipation, and nutritional deficiencies can also be seen. We present a case of a 4-year-old boy who was found to have celiac disease after presenting with diarrhea, abdominal pain, weight loss, and new-onset pancytopenia. Symptoms resolved, and laboratory values normalized after the initiation of a gluten-free diet, indicating the bone marrow suppression was due to celiac disease, which needs to be considered when hematologic abnormalities are present, even in the absence of gastrointestinal symptoms.

Multimodal Therapy Including Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy Can Result in Long-term Disease-free Survival in Pediatric Desmoplastic Small Round Cell Tumor With Extraperitoneal Disease.

Desmoplastic small round cell tumor is a rare sarcoma with 5-year overall survival of 15%. An 8-year-old female presented with diffuse abdominal/pelvic desmoplastic small round cell tumor including numerous liver metastasis. She underwent neoadjuvant chemotherapy followed by cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Residual disease was found shortly after CRS/HIPEC which was resected, followed by whole abdomen/pelvic radiation and autologous hematopoietic cell transplant. Previous papers have reported dismal survival in patients with liver metastasis and residual disease arguing against CRS/HIPEC. Our patient remains disease-free over 6 years after completing therapy indicating long-term survival is achievable with aggressive multimodal therapy.

Liver failure and x-linked immunodeficiency type 47.

Patients with defects in the ATP6AP1 gene have rarely been described. ATP6AP1-related disorders are a subtype of CDG, which result in enzyme deficiencies affecting multiple organ systems ranging from mild to life-threatening. Of the 13 patients described, all had hepatopathy, but this is the first case to be successfully transplanted. We describe two brothers who developed hyperbilirubinemia shortly after birth and progressed to liver failure, case 1 by 12 months of age, with successful transplant 2 years later, and case 2 by 4 months of age, who passed away while awaiting liver transplant. Both boys were found to have a new variant in the ATP6AP1 gene: c.932/p.Leu311Gln. Although the identified ATP6AP1 gene variant was classified as unknown significance at the time, both children's phenotypes fit with what has been described for ATP6AP1-related disorders. Therefore, this result appears to have been diagnostic for both boys. This rare type of CDG, X-linked immunodeficiency type 47 (OMIM #300972), particularly in patients who progress to liver failure requiring transplant, should be included on the differential of liver failure in infants and toddlers, and its gene should be added to the diagnostic workup for such cases.

Submucosal Supernumerary Smooth Muscle Coat: A Common Histologic Finding in Mowat-Wilson Syndrome With or Without Hirschsprung Disease.

BACKGROUND: Mowat-Wilson syndrome (MWS) is a multiorgan system disorder caused by ZEB2 (zinc finger E-box-binding homeobox 2) mutations or deletions. One common manifestation is constipation, and approximately half of the patients have Hirschsprung disease (HSCR). In addition to classic histologic features of HSCR, an unusual supernumerary intestinal muscle coat was recently reported in a patient of MWS with HSCR. A similar smooth muscle alteration, segmental additional circular muscle coat, had been described in the specimens from patients with intestinal pseudo-obstruction without MWS or HSCR. METHOD: Rectal biopsies and rectosigmoidectomy specimens from MWS patients were identified by retrospective reviews of surgical pathology records. Routinely prepared glass slides were examined to determine whether any smooth muscle structural alteration was present. Clinical information was obtained by chart review. RESULTS: Six MWS patients were identified. A supernumerary smooth muscle coat in the submucosa was present in 3 of them, including 2 of the 4 patients with HSCR. CONCLUSION: The structural anomaly, termed submucosal supernumerary smooth muscle coat, is not a syndrome-specific pathological feature. However, it appears to be more common than expected in MWS and is consistent with contemporary models for the roles of ZEB2 and related cell signaling pathways in the patterning of intestinal musculature during embryonic development.

Diffuse Midline Glioma With Osseous Metastases at Diagnosis: A Case Report.

Extraneural metastasis is extremely rare in pediatric patients with high-grade glioma and carries a grim prognosis. Detection of metastases at initial presentation is even rarer. A 15-year-old adolescent girl presented with paraplegia, urinary retention, and a constellation of systemic symptoms. Imaging showed a fourth ventricular lesion, innumerable intradural lesions, leptomeningeal seeding throughout the neuraxis, and numerous osteoblastic lesions involving the spine, ribs, sternum, pelvis, humerus, and femurs. Pathology confirmed metastatic diffuse midline glioma, H3K27M-mutant. Our patient died 2 weeks after initial presentation. Further work is needed to develop effective treatment strategies for these high-risk patients.

Ganglioglioma in a Survivor of Infantile Glioblastoma.

Congenital tumors account for 2% to 4% of all pediatric central nervous system tumors. Glioblastoma multiforme (GBM) represents a small subset of these tumors. Despite harboring histologic features similar to older patients, infants with GBM exhibit improved survival and respond more favorably to surgery and chemotherapy. To highlight this tumor's unique behavior, we report the case of a survivor of infantile GBM who developed a recurrent tumor in the surgical bed 6 months after diagnosis. The tumor was ultimately resected and was a ganglioglioma. This case shows both a favorable clinical outcome to an infantile GBM and this tumor's natural history.

Spheno-Orbital Aneurysmal Bone Cyst in a 10-Month-Old Infant.

BACKGROUND: Aneurysmal bone cysts are benign bone lesions affecting long bones and vertebrae; only 2%-6% have cranial involvement, and even fewer show sphenoid or intraorbital involvement. Gross total resection is the treatment of choice. CASE DESCRIPTION: A 10-month-old girl presented with unilateral proptosis and no neurologic deficits. Imaging studies revealed an extensive right-sided skull base cystic lesion centered on the sphenoid wing with extension into the orbit anteriorly and the pterygoid plates inferiorly. She underwent a modified osteoplastic orbitozygomatic craniotomy for resection of the extradural tumor. Postoperative imaging showed successful decompression of the intraorbital contents with no residual tumor. She remained neurologically intact and was discharged on postoperative day 2. Histologic examination revealed the lesion to be consistent with an aneurysmal bone cyst. At 3-month follow-up, her proptosis had resolved, neurologic examination was nonfocal, and there was no radiographic evidence of recurrence. CONCLUSIONS: To our knowledge, this is the youngest patient reported to have a spheno-orbital aneurysmal bone cyst. Such lesions in this age group present practical management challenges. By using a modified osteoplastic orbitozygomatic craniotomy, we achieved a gross total resection with minimal brain retraction, avoided the need for plating and suturing at the orbital rim, maintained a vascularized bone flap that is less susceptible to infection, and maintained normal temporalis muscle anatomy with excellent cosmetic results.

A model of TH17-associated ileal hyperplasia that requires both IL-17A and IFNγ to generate self-tolerance and prevent colitis.

Homeostasis in the ileum, which is commonly disrupted in patients with Crohn's disease, involves ongoing immune responses. To study how homeostatic processes of the ileum impact CD4+T cell responses, we used TCR transgenic tools to breed mice that spontaneously produced CD4+T cells reactive to an antigen expressed in the ileum. At an early age, the ilea of these mice exhibit crypt hyperplasia and accumulate increased numbers of TH17 cells bearing non-transgenic clonotypes. Half of these mice subsequently developed colitis linked to broad mucosal infiltration by TH17 and TH1 cells expressing non-transgenic clonotypes, chronic wasting disease and loss of ileal crypt hyperplasia. By contrast, adult mice with normal growth continued to exhibit TH17-associated ileal crypt hyperplasia and additionally accumulated ileal-reactive Treg cells. Both IL-17A and IFNγ were protective, as their deficiency precluded ileal-reactive Treg accumulation and exacerbated colitic disease. IL-23R blockade prevented progression to colitis, whereas nTreg cell transfers prevented colitic disease, ileal crypt hyperplasia and ileal-reactive Treg accumulation. Thus, our studies identify an IL-17A and IFNγ-dependent homeostatic process that mobilizes ileal-reactive Treg cells and is disrupted by IL-23.

Herpes Simplex Virus Esophagitis in Immunocompetent Children: A Harbinger of Eosinophilic Esophagitis?

Herpes simplex virus (HSV) is a common cause of infectious esophagitis. The aim of this retrospective study is to identify comorbid and predisposing conditions and sequelae of HSV esophagitis in immunocompetent children. We reviewed 16 cases of HSV esophagitis diagnosed from January 1982 to March 2016. Five patients were immunosuppressed, 11 were immunocompetent and included in the study. Three (27%) had no other significant medical history. Five patients (45%) had repeat biopsies following their HSV infection, which showed eosinophilic infiltrate consistent with current diagnostic criteria of eosinophilic esophagitis (EoE), one of whom had known EoE. Environmental allergies and/or asthma were present in 4 of 5 of these patients. Among the immunocompetent patients, EoE was a comorbidity in almost half, although biopsies at the time of HSV esophagitis did not show diagnostic features of EoE. Clinical follow-up is therefore warranted for immunocompetent children presenting with HSV esophagitis, particularly those with atopic conditions.

Successful Treatment of Invasive Conidiobolus Infection During Therapy for Acute Lymphoblastic Leukemia.

Invasive fungal infections are a serious cause of morbidity and mortality in patients with hematologic malignancies. Conidiobolus species are molds within the order Entomophthorales and may disseminate to become rapidly fatal in immunocompromised individuals. This species of fungal infections are often multidrug resistant (MDR) and present unique therapeutic challenges. Reports of Conidiobolus infections are rare in pediatric oncology. We report the successful treatment of an adolescent male with B-cell lymphoblastic leukemia and MDR invasive sinopulmonary Conidiobolus infection with emphasis on early and aggressive neutrophil support with surgical debridement. The strategies described could be applied to other MDR fungal infections.

Expanding the Phenotype of ALK-positive Histiocytosis: A Report of 2 Cases.

ALK-positive histiocytosis is a recently described rare histiocytic proliferative disorder of early infancy. When infants present with anemia, thrombocytopenia, and hepatosplenomegaly, this entity should be included in the differential diagnosis along with hemophagocytic lymphohistiocytosis, metabolic/storage diseases, hematopoietic malignancies, and autoimmune thrombocytopenia. We report 2 new cases of ALK-positive histiocytosis, one with kidney involvement and the other with extensive bone marrow involvement in addition to an overt liver disease. Renal involvement by ALK-positive histiocytosis has not been reported. The infiltrating histiocytes in this case showed Rosai-Dorfman disease-like morphology including emperipolesis. The histiocytes in the second case with extensive bone marrow involvement had foamy cytoplasm initially suggesting storage disease. Our 2 cases highlight previously unrecognized diversity of ALK-positive histiocytosis in clinical manifestation, organ involvement, and cytomorphologic features and further elucidate the diagnostic challenges of this rare entity.

Langerhans cell histiocytosis of the digestive tract identified on an upper gastrointestinal examination.

Langerhans cell histiocytosis (LCH) with involvement of the gastrointestinal tract is rare and typically identified in patients with systemic disease. We describe a 16-month-old girl who initially presented with bilious vomiting, failure to thrive and a rash. An upper gastrointestinal (GI) examination revealed loss of normal mucosal fold pattern and luminal narrowing within the duodenum, prompting endoscopic biopsy. Langerhans cell histiocytosis of the digestive tract was confirmed by histopathology. A skeletal survey and skin biopsy identified other systemic lesions. Although uncommon, it is important to consider LCH in the differential diagnosis for gastrointestinal symptoms of unclear origin, especially when seen with concurrent rash. Findings of gastrointestinal involvement on upper GI examination include loss of normal mucosal fold pattern and luminal narrowing in the few published case reports.

A Case of Necrotizing Epiglottitis Due to Nontoxigenic Corynebacterium diphtheriae.

Diphtheria is a rare cause of infection in highly vaccinated populations and may not be recognized by modern clinicians. Infections by nontoxigenic Corynebacterium diphtheriae are emerging. We report the first case of necrotizing epiglottitis secondary to nontoxigenic C diphtheriae. A fully vaccinated child developed fever, poor oral intake, and sore throat and was found to have necrotizing epiglottitis. Necrotizing epiglottitis predominantly occurs in the immunocompromised host. Laboratory evaluation revealed pancytopenia, and bone marrow biopsy was diagnostic for acute lymphoblastic leukemia. Clinicians should be aware of aggressive infections that identify immunocompromised patients. This case highlights the features of a reemerging pathogen, C diphtheriae.