Considerations for liver transplantation in deoxyguanosine kinase deficiency: A case series and review of the literature.

BACKGROUND: Deoxyguanosine kinase (DGUOK) deficiency is a rare mitochondrial disorder characterized by early onset liver failure and varying degrees of neurologic dysfunction. Patients typically present during infancy with progressive hepatic dysfunction leading to liver failure, which can precede neurologic deterioration. Outcomes posttransplantation are historically worse than average and the role of liver transplantation remains controversial. These factors, in combination with the increasing number of patients being diagnosed via molecular genetic testing, may impede waitlist access. METHODS: We report our single-center experience with three patients with DGUOK deficiency, all of whom were considered for transplant. We review the current literature regarding management and discuss the role of liver transplantation in DGUOK deficiency-associated liver failure. RESULTS: Two patients presented with hypoglycemia, conjugated hyperbilirubinemia, and lactic acidosis within the first week of life, were diagnosed with DGUOK deficiency prior to 2 months of age and had severe neurologic involvement. The third patient presented in later infancy was diagnosed with DGUOK deficiency at 18 months of age and had minimal neurologic involvement. All three patients were considered for transplant, though only two patients were listed. All three died from complications of end-stage liver failure prior to liver transplantation between the ages of 5-20 months. CONCLUSION: Selection for liver transplantation in DGUOK deficiency is complex, requiring a multidisciplinary team approach. Recent data suggest that liver transplantation can be successful in select patients with absent or mild neurologic manifestations. National databases reporting long-term outcomes posttransplantation are needed.

Is Endoscopic Assessment of the Esophagus and Stomach Enough to Determine the Need for Biopsy at These Sites in Pediatric Patients Undergoing Endoscopy for Elevated TTG?

OBJECTIVES: The goal of our study was to determine whether visual assessment of the esophagus and stomach could predict abnormal histology and determine the frequency of interventions based on biopsies in patients undergoing endoscopy for elevated tissue transglutaminase immunoglobulin A antibody (TTG). METHODS: Pathology records were searched for patients with biopsy performed for elevated TTG. Pathology report, endoscopy report, and follow-up were obtained and slides from the duodenum reviewed. Pathology was considered gold standard for sensitivity and specificity calculations. RESULTS: 240 patients were included. 215 patients had esophageal biopsies performed. Esophageal endoscopic visual assessment had sensitivity of 47% and specificity of 93% for abnormal histology. 16(7%) patients had therapy or referral related to results and, of these, 6(38%) had visually normal endoscopy. 237 biopsies were performed of stomach. Gastric endoscopic visual assessment had a sensitivity and specificity of 20% and 87%. 24(10%) patients had therapy based on findings and, of these, 12 (50%) had visually normal endoscopy. CONCLUSIONS: Endoscopic assessment of esophagus and stomach has low sensitivity and high specificity for pathologic abnormalities when indication for endoscopy is elevated TTG. When endoscopy is visually normal clinical interventions based on biopsy are rare, and foregoing biopsy may be considered.

Late graft loss after intestinal transplantation.

PURPOSE OF REVIEW: Despite improvement in short-term outcomes after intestinal transplantation in the last 20 years, long-term rates of graft attrition and patient survival remain unchanged, with worse outcomes compared with other solid organ transplants. This review investigates the multiple causes of late graft loss, including chronic rejection, infection, graft-versus-host disease, posttransplant lymphoproliferative disorder and postsurgical complications. RECENT FINDINGS: New insights into immunology of the intestine and evolution of immunosuppression, as well as review of current persistent causes of late graft loss, shed light on findings that may help improve long-term intestinal allograft survival. SUMMARY: Although intestinal transplantation remains a life-saving intervention with significant advancements since its inception, further understanding of mechanisms of injury is needed to improve long-term outcomes and prevent late intestinal graft loss.

Do Histologic Features Help Predict Colectomy in Pediatric Patients Presenting With Acute Severe Colitis?

BACKGROUND: Multiple prior studies have looked at clinical and laboratory parameters in ulcerative colitis to predict prognosis, but individual histologic features of inflammation and their prognostic significance have not been well studied. The purpose of our study was to determine whether histologic features at presentation with acute severe colitis predict colectomy in pediatric patients. METHODS: Patients were identified retrospectively through the gastroenterology and pathology databases. Demographic information, duration of disease, laboratory data, endoscopic appearance at scope, and histologic features of inflammation were reviewed along with medical therapies. Patients who underwent surgery within 90 days of hospitalization were compared to those who did not. RESULTS: Fifty patients with acute severe colitis, defined as Pediatric Ulcerative Colitis Activity Index ≥65, were included. Sixteen patients had colectomies performed within 90 days of presentation. No statistically significant difference was found between the surgery and no-surgery groups for patient age, albumin, hemoglobin, or C-reactive protein, though hemoglobin trended toward significance, P = .05. The endoscopic Mayo score and histologic features of inflammation (architectural changes, chronic inflammation, eosinophils, neutrophils within the lamina propria, neutrophils in epithelium, crypt destruction, and ulceration) were similar between groups. CONCLUSION: In pediatric patients presenting for hospitalization with acute severe colitis, no histologic features of inflammation predicted colectomy within 90 days.

Effects of Tumor Necrosis Factor Alpha Inhibitors on Lymph Node and Ileocecal Mucosa-Associated Lymphoid Tissue Architecture in Patients With Inflammatory Bowel Disease.

BACKGROUND: Antitumor necrosis alpha (TNFα) therapy is often used in the management of patients with inflammatory bowel disease (IBD) and may have effects on lymphoid tissue architecture and function. The goal of our study was to characterize the effects of TNFα inhibitors on mesenteric lymph node and mucosa-associated lymphoid tissue in patients with IBD. METHODS: We examined lymphoid tissue morphology in IBD patients treated with TNFα inhibitors compared to untreated controls. Intestinal resections from 19 patients (10 anti-TNFα treated and 9 controls) were reviewed. Immunohistochemistry for CD21, CD20, and CD3 was performed on ileocecal valve lymphoid tissue and mesenteric lymph nodes from the resection specimens to assess follicular architecture. RESULTS: Relative to control groups, TNFα-treated groups showed less preserved germinal center architecture, evidenced by lower overall semiquantitative scores for follicular architecture. Likewise, the percentage of secondary follicles to total follicles was decreased in patients treated with TNFα blockade. CONCLUSIONS: Our results suggest that TNFα inhibitors may play a role in disruption of lymphoid germinal center architecture in patients with IBD. Awareness of this disrupted lymphoid morphology when examining histologic sections from patients with IBD treated with TNFα inhibitors may prevent unnecessary studies to exclude a lymphoproliferative disorder.

Hepatopulmonary Syndrome in an Adolescent With Insidious Hypoxia and Small Intrahepatic Portal Venous Shunts: Posttransplant Benefit From Sildenafil.

We report a patient without known preexisting liver disease who presented with hepatopulmonary syndrome (HPS) due to aberrant intrahepatic portal venous development leading to portosystemic shunting. Liver transplantation resulted in resolution of portal hypertension and HPS and sildenafil was safely tolerated in the treatment of persistent fatigue and hypoxemia. Twelve months later, patient has normal allograft function and has returned to normal activity.

Correlation of Endoscopic and Histologic Severity Scores in Pediatric Ulcerative Colitis at First Presentation.

Detailed histologic scoring systems have been developed for the assessment of disease activity in ulcerative colitis. Literature from adult patients has shown some correlation between endoscopy and histology, and reproducibility of histologic scoring systems has also been supported. The effectiveness of endoscopic appearance at predicting histologic scores in pediatric patients has not been well studied, and none of the histologic scoring systems used in adults have had interobserver reproducibility assessed in pediatric patients. We reviewed endoscopic images and concurrent biopsies using Mayo and Geboes scores from the distal colon and rectum in untreated pediatric patients at the presentation of presumed ulcerative colitis based on clinical and endoscopic findings. Interobserver concordance was calculated by weighted-kappa statistic. The averaged histologic scores were compared to endoscopy scores using Spearman's coefficient. Correlation between endoscopic score and each histologic score was weakly to moderately positive, whereas interobserver agreement for histologic scores was fair to moderate, suggesting that the Geboes scoring system has value in pediatric patients. For each histologic parameter, the average score was lower than the average endoscopic score. Examination of larger pediatric cohorts, treated patients, correlations of clinical outcomes with individual histologic parameters, and alternate scoring systems may contextualize these findings.

Hepatic Adenoma Arising in a Patient With Alagille Syndrome: A Case Report.

Alagille syndrome is associated with decreased bile ducts, cardiac abnormalities, vertebral body fusion defects, and a typical facies. While regenerative nodules and hepatocellular carcinoma have been described in these patients, hepatic adenoma has not. Herein, we present a patient with Alagille syndrome caused by a mutation in NOTCH2 with a hepatic adenoma. The clinical, imaging, and histologic features are discussed.

A tip-predominant distribution of villous intraepithelial lymphocytes is not specific to celiac disease in children with Marsh I lesions.

OBJECTIVES: To assess if the distribution of villous intraepithelial lymphocytes (IELs) in a pediatric cohort with Marsh I histopathology is specific to celiac disease (CeD). METHODS: Multicenter, retrospective case-control study between January 2001 and December 2019 in children (<18 years) with and without CeD with intraepithelial lymphocytosis and normal villous architecture. Pathology specimens were reviewed by 2 study pathologists who were blinded to the final diagnosis. Morphologic features (villous height to crypt depth ratio [Vh:Cd]) and IELs in the villous tip, top, or bottom half of the villus were quantified. RESULTS: Of the 97 children with Marsh I histopathology identified during the study period, 63 were excluded due to an insufficient number of well-oriented villous-crypt complexes or a Vh:Cd less than 2. Villous IELs were measured in 34 cases (14 CeD, 20 non-CeD controls). There was no difference between the non-CeD and CeD groups in the mean IELs at the villous tip (14.0 ± 7.1 vs 11.7 ± 6.0, P = .31), top (46.4 ± 18.4 vs 38.3 ± 10.8, P = .11), or bottom (29.8 ± 16.8 vs 28.5 ± 12.8, P = .80) half of each villus, respectively. CONCLUSIONS: The distribution of IELs in Marsh I lesions is not specific for CeD.

Clinical Data Do Not Reliably Predict Duodenal Histology at Follow-up in Celiac Disease: A 13 Center Correlative Study.

Validated nonbiopsy methods to assure duodenal mucosal healing in celiac disease are lacking, yet ongoing mucosal injury is associated with anemia, osteoporosis, and lymphoma. Most providers utilize clinical data as surrogates of mucosal status to avoid additional esophagogastroduodenoscopy. The reliability of such surrogates to predict mucosal recovery has been incompletely evaluated. The aim of this study was to rigorously assess patterns of histologic mucosal recovery at follow-up in celiac disease and to correlate findings with clinical data. Gastrointestinal pathologists from 13 centers evaluated initial and follow-up duodenal biopsies from 181 celiac disease patients. Marsh scores and intraepithelial lymphocytes (IELs)/100 enterocytes were assessed blindly. Histology at follow-up was correlated with symptoms, immunoglobulin A anti-tissue transglutaminase titers and gluten-free diet adherence. Fifty-six/181 (31%) patients had persistent villous blunting and 46/181 (25%) patients had just persistently elevated IELs at follow-up, with only 79/181 (44%) patients having complete histologic remission. IEL normalization (82/181; 45%) lagged villous recovery (125/181;69%). In a minority of patients, villous blunting was limited to proximal duodenal biopsies. No correlation was found between Marsh scores and symptoms, normalization of immunoglobulin A anti-tissue transglutaminase serology, or diet adherence. Children showed greater recovery of Marsh score ( P <0.001) and IELs ( P <0.01) than adults. Persistent mucosal injury is common in celiac disease, with discordant villous/IEL normalization. Pathologist awareness of expected findings in celiac disease follow-up biopsies, including their frequent lack of correlation with clinical data, is important for patient management, and has implications for eligibility criteria for therapeutics currently in development.

Computer-Based Natural Language Search Applied to the Electronic Medical Record for Tonsil Triage.

OBJECTIVES: To determine significant histologic findings in tonsils and categorize clinical settings in which they occur to identify cases benefiting from histopathologic examination using a computer-based natural language search (NLS) applied to the electronic medical record. METHODS: The pathology database was queried for tonsillectomy cases accessioned between 2002 and 2018. Tonsils with microscopic examination were reviewed, and indication for examination and diagnoses were tallied. Clinical risk of malignancy was correlated with findings. A NLS was used to interrogate preoperative clinical records of the same group of patients. The search identified cases at risk of significant histologic findings and was implemented as part of standard practice. RESULTS: Of the 18,733 bilateral tonsillectomies identified in the pathology database, 494 were palatine tonsils that underwent microscopic examination, 134 had indications concerning for malignancy, and 14 had significant findings on histologic examination. When the NLS was applied to the medical record of the same group, 223 cases were identified as having risk of malignancy, including all flagged by surgeons and pathologists and 89 additional cases. Clinical implementation resulted in identification of all cases benefiting from examination. CONCLUSIONS: A NLS applied to the electronic medical record to select tonsils for examination was superior to relying on surgeons and pathologists.

To DGP-IgG or not? a comparison of TTG-IgA and DGP-IgG.

BACKGROUND: We assessed the diagnostic utility of deamidated gliadin peptide immunoglobulin G (DGP-IgG) in pediatric patients without immunoglobulin A deficiency who underwent tissue transglutaminase immunoglobulin A (TTG-IgA) screening and biopsy. METHODS: Patients who had TTG-IgA performed in our laboratory had sample frozen over 1.5 y. If a patient underwent biopsy within 6 months of serology, DGP-IgG was performed on frozen sample. All testing was performed on the BioPlex 2200. Biopsies were assigned a modified Marsh-Oberhuber score. The sensitivity, specificity, and positive and negative predictive values were calculated for TTG-IgA and DGP-IgG for values ≥ 15 u/ml, 15-149 u/ml, and ≥ 150 u/ml using biopsy as gold standard. RESULTS: A total of 458 patients were included. Sensitivity and specificity for DGP-IgG ≥ 15 u/ml and Marsh ≥ 2 was 76% and 87.5% and TTG-IgA ≥ 15 was notably higher at 93.3% and 92.2%. Sensitivity and specificity of DGP-IgG were 66% and 88.9% at moderate and 29.3% and 98.4% at high increases. The positive predictive value of DGP-IgG for celiac disease in TTG-IgA negative patients was 2.8%. CONCLUSIONS: Our study suggests DGP-IgG does not add significant value in patients screened for celiac disease.

Evaluation of BioPlex 2200 tTG-IgA Diagnostic Performance for Serology-Based Diagnosis of Celiac Disease.

OBJECTIVES: Forgoing biopsy for the diagnosis of celiac disease in children with tissue transglutaminase immunoglobulin A (tTG-IgA) levels greater than or equal to 10 times the upper limit of normal (≥10×ULN) has been advocated by the European Society of Paediatric Gastroenterology, Hepatology and Nutrition. METHODS: Our retrospective study tested the specificity and positive predictive value (PPV) of the BioPlex 2200 assay (Bio-Rad Laboratories) in diagnosing celiac disease at the ≥10×ULN tTG-IgA threshold, which is ≥150 U/mL (negative <15 U/mL). We used the tTG-IgA and duodenal biopsy results within 6 months following tTG-IgA measurements from 542 patients who had any number of duodenal biopsy fragments, of whom 165 patients had 5 or more tissue fragments. Sensitivity and specificity of the test were calculated using histology as the gold standard for Marsh class 2 and above. RESULTS: For histopathologic findings in the duodenum with Marsh 2 and higher, the specificity and PPV of the BioPlex 2200 at ≥10×ULN tTG-IgA were 99.5% and 95.4% using all biopsies and 97.9% and 94.9% for biopsies with 5 or more tissue fragments. CONCLUSIONS: Should clinical considerations preclude endoscopy, the BioPlex 2200 assay at ≥10×ULN TTG-IgA could be considered highly suggestive of disease.

Neurogenin-3 Enteric Endocrinopathy: A Rare Case of Pediatric Congenital Diarrhea and Diabetes Mellitus.

Disorders of intestinal enteroendocrine cells (EEC) are a rare cause of congenital diarrhea and diabetes. The gene NEUROG3 is essential in EEC differentiation, and mutations in this gene lead to a paucity of EEC in the intestine and pancreas, often presenting clinically as congenital diarrhea and diabetes mellitus. We present the earliest known diagnosis of NEUROG3-associated enteric endocrinopathy, which was identified on a neonatal diabetes genetic panel sent at 4 weeks of age. Our patient presented with severe diarrhea, malnutrition, electrolyte derangements, and neonatal diabetes. He was started on parenteral nutrition at 3 months of age for nutritional and hydration support and required long-acting insulin for his diabetes. We demonstrate significant reduction in EEC, including cells expressing glucagon-like peptide-1, in intestinal biopsies from our patient, raising the possibility that loss of glucagon-like peptide-1 contributes to NEUROG3-associated diarrhea and diabetes mellitus. This case advances our understanding of the presentation, diagnosis, and management of this rare disease.

Congenital Cytomegalovirus and Hepatic Failure: An Underrecognized Complication.

Congenital cytomegalovirus infection is the most common congenital infection. Although most infants with congenital cytomegalovirus infection are asymptomatic at birth, a subset will have readily apparent clinical and/or laboratory manifestations including hepatitis; progression to hepatic failure has not previously been described in term infants who initiated antiviral treatment shortly after birth. We present 2 term infants with congenital cytomegalovirus infection and hepatitis who progressed to hepatic failure despite initial laboratory improvement on therapy.

Ovarian sex cord-stromal tumors, pleuropulmonary blastoma and DICER1 mutations: a report from the International Pleuropulmonary Blastoma Registry.

OBJECTIVE: Pleuropulmonary blastoma (PPB) is a childhood cancer arising from pleuropulmonary mesenchyme. This neoplasm is a sentinel disease in a familial tumor syndrome recently found to be associated with germline mutations in DICER1. Observations of ovarian sex cord-stromal tumors (OSCST) in PPB kindreds led to further study. We sought to characterize ovarian tumors seen in probands and families with PPB and PPB-related conditions and define germline DICER1 status. METHODS: Patient and family records of pathology-reviewed PPB cases enrolled in the International PPB Registry (IPPBR) were searched for ovarian tumors. Ovarian tumor pathology specimens were obtained and centrally reviewed. Germline DNA from patients with ovarian tumors was tested for DICER1 mutations. Three additional OSCST patients registered in the IPPBR were also tested for mutations in DICER1. RESULTS: Among 296 kindreds including 325 children with PPB, we observed three children with both PPB and Sertoli-Leydig cell tumors (SLCT)/Sertoli cell tumors. Among family members of PPB patients, we identified six OSCST (three SLCT, one Sertoli cell tumor, one juvenile granulosa cell tumor, one gynandroblastoma). Age at ovarian tumor diagnosis was youngest in PPB probands and younger in family members than in OSCST in general. Germline DICER1 mutations were identified in four of six patients with OSCST from PPB kindreds and in two of three children with OSCST and no personal or family history of PPB. CONCLUSIONS: Primary ovarian neoplasms, particularly OSCST, are a manifestation of the familial PPB syndrome and may be the initial clinical presentation of DICER1 mutations within a family.

Progressive Preretinal Fibrosis with Late, Ossifying, Proliferative Retinopathy following Treatment for Retinoblastoma.

We report a case of retinal atrophy and progressive preretinal fibrosis in an eye previously treated with intravenous and intra-arterial chemotherapy (IAC), which evolved immediately after treatment with intravitreal injection of melphalan. The atrophy and fibrosis progressed later to proliferative retinopathy with dystrophic ossification. The patient was originally diagnosed with bilateral retinoblastoma at 4 months of age and was treated with systemic chemotherapy followed by IAC. New vitreous seeds developed and required treatment with intravitreal chemotherapy. There was resolution of vitreous seeding after 2 doses of intravitreal melphalan, but clinically the eye developed new, widespread retinal atrophy and fibrosis within 1 month of the second injection. This was followed by phthisis and late proliferative retinopathy nearly 1 year later. Retinoblastoma specialists should be aware of this potential complication of combined chemotherapy treatments.

Pediatric biliary disorders: Multimodality imaging evaluation with clinicopathologic correlation.

The spectrum of pathologies affecting the biliary tree in the pediatric population varies depending on the age of presentation. While in utero insults can result in an array of anatomic variants and congenital anomalies in newborns, diverse acquired biliary pathologies are observed in older children. These acquired pathologies display different presentations and consequences than adults. Multimodality imaging assessment of the pediatric biliary system is requisite to establishing an appropriate management plan. Awareness of the imaging features of the various biliary pathologies and conveying clinically actionable information is essential to facilitate appropriate patient management. In this paper, we will illustrate the anatomy and embryology of the pediatric biliary system. Then, we will provide an overview of the imaging modalities used to assess the biliary system. Finally, we will review the unique features of the pediatric biliary pathologies, complemented by histopathologic correlation and discussions of clinical management.

Respiratory infections and chronic cough due to triple A (Allgrove) syndrome.

Cough and respiratory infections are common in pediatrics. Our case report illustrates the need for pediatricians to consider rare diagnoses such as genetic syndromes and primary gastrointestinal motility disorders in patients with unremitting respiratory and gastrointestinal symptoms. Early identification provides early intervention and reduces long-term morbidity for pediatric patients.