More than keratitis, ichthyosis, and deafness: Multisystem effects of lethal GJB2 mutations.

BACKGROUND: Infant death in keratitis-ichthyosis-deafness (KID) syndrome is recognized; its association with specific genotypes and pathophysiology is inadequately understood. OBJECTIVE: We sought to discover characteristics that account for poor outcomes in lethal KID syndrome. METHODS: We collected 4 new cases and 9 previously reported, genotyped cases of lethal KID syndrome. We performed new molecular modeling of the lethal mutants GJB2 p.A88V and GJB2 p.G45E. RESULTS: Infant death occurred in all patients with GJB2 p.G45E and p.A88V; it is unusual with other GJB2 mutations. Early death with those 2 "lethal" mutations is likely multifactorial: during life all had ≥1 serious infection; most had poor weight gain and severe respiratory difficulties; many had additional anatomic abnormalities. Structural modeling of GJB2 p.G45E identified no impact on the salt bridge previously predicted to account for abnormal central carbon dioxide sensing of GJB2 p.A88V. LIMITATIONS: This clinical review was retrospective. CONCLUSION: GJB2 p.G45E and p.A88V are the only KID syndrome mutations associated with uniform early lethality. Those electrophysiologically severe mutations in GJB2 reveal abnormalities in many organs in lethal KID syndrome. All patients with KID syndrome may have subtle abnormalities beyond the eyes, ears, and skin. Early genotyping of KID syndrome births will inform prognostic discussion.

Biliary drainage as treatment for allograft steatosis following liver transplantation for PFIC-1 disease: A single-center experience.

Development of macrovesicular steatosis post-LT in patients with PFIC-1 is increasingly being observed, with the etiology not fully understood. We highlight successful and effective EBD for reversal of allograft steatosis in 2 patients with PFIC-1 disease and discuss our experience with internal biliary diversion in this patient population.

Hepatic Malignancy in an Infant with Wolf-Hirschhorn Syndrome.

INTRODUCTION: Wolf-Hirschhorn syndrome (WHS) is a contiguous gene syndrome involving deletions of the chromosome 4p16 region associated with growth failure, characteristic craniofacial abnormalities, cardiac defects, and seizures. CASE REPORT: This report describes a six-month-old girl with WHS with growth failure and typical craniofacial features who died of complex congenital heart disease. Genetic studies revealed a 9.8 Mb chromosome 4p-terminal deletion. At autopsy, the liver was grossly unremarkable. Routine sampling and histologic examination revealed two hepatocellular nodular lesions with expanded cell plates and mild cytologic atypia. Immunohistochemical staining revealed these nodules were positive for glutamine synthetase and glypican 3, with increased Ki-67 signaling and diffuse CD34 expression in sinusoidal endothelium. These findings are consistent with hepatoblastoma or hepatocellular carcinoma. CONCLUSIONS: A possible association between WHS and hepatic malignancy may be an important consideration in the care and management of WHS patients.

A comparison of suction and full-thickness rectal biopsy in children.

BACKGROUND: Rectal biopsy evaluation by an experienced pathologist is the gold standard in diagnosis of Hirschsprung's disease (HD). Although both suction rectal biopsy (SRB) and full-thickness (FTRB) rectal biopsy are performed, the ability for SRB to obtain adequate tissue in older children has been questioned. We hypothesized that SRB and FTRB yield tissue specimens of different size but are equally adequate for diagnosis. METHODS: Records of children who underwent rectal biopsy to evaluate for HD between January 2007 and July 2014 were reviewed. Volume, percent submucosa, and specimen adequacy were compared between biopsy techniques, and the effect of age on biopsy adequacy was assessed. Data were analyzed by mixed-effects models with covariate adjustment for age at biopsy and Fisher's exact test. RESULTS: Forty-seven children underwent a total of 58 biopsies, 45 SRB and 13 FTRB. Thirty-seven were performed before 12 mo of age, and 21 after 12 mo of age. Volume of SRB specimens was significantly smaller than FTRB across ages (14.8 ± 7.8 mm(3)versus 121.3 ± 13.8 mm(3), P = 0.0001). Percent submucosa did not differ significantly between SRB and FTRB specimens across ages (63.8 ± 2.7% versus 66.5 ± 4.3%, P = 0.575). The number of inadequate biopsies was low and not significantly different across ages (P = 0.345), or when comparing by biopsy method (P = 0.689). All biopsies were clinically diagnostic. There were no complications. CONCLUSIONS: Tissue specimens obtained by SRB are smaller than those obtained by FTRB, especially in older children. SRB and FTRB appear equivalent in their ability to provide adequate submucosa. Differences in cost and patient satisfaction between rectal biopsy techniques must be studied to further define the best overall technique.

Prevalence and Clinical, Endoscopic, and Pathological Features of Duodenitis in Children.

OBJECTIVES: Although gastritis and esophagitis are well studied in children, there is very limited literature on duodenitis in children. We aimed to assess the prevalence, etiology, clinical, endoscopic, and pathological features in a large cohort of unselected children with duodenitis. METHODS: We reviewed the pathology reports of all the upper endoscopies performed at our institution during 5 years to identify children with duodenitis. Biopsy sections were reviewed to confirm the diagnosis of duodenitis. Demographic, clinical, endoscopic data, and the presence of associated gastritis and esophagitis were noted in all of the children with duodenitis. The etiology of duodenitis was correlated with the patients' clinical diagnosis. RESULTS: Out of 2772 children who had endoscopy, 352 had duodenitis with the prevalence rate of 12.7%. Gastritis was seen in 64% of children with duodenitis compared with 46% of children without duodenitis (P < 0.001). Common indications for endoscopy in children with duodenitis were abdominal pain, positive celiac serology, and diarrhea. The most common etiology was celiac disease (32%), followed by Crohn disease (13%), ulcerative colitis (3%), and Helicobacter pylori infection (6%). In 63% of cases, the endoscopic appearance of duodenum was normal. Cryptitis, villous changes, and cellular infiltration were noted on histology. CONCLUSIONS: Prevalence of duodenitis is 12.7% in children undergoing endoscopy. Celiac disease and inflammatory bowel disease are common causes of duodenitis. Associated gastritis is common in children with duodenitis, and the correlation of endoscopic appearance with histology is poor.

Eosinophilic gastritis in children: clinicopathological correlation, disease course, and response to therapy.

OBJECTIVES: Eosinophilic gastritis (EG), defined by histological criteria as marked eosinophilia in the stomach, is rare, and large studies in children are lacking. We sought to describe the clinical, endoscopic, and histopathological features of EG, assess for any concurrent eosinophilia at other sites of the gastrointestinal (GI) tract, and evaluate response to dietary and pharmacological therapies. METHODS: Pathology files at our medical center were searched for histological eosinophilic gastritis (HEG) with ≥70 gastric eosinophils per high-power field in children from 2005 to 2011. Pathology slides were evaluated for concurrent eosinophilia in the esophagus, duodenum, and colon. Medical records were reviewed for demographic characteristics, symptoms, endoscopic findings, comorbidities, and response to therapy. RESULTS: Thirty children with severe gastric eosinophilia were identified, median age 7.5 years, 14 of whom had both eosinophilia limited to the stomach and clinical symptoms, fulfilling the clinicopathological definition of EG. Symptoms and endoscopic features were highly variable. History of atopy and food allergies was common. A total of 22% had protein-losing enteropathy (PLE). Gastric eosinophilia was limited to the fundus in two patients. Many patients had associated eosinophilic esophagitis (EoE, 43%) and 21% had eosinophilic enteritis. Response to dietary restriction therapy was high (82% clinical response and 78% histological response). Six out of sixteen patients had persistent EoE despite resolution of their gastric eosinophilia; two children with persistent HEG post therapy developed de novo concurrent EoE. CONCLUSIONS: HEG in children can be present in the antrum and/or fundus. Symptoms and endoscopic findings vary, highlighting the importance of biopsies for diagnosis. HEG is associated with PLE, and with eosinophilia elsewhere in the GI tract including the esophagus. The disease is highly responsive to dietary restriction therapies in children, implicating an allergic etiology. Associated EoE is more resistant to therapy.

Postnatal sonographic spectrum of prenatally detected abdominal and pelvic cysts.

OBJECTIVE: The purpose of this article is to illustrate the sonographic findings of a spectrum of neonatal abdominal and pelvic cystic lesions. CONCLUSION: Neonatal abdominal and pelvic cystic lesions can arise from many organs, and they have a broad differential diagnosis. Distinctive sonographic findings may be present and can help establish the correct cause and guide proper management.

Novel FOXF1 deep intronic deletion causes lethal lung developmental disorder, alveolar capillary dysplasia with misalignment of pulmonary veins.

Haploinsufficiency of FOXF1 causes an autosomal dominant neonatally lethal lung disorder, alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV). We identified novel 0.8-kb deletion within the 1.4-kb intron of FOXF1 in a deceased newborn diagnosed with ACDMPV. The deletion arose de novo on the maternal copy of the chromosome 16, and did not affect FOXF1 minigene splicing tested in lung fibroblasts. However, FOXF1 transcript level in the ACDMPV peripheral lung tissue was reduced by almost 40%. We found that, in an in vitro reporter assay, the FOXF1 intron exhibited moderate transcriptional enhancer activity, correlating with the presence of binding sites for expression regulators CTCF and CEBPB, whereas its truncated copy, which lost major CTCF and CEBPB-binding sites, inhibited the FOXF1 promoter. Our data further emphasize the importance of testing the non-protein coding regions of the genome currently not covered by diagnostic chromosomal microarray analyses or whole-exome sequencing.

Progressive familial intrahepatic cholestasis (PFIC) type 1, 2, and 3: a review of the liver pathology findings.

Progressive familial intrahepatic cholestatic diseases encompass a group of autosomal recessive hereditary diseases, which usually present in infancy or childhood, with cholestasis of hepatocellular origin. The currently preferred nomenclature for the three PFIC disorders that have been characterized to date is FIC1 deficiency, BSEP deficiency, and MDR3 deficiency, relating to mutations in the specific genes involved in bile acid formation and transport. Since the first description of these diseases, extensive clinical, biochemical, and molecular studies have increased our understanding of the features specific to each one of them. This review focuses mainly on the liver histology, summarizing their characteristic pathologic features, the correlation to specific genotypes, and complications arising with disease progression.

Gastrointestinal Zygomycosis in a Preterm Neonate Associated With Contaminated Probiotics.

A neonate of 29 weeks' gestation who received probiotics developed clinical signs suggesting surgical necrotizing enterocolitis. A specimen of resected ileum revealed fungal forms within the bowel wall. Rhizopus oryzae was detected via DNA sequencing from probiotic powder and tissue specimens from the infant. To our knowledge, this is the first report linking gastrointestinal zygomycosis to the administration of contaminated probiotics.

The changing face of post-transplant lymphoproliferative disease in the era of molecular EBV monitoring.

Pediatric PTLD is often associated with primary EBV infection and immunosuppression. The aim was to retrospectively review the spectrum of histologically documented PTLD for two time intervals differentiated by changes in use of molecular EBV monitoring. Eleven of 146 patients (7.5%) in 2001-2005 (Era A) and 10 of 92 (10.9%) in 1993-1997 (Era B) were diagnosed with PTLD. The median age at liver transplantation (0.8 and 0.9 yr, respectively) and the median duration between liver transplant and diagnosis of PTLD (0.6 and 0.7 yr, respectively) were similar in both eras. However, patients in Era A presented with significantly less advanced histological disease compared to patients in Era B (p=0.03). Specifically, nine patients (82%) in Era A had Pl hyperplasia/polymorphic PTLD, whereas in Era B, six had advanced histological disease (five monomorphic and one unclassified). Three transplant recipients in Era B died secondary to PTLD, whereas there were no PTLD-related deaths in Era A (p=0.03). Heightened awareness of risk for PTLD, alterations in baseline immunosuppression regimens, implementation of molecular EBV monitoring, pre-emptive reduction in immunosuppression and improved therapeutic options may have all contributed to a milder PTLD phenotype and improved clinical outcomes.

SARS-CoV-2 infection of the placenta.

BACKGROUNDThe effects of the novel coronavirus disease 2019 (COVID-19) in pregnancy remain relatively unknown. We present a case of second trimester pregnancy with symptomatic COVID-19 complicated by severe preeclampsia and placental abruption.METHODSWe analyzed the placenta for the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) through molecular and immunohistochemical assays and by and electron microscopy and measured the maternal antibody response in the blood to this infection.RESULTSSARS-CoV-2 localized predominantly to syncytiotrophoblast cells at the materno-fetal interface of the placenta. Histological examination of the placenta revealed a dense macrophage infiltrate, but no evidence for the vasculopathy typically associated with preeclampsia.CONCLUSIONThis case demonstrates SARS-CoV-2 invasion of the placenta, highlighting the potential for severe morbidity among pregnant women with COVID-19.FUNDINGBeatrice Kleinberg Neuwirth Fund and Fast Grant Emergent Ventures funding from the Mercatus Center at George Mason University. The funding bodies did not have roles in the design of the study or data collection, analysis, and interpretation and played no role in writing the manuscript.

Rapid evolution of congenital hepatic fibrosis after liver transplantation for acute liver failure: the potential role of extrahepatic factors.

A 9-year-old male underwent deceased donor liver transplantation for idiopathic fulminant hepatic failure. In the postoperative period, a review of perioperative biopsies of the donor liver revealed mild features of congenital hepatic fibrosis. Over the ensuing year, the recipient developed severe complications of congenital hepatic fibrosis including multiple episodes of cholangitis and progressive portal hypertension. After a second transplant, the patient had no further episodes of cholangitis and/or features of portal hypertension. Examination of the explanted liver revealed remarkable progression of the congenital hepatic fibrosis, suggesting that the phenotype of this disease may be dependent in part on extrahepatic factors.

Renal benign epithelial nodal inclusions.

There are 3 case series reports describing benign epithelial inclusions in nodal sinuses of perinephric lymph nodes of pediatric patients. The majority of these inclusions were observed in perinephric lymph nodes removed during nephrectomies from pediatric patients with Wilms' tumors. We report 2 cases of benign renal tubular epithelial inclusions located in the perinephric hilar lymph nodes. One of our cases is, to our knowledge, the first case of benign renal epithelial inclusions reported in an adult patient.

Esophageal subepithelial fibrosis in children with eosinophilic esophagitis.

OBJECTIVES: Esophageal subepithelial fibrosis has been reported in adults with eosinophilic esophagitis (EE). Our goal was to determine the prevalence of esophageal fibrosis in children with EE, to determine whether it is specific for EE, and to correlate it with clinical and pathological features. PATIENTS AND METHODS: Twenty-one children with EE, 7 with eosinophilic gastroenteritis, 6 with gastroesophageal reflux disease, and 17 control children were studied. Distal esophageal biopsy specimens containing lamina propria were evaluated for extent of subepithelial collagen deposition by use of trichrome staining. Fibrosis was defined as abnormally increased collagen deposition, determined after the establishment of normal patterns on sections of esophagus from pediatric autopsies. Maximum numbers of intraepithelial and lamina propria eosinophils per high-power field by hematoxylin and eosin staining and mast cells per high-power field by immunohistochemical staining for tryptase were determined. Eosinophil and mast cell degranulation in epithelium and lamina propria was determined by use of immunohistochemical staining for major basic protein and tryptase, respectively. The patients' records were reviewed. RESULTS: Esophageal subepithelial fibrosis was present in 12 (57%) patients with EE, 1 with eosinophilic gastroenteritis, 0 with gastroesophageal reflux disease, and 1 control patient. Forty-two percent of those with fibrosis had dysphagia, 80% of whom had food impactions; these symptoms were present only in patients with fibrosis. Within the EE group, fibrosis was not associated with duration of symptoms or with increasing numbers of infiltrating eosinophils/mast cells, but it was associated with eosinophil degranulation. CONCLUSIONS: Esophageal subepithelial fibrosis is prevalent in EE and is specific for the disease in children. It is associated with dysphagia, and it may explain and predict future esophageal dysmotility. Fibrosis is related to the extent of esophageal eosinophil activation, as evidenced by eosinophil degranulation.

Pathologic Characteristics, Natural History, and Prognostic Implications of BRAFV600E Mutation in Pediatric Papillary Thyroid Carcinoma.

The BRAFV600E mutation is the most common genetic aberration in papillary thyroid cancer (PTC), found in up to 68% of PTC in adults where it is associated with aggressive features. The incidence of this mutation in pediatric PTC is less frequent, reported as 0%-20% in the past and up to 63% in one recent series. Data suggest the mutation is not associated with an aggressive course in children; however, there are limited numbers of reported case series, so the prognostic implications remain poorly understood. The aim of this retrospective study was to examine the histologic characteristics and clinical outcomes of BRAF positive pediatric PTC at a single institution. A 12-year retrospective review of all thyroidectomies performed at a tertiary medical center identified 59 pediatric cases with a surgical pathology diagnosis of PTC. Fifty patients had BRAFV600E mutation analysis data and were selected for further study. BRAFV600E mutations were present in 48% of cases (n = 24) and absent in 52% (n = 26). The molecular characteristics of the BRAF negative cases will further be evaluated in future studies. BRAF positive cases occurred in patients who were on average older than the BRAF negative patients. Classic histology PTC was present in both BRAF positive and negative cases; however, only cases with classic PTC histology were positive for the mutation. No patients died and BRAF mutation was not associated with an increased recurrence rate. Our study supports BRAFV600E is more common in children than previously thought and does not portend a more aggressive clinical course.

Congenital Cystic Lung Lesions: Evolution From In-utero Detection to Pathology Diagnosis-A Multidisciplinary Approach.

Congenital cystic lung lesions are a group of rare pathologies that are usually diagnosed in the prenatal period. The majority of these lesions are diagnosed at pathology examination as congenital pulmonary airway malformations (CPAM) and bronchopulmonary sequestration (BPS). These lesions are typically managed by surgical intervention within the first year of life and have an excellent prognosis. We examined the evolution of imaging appearances from prenatal diagnosis to postnatal work-up of these lesions and correlate imaging and pathological findings. An 8-year retrospective review of the perinatal and pathology database of a single tertiary care center identified 42 cases of congenital cystic lung lesions of which 36 had known prenatal ultrasound and prenatal course available. Final pathologic diagnoses were 15 CPAM (41%), 7 BPS (19%), and 9 hybrid BPS and CPAM lesions (25%). Five cases with bronchial atresia were also identified (either in isolation or associated with CPAM or BPS). The overall characteristics of these lesions by prenatal ultrasound, postnatal imaging, and ultimate histopathologic diagnosis are described.

An immunohistochemical algorithm to facilitate diagnosis and subtyping of rhabdomyosarcoma: the Children's Oncology Group experience.

Immunohistochemistry remains the current ancillary method of choice in the pathologic evaluation of small blue round-cell tumors. In at least 20% of cases of rhabdomyosarcoma (RMS), it is considered an essential factor in the final and/or differential diagnosis of the malignancy. Newer immunostains (antimyogenin, MyoD1) generated against intranuclear myogenic transcription factors offer pathologists the best hope for improving the sensitivity and specificity of RMS diagnosis. A large series of RMS (956) were studied consecutively from the intergroup rhabdomyosarcoma study and children's oncology group files, along with multiple other malignant, benign or reactive lesions. A panel of antibodies to muscle-related antigens (myogenin, MyoD1, desmin, muscle-specific actin) was studied using formalin-fixed, paraffin-embedded tissue, an avidin-biotin/peroxidase complex immunohistochemical technique, antigen retrieval technique as appropriate, and automated immunostaining. Myogenin and MyoD1 were equally sensitive (positive for 97% of RMS cases), with both also showing similar specificity (90% vs. 91% of cases) for the diagnosis of RMS. Myogenin and MyoD1 staining were sometimes intact in areas of coagulative tumor necrosis, but negated by B5 fixation. Isolated, rare benign myogenin-positive nuclei were seen infrequently in reactive lymph nodes. Specifically, both myogenin and MyoD1 had significantly greater extent of expression for alveolar RMS (ARMS) than embryonal RMS (ERMS) (both with P < 0.001). Similarly, both myogenin (P = 0.001) and MyoD1 (P < 0.001) had significantly higher expression for ARMS than RMS, not otherwise specified (NOS). They were never expressed in undifferentiated sarcomas; however, reactive or regenerative myocytes did show expression. Immunostains against intranuclear myogenic transcription factors are, at present, the best available markers for confirming the diagnosis of RMS. Their differential expression in reactive myogenic lesions, variability in ARMS versus ERMS, and absence in undifferentiated sarcomas suggest new biologic questions to be explored in future studies.

Cryptosporidiosis presenting as acute appendicitis: a case report.

Although uncommon in the United States, cryptosporidiosis can be life-threatening in an immunosuppressed host. Rarely, an acute infection of this gastrointestinal illness can present as another disease entity. We present only the third reported case of cryptosporidial infection presenting as acute appendicitis in a 17-year-old HIV+ patient.

Sonographic distinction between acute suppurative appendicitis and viral appendiceal lymphoid hyperplasia ("pink appendix") with pathological correlation.

The viral etiology of mesenteric lymphadenitis may also affect the lymphoid tissue of the appendix in children giving rise to symptomatic appendiceal lymphoid hyperplasia, the so-called "pink appendix." The present study used ultrasound (US) to determine if certain sonographic features correlated with appendiceal pathological findings. Our results indicate that a fluid-filled appendix always correlates with a suppurative or mixed pathological appearance that likely merits surgery. A lymphoid predominant pathological appearance occurred only in cases where appendiceal wall thickening alone was seen on US. This pilot project therefore shows that US has the potential to stratify acute appendix patients into different treatment regimens, given that lymphoid hyperplasia could be treated conservatively. Further studies correlating other clinicoradiological parameters with this sonographic appearance are warranted.