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For newborns suspected having childhood interstitial lung disease (ChILD), the sequencing of genes encoding surfactant proteins is recommended. However, it is still difficult to interpret the clinical significance of those variants found. We report a full-term born female infant who presented with respiratory distress and failure to thrive at 2 months of age and both imaging and lung biopsy were consistent with ChILD. Her genetic test was initially reported as a variant of unknown significance in surfactant protein C (c.202G > T, p.V68F), which was modified later as likely pathogenic after reviewing a report of the same variant as causing ChILD. The infant was placed on noninvasive ventilation and treated with IV Methylprednisolone, Hydroxychloroquine, and Azithromycin but did not show significant clinical and radiological improvement underwent tracheostomy and is awaiting lung transplantation at 8 months of age. The challenges interpreting the genetic results are discussed., Author(s): Hyunbin Park [sup.1], Aneela Bidiwala [sup.1], Laura A. Conrad [sup.1], Nasr Aborawi [sup.1], Michelle Ewart [sup.2], Maureen Josephson [sup.3], Lawrence M. Nogee [sup.4], Raanan Arens [sup.1] Author Affiliations: (1) [...]

Infantile digital fibroma is a rare benign lesion that usually occurs during the first 2 years of life. It can be multiple, but it is usually a single lesion. If it grows large enough it can cause joint deformities or interfere with everyday activities. Microscopically, the neoplastic cells usually have inclusion bodies that are best highlighted with a Masson trichrome stain but can often be seen on hematoxylin-eosin staining. Treatment for this entity is usually watchful waiting because of its ability to spontaneously regress, but excision is recommended if the lesion is symptomatic. More recently, fluorouracil or injectable steroids have shown great promise in inducing regression without the complications that accompany surgery. (Arch Pathol Lab Med. 2016; 140:1153-1156; doi: 10.5858/arpa.2015-0492-RS), Infantile digital fibroma is a rare benign tumor made up of mostly myofibroblasts, (1,2) with approximately 200 cases reported in the English-language literature. (3) This entity was first described by [...]

LAG-3, through interaction with a variety of ligands, regulates T cell function via inhibition of T cell proliferation and activation. It has been demonstrated to be overexpressed on tumor infiltrating lymphocytes (TILs) of a variety of cancers with associated poor outcomes. The purpose of this study is to characterize the expression pattern and clinical significance of LAG-3 in pediatric Hodgkin lymphoma (HL). Patient tumor samples from Children's Oncology Group clinical trial AHOD0031 with matched patient outcome data were analyzed for the expression of LAG-3 and PD-L1 using immunohistochemistry. 73/115 patients (63%) demonstrated positive LAG-3 staining. No demographic or survival outcome data were significantly associated with LAG-3 expression. Interestingly, patients with the lowest density of expression were found to have the worst EFS, and those with highest density of expression demonstrated the best EFS. There was a positive statistically significant relationship between presence of LAG-3 and PD-L1 expression. This project is innovative in its characterization of LAG-3 as an immune checkpoint target in pediatric HL. [ABSTRACT FROM AUTHOR]

Pediatric liver transplant recipients are at risk of developing graft fibrosis which can affect patient survival. VCTE is a non‐invasive tool that measures LSM and has been shown to correlate with hepatic fibrosis. The aim of this study was to therefore evaluate the ability of LSM to predict fibrosis in pediatric liver transplant recipients with different graft types. We performed a cross‐sectional study evaluating LSM of 28 pediatric liver transplant recipients who underwent a total of 20 liver biopsies within 1 month of LSM. LSM was compared to liver histology as well as graft type: WL or PL. The median LSM of all post‐transplant patients was 5.6 kPa (range = 2.7‐18.3). There was a statistically significant correlation between LSM and METAVIR fibrosis score (P =.001) and LAF score (P <.001). There was no difference in LSM between graft type (P =.088). The AUROC curve for LSM predicting any significant fibrosis (F ≥ 2) was 0.863. A cutoff value of 7.25 had a sensitivity of 71%, specificity of 100%, NPV of 87%, and PPV of 100% for significant fibrosis. LSM by VCTE is feasible in pediatric liver transplant recipients regardless of graft type. We found a significant correlation between LSM and hepatic fibrosis and established a cutoff value that may help determine which patients warrant further evaluation for graft fibrosis. [ABSTRACT FROM AUTHOR]

Background We describe the differential diagnosis of an obese 12-year-old boy of Mexican origin who presented with a 6-year history of abnormal lipid profile and elevated liver transaminase levels. Methods The patient underwent routine clinical testing, an abdominal ultrasound and, ultimately, a liver biopsy. Based on the histologic findings, a serum leukocyte lysosomal acid lipase (LAL) assay and DNA sequencing of the lipase A (LIPA) gene were performed. Results Liver biopsy revealed diffuse microvesicular steatosis with clusters of foamy histiocytes in the lobules and portal areas. Our differential diagnosis included nonalcoholic fatty liver disease; medication-induced hepatotoxicity; glycogenic hepatopathy; medium-chain acyl coenzyme A dehydrogenase or long-chain acyl coenzyme A dehydrogenase deficiency; and lysosomal storage disorders, including Niemann-Pick disease and lysosomal acid lipase deficiency (LAL-D). Serum LAL activity was absent, and DNA sequencing confirmed homozygous mutation in LIPA. Conclusions Although it occurs rarely, LAL-D should be considered in the differential diagnosis of microvesicular steatosis for a timely diagnosis. [ABSTRACT FROM AUTHOR]

One cause of neonatal cholestasis (NC) is paucity of intrahepatic bile ducts which can be associated with Alagille syndrome or non- syndromic. Alagille syndrome is caused by autosomal dominant mutations in the Notch signaling pathway ligand Jagged1 in 94% of patients and mutations in the NOTCH2 receptor in <1% of patients. This is a retrospective case series studying infants with neonatal cholestasis found to have variants of unknown significance (VOUS) in NOTCH2. Sorting intolerant from tolerant (SIFT) and polymorphism phenotyping (PolyPhen) were utilized to predict a damaging effect. Five infants with NC without other features of Alagille syndrome were found to have one copy of a VOUS in NOTCH2, predicted to be damaging by SIFT and PolyPhen. Our cases support the notion that NOTCH2 mutations may result in hypoplastic biliary system. Further characterization of these variants is important to assist with our clinical approach to NC. [ABSTRACT FROM AUTHOR]

Aim: Nonalcoholic fatty liver disease (NAFLD) is associated with obesity and affects roughly 10% of children. However, NAFLD is often diagnosed by exclusion - that is, obese children with an elevated alanine aminotransferase (ALT) are screened for other liver diseases in the absence of a biopsy. This testing is nonstandardized, and professional society recommendations differ. This study examines the yield of testing for disorders other than NAFLD in this patient population.Methods: A retrospective study was performed in 120 obese, asymptomatic, noncholestatic children with an ALT ≥40 U/L and additional diagnostic testing.Results: No patients were found to have Wilson's, hepatitis A, hepatitis B, hepatitis C, cytomegalovirus, alpha-1 antitrypsin deficiency, autoimmune hepatitis, celiac disease or Epstein-Barr virus. Only one patient (1/120) was identified with definite disease other than NAFLD, which was muscular dystrophy. The positive predictive value of a screening test was 5%, and the specificity was 97%. Of 70 children with an abdominal ultrasound, no significant abnormalities were identified.Conclusion: Extensive testing in asymptomatic, noncholestatic, obese children with an elevated ALT may be of limited diagnostic value and false-positive tests are likely. Large, prospective studies are needed to help focus the work up in this patient population. [ABSTRACT FROM AUTHOR]

Abstract Background Nonalcoholic fatty liver disease (NAFLD) is strongly associated with obesity and is the most common liver disease in the developed world. In children with suspected NAFLD, present guidelines suggest consideration of alternative diagnoses via extensive blood testing, though the yield of this work up is unknown. Furthermore, the gold standard diagnostic test for NAFLD remains liver biopsy, making the development of non-invasive tests critically important. Objectives Our objectives are: 1) to determine the accuracy of elastography and multiple serum biomarkers – each assessed individually and as algorithms (including those previously tested in adults) – for the diagnosis of nonalcoholic steatohepatitis (NASH) and early fibrosis in children and (2) to examine the utility of extensive testing for rare alternative diagnoses in overweight or obese children with elevated alanine aminotransferase (ALT) suspected to have NAFLD. Design This is an ongoing, cross-sectional study in children 2–18 years of age with up to 2 years of prospective follow up. Eligible patients are asymptomatic, overweight or obese, and have an ALT ≥35 U/L upon enrollment. Two forms of elastography are obtained serially along with anthropometric data and routine laboratory tests. Elastography and serum biomarkers are also performed immediately prior to any clinically-indicated biopsy. Methods Between April 2015 and April 2018, 193 children have been enrolled in this ongoing study and 71 have undergone liver biopsy. Here we carefully report the rationale, methodology, and preliminary data for this study. [ABSTRACT FROM AUTHOR]

Objectives: The relationship between vitamin D deficiency (VDD) and pediatric nonalcoholic fatty liver disease (NAFLD) remains uncertain due to conflicting results and few studies with histologic endpoints. We therefore used multiple imaging and histologic NAFLD endpoints to more comprehensively assess the association between VDD and NAFLD in a large pediatric population., Methods: Data were obtained from an ongoing pediatric NAFLD study in Bronx, NY. Briefly, overweight and obese children aged 2-18 years with alanine aminotransferase (ALT) levels ≥ 35 U/L were serially enrolled. Liver biopsy was obtained in accordance with clinical guidelines. All participants had liver imaging, namely, controlled attenuation parameter (CAP; Echosens, France) to assess steatosis and, to assess fibrosis, vibration controlled transient elastography (VCTE; FibroScan™, Echosens, France) and acoustic radiation force impulse (ARFI; Philips, Netherlands) imaging. Levels of 25-hydroxyvitamin D were measured serologically., Results: N=276 (88%) of 315 participants had 25-OH vitamin D results, of whom 241 (87%) were Hispanic, 199 (72%) were male, and 92 (33%) underwent liver biopsy. VDD was univariately associated with high waist circumference (p=0.004), high-density lipoprotein level (p=0.01), season (p=0.009), and CAP score (p=0.01). In multivariate analysis, only waist circumference (p=0.0002) and biopsy inflammation grade (p=0.03) were associated with VDD, though the latter had not approximated statistical significance in univariate analysis (p=0.56). There was no association between VDD and hepatic steatosis, ballooning, NAFLD Activity Score, ARFI or VCTE elasticity scores., Conclusions: VDD was not associated with NAFLD defined by imaging and histologic endpoints, except for a possible relation with histologic inflammation grade.

p63 proteins are p53 homologs that are postulated to regulate squamous stem cell commitment. An immunohistochemical survey of p63 expression in normal thyroid and in reactive, neoplastic, and inflammatory thyroid disorders was performed. Sections from routinely fixed and processed archival thyroidectomy specimens were pretreated with citric acid, pH 6.0, for antigen retrieval, then incubated overnight with anti-p63 monoclonal antibody 4A4. Slides were stained using a streptavidin-biotin kit and diaminobenzidine as a chromagen, and then were counterstained with hematoxylin. The results showed that p63 expression was negative in normal thyroid tissue, nodular goiters, and oncocytic follicular adenomas. Positivity was rare and weak in follicular adenomas. p63-positive foci were commonly found in Hashimoto's thyroiditis (1 or more foci in 78.8% of cases), but rare in Graves' disease. Twenty-seven of 33 papillary thyroid carcinomas (81.8%) displayed p63-positive foci. Staining was uncommon in follicular carcinomas and rare in medullary carcinomas. One case of insular carcinoma was p63-positive. All squamoid structures were p63-positive; p63-positive structures morphologically consistent with solid cell nests were also identified. Based on the results of this study, we conclude that p63 is commonly expressed in papillary thyroid carcinoma and in Hashimoto's thyroiditis. Given the debated association of papillary thyroid carcinoma with Hashimoto's thyroiditis, it is possible that p63 expression may be a potential pathobiologic link between the two disorders. The finding of p63 in benign squamoid nests supports a possible interrelationship between these structures and both Hashimoto's thyroiditis and papillary carcinoma. The high percentage of papillary carcinomas with p63-positive foci appears to distinguish papillary carcinoma from other neoplasms originating in the thyroid.