Homozygous missense variants in YKT6 result in loss of function and are associated with developmental delay, with or without severe infantile liver disease and risk for hepatocellular carcinoma.

PURPOSE: YKT6 plays important roles in multiple intracellular vesicle trafficking events but has not been associated with Mendelian diseases. METHODS: We report 3 unrelated individuals with rare homozygous missense variants in YKT6 who exhibited neurological disease with or without a progressive infantile liver disease. We modeled the variants in Drosophila. We generated wild-type and variant genomic rescue constructs of the fly ortholog dYkt6 and compared their ability in rescuing the loss-of-function phenotypes in mutant flies. We also generated a dYkt6KozakGAL4 allele to assess the expression pattern of dYkt6. RESULTS: Two individuals are homozygous for YKT6 [NM_006555.3:c.554A>G p.(Tyr185Cys)] and exhibited normal prenatal course followed by failure to thrive, developmental delay, and progressive liver disease. Haplotype analysis identified a shared homozygous region flanking the variant, suggesting a common ancestry. The third individual is homozygous for YKT6 [NM_006555.3:c.191A>G p.(Tyr64Cys)] and exhibited neurodevelopmental disorders and optic atrophy. Fly dYkt6 is essential and is expressed in the fat body (analogous to liver) and central nervous system. Wild-type genomic rescue constructs can rescue the lethality and autophagic flux defects, whereas the variants are less efficient in rescuing the phenotypes. CONCLUSION: The YKT6 variants are partial loss-of-function alleles, and the p.(Tyr185Cys) is more severe than p.(Tyr64Cys).

Utilization of the TRAIN Learning Network for Online Disaster Medicine and Public Health Training During the COVID-19 Pandemic.

OBJECTIVE: The coronavirus disease 2019 (COVID-19) pandemic dramatically accelerated a growing trend toward online and asynchronous education and professional training, including in the disaster medicine and public health sector. This study analyzed the impact of the COVID-19 pandemic on the growth of the TRAIN Learning Network (TRAIN) for the year 2020 and evaluated pandemic-related changes in use patterns by disaster and public health professionals. METHODS: The TRAIN database was queried to determine the change in the number of registered users, total courses completed, and courses completed related to COVID-19 during 2020. RESULTS: In 2020, a total of 755,222 new users joined the platform - nearly 3 times the average added annually over the preceding 5 y (2015-2019). TRAIN users completed 3,259,074 training courses in 2020, more than double the average number of training courses that were completed annually from 2015-2019. In addition, 17.8% of all newly added disaster and public health training courses in 2020 were specifically related to COVID-19. CONCLUSION: Online education provided by TRAIN is a critical tool for just-in-time disaster health training following a disaster event or public health emergency, including in a global health crisis such as a pandemic.

Case report: Spindle cell neoplasm presenting as a spontaneous intestinal perforation in a term infant.

Spontaneous intestinal perforations in the neonatal population are mostly associated with low birth weight, prematurity, and necrotizing enterocolitis. Spontaneous intestinal perforation in the absence of these risk factors is extremely rare and should raise clinical concern for an underlying bowel pathology. Here we present a unique case of a normal-weight, full-term girl with spontaneous intestinal perforation due to a spindle cell neoplasm with a novel BRAF mutation and infantile fibrosarcoma-like morphology. Though rare, malignancy should be considered in the differential diagnosis for bowel perforation in an otherwise healthy, term infant as complete surgical excision can be curative.

The National Disaster Medical System and military combat readiness: A scoping review.

ABSTRACT: A scoping review was conducted to describe the history of the National Disaster Medical System (NDMS) in the context of US military medical preparedness for a large-scale overseas military conflict. National Disaster Medical System civilian hospitals would serve as backups to military treatment facilities if both US Department of Defense and US Department of Veterans Affairs hospitals reached capacity during such a conflict. Systematic searches were used to identify published works discussing the NDMS in the scientific and gray literature. Results were limited to publicly available unclassified English language works from 1978 to January 2022; no other restrictions were placed on the types of published works. Full-text reviews were conducted on identified works (except student papers and dissertations) to determine the extent to which they addressed NDMS definitive care. Data charting was performed on a final set of papers to assess how these works addressed NDMS definitive care. The search identified 54 works published between 1984 and 2022. More than half of the publications were simple descriptions of the NDMS (n = 30 [56%]), and most were published in academic or professional journals (n = 38 [70%]). Only nine constituted original research. There were recurrent criticisms of and recommendations for improving the definitive care component of the NDMS. The lack of published literature on NDMS definitive care supports the assertion that the present-day NDMS may lack the capacity and military-civilian interoperability necessary to manage the casualties resulting from a large-scale overseas military conflict.

Clinical, Laboratory, and Histologic Correlates of Serum Antinuclear Antibody in Hispanic Pediatric Patients With Nonalcoholic Fatty Liver Disease.

OBJECTIVES: The significance of antinuclear antibody (ANA) positivity in pediatric Hispanic patients with nonalcoholic fatty liver disease (NAFLD) is unknown. METHODS: ANA status was correlated with clinical, laboratory, and histologic parameters in Hispanic patients with a histologic diagnosis of NAFLD. RESULTS: Thirty-eight Hispanic children (27 male and 11 female) underwent liver biopsy at a median age of 12.1 years. Twenty patients (53%) had positive ANAs. The ANA-positive patients had higher fasting insulin levels (median [interquartile range (IQR)], 32.4 [25.4] µU/mL) and higher insulin resistance (median [Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) IQR], 5.9 [3.1]) than the ANA-negative patients (fasting insulin: median [IQR], 17 [13.9] µU/mL and median [HOMA-IR IQR], 3.5 [2.6] µU/mL; P = .05 and .01, respectively). Serum high-density lipoprotein (HDL) cholesterol levels were higher in the ANA-negative patients (median [IQR], 47 [18] mg/dL) than the ANA-positive patients (38 [12] mg/dL) (P = .03). There were no statistical differences in a series of demographic, clinical, laboratory, and histologic parameters between the ANA-positive and the ANA-negative patients. At a median follow-up of 2.6 years, alanine aminotransferase was significantly lower than the baseline levels in both groups. In 1 patient undergoing ANA retesting, the titer had normalized from a baseline of 1:1,280 3.8 years earlier. CONCLUSIONS: In pediatric Hispanic patients with NAFLD, a positive ANA result is associated with insulin resistance and lower HDL cholesterol levels.

Secretory Carcinoma of the Salivary Gland: A Rarity in Children.

Originally described as mammary analog secretory carcinoma (SC), SC of the salivary gland is a rare malignancy with morphologic and molecular similarities to SC of the breast. We present 2 children with salivary gland SC with the classic ETV6-NTRK3 gene fusion, including 1 with lymph node metastases. Both patients underwent surgical resection and were in remission 24 months postsurgery. One patient was additionally found to have synchronous papillary thyroid carcinoma with a TFG-MET fusion. A review of published cases highlights the expanding molecular profile and confirms the favorable course of salivary gland SC after surgical resection.

Thyroid surgery outcomes at a children's hospital: The value of a multidisciplinary team approach.

BACKGROUND: Our purpose is to describe the structure, function and outcomes of our multidisciplinary pediatric thyroid program and to evaluate our experience in comparison to other high-volume centers. METHODS: We reviewed all thyroid operations performed 10/2012 through 09/2019, and examined number of cases per year, patient demographics, procedures, final diagnoses and results. Primary outcomes were hypoparathyroidism and recurrent laryngeal nerve (RLN) injury at 12 months. Data were analyzed using descriptive statistics and univariate analyses. RESULTS: We performed 294 thyroid operations on 279 patients. Seventy-nine percent were female. Median age was 15 years (IQR: 12-17). Operations included total thyroidectomy (65%), lobectomy (30%) and completion thyroidectomy (5%). Most common diagnoses were Graves' disease (35%), malignancy (29%), and benign nodule (20%). We developed an evidence-based clinical pathway and conducted weekly multidisciplinary meetings. A clinical data specialist reviewed process and outcome measures routinely. Overall, 6 patients (2.0%) had hypoparathyroidism and 2 (0.7%) had unilateral RLN injury at 12 months. Two of the patients with clinical suspicion of permanent hypoparathyroidism were ultimately weaned off calcium. Both patients with RLN injury had extensive locally advanced malignant disease involving the nerve. CONCLUSIONS: Our multidisciplinary team achieved excellent long-term outcomes for pediatric thyroid surgery comparable to other high-volume pediatric and adult centers.

Pediatric Tracheal Lobular Capillary Hemangioma: A Case Report and Review of the Literature.

Chronic cough is a common complaint in the pediatric population and can have many different etiologies. We present a rare case of a tracheal lobular capillary hemangioma (LCH), also known as pyogenic granuloma, causing chronic cough in a child. In this case, the tracheal LCH was managed successfully with laser ablation. A review of the literature reveals only 2 other reported pediatric cases of tracheal LCH. Laryngoscope, 131:1729-1731, 2021.

Integrated DNA and RNA sequencing reveals targetable alterations in metastatic pediatric papillary thyroid carcinoma.

BACKGROUND: Pediatric papillary thyroid carcinoma (PTC) is clinically and biologically distinct from adult PTC. We sequenced a cohort of clinically annotated pediatric PTC cases enriched for high-risk tumors to identify genetic alterations of relevance for diagnosis and therapy. METHODS: Tumor DNA and RNA were extracted from FFPE tissue and subjected to next-generation sequencing (NGS) library preparation using a custom 124-gene hybridization capture panel and the 75-gene Archer Oncology Research Panel, respectively. NGS libraries were sequenced on an Illumina MiSeq. RESULTS: Thirty-six pediatric PTC cases were analyzed. Metastases were frequently observed to cervical lymph nodes (29/36, 81%), with pulmonary metastases less commonly found (10/36, 28%). Relapsed or refractory disease occurred in 18 patients (18/36, 50%). DNA sequencing revealed targetable mutations in 8 of 31 tumors tested (26%), most commonly BRAF p.V600E (n = 6). RNA sequencing identified targetable fusions in 13 of 25 tumors tested (52%): RET (n = 8), NTRK3 (n = 4), and BRAF. Mutually exclusive targetable alterations were discovered in 15 of the 20 tumors (75%) with both DNA and RNA analyzed. Fusion-positive PTC was associated with multifocal disease, higher tumor staging, and higher American Thyroid Association risk levels. Both BRAF V600E mutations and gene fusions were correlated with the presence of cervical metastases. CONCLUSIONS: Targetable alterations were identified in 75% of pediatric PTC cases with both DNA and RNA evaluated. Inclusion of RNA sequencing for detection of fusion genes is critical for evaluation of these tumors. Patients with fusion-positive tumors were more likely to have features of high-risk disease.

Biliary Atresia Patients With Successful Kasai Portoenterostomy Can Present With Features of Obliterative Portal Venopathy.

OBJECTIVE: Study of liver explants of biliary atresia (BA) patients with successful Kasai portoenterostomy (KP). METHODS: Pathology and medical records of BA liver explants from January 2009 to June 2018 with successful KP were reviewed along with appropriate controls. RESULTS: Fourteen out of 68 (20.6%) BA patients with LT had a successful KP. Median age at BA diagnosis, KP and LT was 60.5 days, 61 days, and 10 years, respectively, with conjugated bilirubin (c-bil) normalizing at 12.5 weeks after KP. Advanced fibrosis was diffuse in 2/14 (14.3%) explants, limited to periphery in 11/14 (78.6%) and absent in 1. Hilar partial nodular transformation (PNT) was seen in 11 explants (78.6%) and diffuse nodular regenerative hyperplasia (NRH) in 2 (14.3%). Areas of PNT and NRH showed diffuse portal sclerosis (100%), complete and incomplete portal vein (PV) stenosis (100%), PV herniation (100%), hypervascular portal tracts (20%), periportal abnormal vessels (100%), abundant lymphatic collaterals (100%), mild medial hepatic arterial hypertrophy (100%), and delicate fibrous septae (100%). Extrahepatic PVs showed variable luminal occlusion with mean PV intima to full thickness ratio of 0.6 +/- 0.11; significantly higher than age-matched noncirrhotic (n = 27, 0.08 +/- 0.09; P < 0.0001) and cirrhotic controls (n = 19, 0.34 +/- 0.2; P = 0.0015); and comparable to BA patients with failed KP (P = 0.82) and without KP (P = 0.04). CONCLUSIONS: BA patients with successful KP can present with obliterative portal venopathy (OPV). In the context of optimal bile drainage, portal hypertension may not be because of advanced parenchymal fibrosis but possibly because of OPV. Vascular abnormalities of the PV system should be investigated in BA patients.

Salvage sacrococcygeal resection for yolk sac tumors after chemotherapy: report of 2 cases.

Pediatric germ cell tumors (GCTs) are neoplasms that originate from primordial germ cells and, according to their site of presentation, are classified as gonadal or extragonadal. The most common site of extragonadal GCTs in children is the sacrococcygeal region, and the standard management is multimodal with a focus on chemotherapy. In selected instances, sacrococcygeal resection is performed. Herein, the authors report on 2 patients who presented with presacral yolk sac tumors managed with multimodal treatment. Both patients underwent salvage sacrococcygeal resection for oncological control and surgical removal of the sacral vertebral elements: a 27-month-old girl with a recurrent sacrococcygeal yolk sac tumor following chemotherapy and initial resection and a 24-month-old boy in whom a primary sacrococcygeal yolk sac tumor was resected following chemotherapy. These 2 cases illustrate the complexity in the management of these unusual tumors and will help neurosurgeons with the understanding of yolk sac tumors in the sacrococcygeal region.

Successful treatment of metachronous contralateral intratubular germ cell neoplasia with partial orchiectomy and low-dose radiation in a patient previously treated for testicular carcinoma.

Intratubular germ cell neoplasia (ITGCN) of the testis is a precursor to testicular germ cell tumor (TGCT), which can lead to the development of invasive cancer. In patients with a history of previously treated unilateral TGCT, treatment for ITGCN of the contralateral testis needs to be balanced with the risks of subsequent infertility. Here, we present a 17- year- old patient with ITGCN diagnosed after treatment of contralateral nonseminomatous TGCT who was successfully treated with a partial orchiectomy followed by low-dose radiation with preservation of his testosterone production.

Cutaneous Mucormycosis in Solid Organ Transplant Recipients after Hurricane Harvey: Short- and Long-term Management.

In the fall of 2017, Hurricane Harvey, one of the most costly hurricanes in American history, ravaged the Texas Gulf Coast, interrupting basic sanitation systems to hundreds of thousands of Texas residents. In the aftermath of Hurricane Harvey, our Houston hospitals noted an uptick in the incidence of cases of mucormycosis. Among the most vulnerable and affected have been immunocompromised transplant recipients. Here, we describe the successful management of 2 patients with atypical presentations of mucormycosis, 2 cutaneous infections after liver transplantation. Our comprehensive treatment strategy based upon guidelines and experience included coordinating aggressive surgical and medical therapies. We discuss our approach to surgical management including the extent and frequency of debridement, the methods of assessing disease-free margins, and minimizing the morbidity of radical debridement with temporary coverage and forethought to long-term reconstruction. Additionally, we describe the concurrent medical management, including type, route, and duration of antifungal therapy, minimizing suppression of the innate immune system, and optimizing the wound healing environment through maintaining nutritional status.

Obliterative Portal Venopathy Without Cirrhosis Is Prevalent in Pediatric Cystic Fibrosis Liver Disease With Portal Hypertension.

Cystic fibrosis liver disease (CFLD) has long been postulated to be secondary to dysfunctional cystic fibrosis transmembrane conductance regulator in the apical biliary epithelium, leading to bile stasis and eventually cirrhosis with portal hypertension. However, pathologic changes in the cystic fibrosis (CF) liver are distinct from the pancreas and lungs in that fibrocystic changes are absent.1,2 Furthermore, the lack of clinically evident biliary obstruction and liver dysfunction suggest there may be alternative mechanisms that contribute to CFLD. Two recent studies in young adults described obliterative portal venopathy (OPV) and noncirrhotic portal hypertension (NCPH) as the predominant pathophysiology in young adults (median, 22 y) with CFLD.3,4 It is unknown if OPV develops early in childhood. Herein, we report the clinical features and liver pathology in 17 explants from children and adolescents with CF, representing 13.6% (17 of 125) of the CF liver transplant population in the United States according to the United Network for Organ Sharing and Organ Procurement and Transplantation Network.

Generation of patient-derived tumor xenografts from percutaneous tumor biopsies in children with bone sarcomas.

One of the limitations of performing percutaneous biopsies in patients with bone sarcomas is the small amount of tumor that can be obtained for research purposes. Here, we describe our experience developing patient-derived tumor xenografts (PDXs) using percutaneous tumor biopsies in children with bone sarcomas. We generated 14 bone sarcoma PDXs from percutaneous tumor biopsies. We also developed eight bone sarcoma PDXs from surgical resection of primary bone tumors and pulmonary metastases. A multidisciplinary team approach was critical to establish an accurate diagnosis and to provide adequate tumor samples for PDX generation.

Response to Lenvatinib in Children with Papillary Thyroid Carcinoma.

BACKGROUND: Papillary thyroid carcinoma (PTC) is the most common thyroid malignancy in children and adolescents. Infrequently, children with PTC may present with or develop disease not amenable to surgery or radioactive iodine (RAI), and systemic therapy may be an option. Lenvatinib is an oral tyrosine kinase inhibitor that is approved by the Food and Drug Administration for the treatment of adults with locally recurrent or metastatic, progressive, RAI-refractory well-differentiated thyroid carcinoma. The effect of lenvatinib in children with PTC has not been reported. PATIENT FINDINGS: Three children with metastatic PTC not amenable or refractory to RAI who responded to lenvatinib are reported. All of them developed respiratory distress requiring oxygen caused by extensive bilateral metastatic pulmonary disease. The first patient is a 14-year-old female who was initially treated with sorafenib for extensive PTC not amenable to upfront surgery or RAI. She had progressive pulmonary disease after five months, and was subsequently treated with oral lenvatinib (14 mg/m2/day). She was weaned to room air after eight weeks. The second patient is a 15-year-old male who was treated with lenvatinib (14 mg/m2/day) for iodine non-avid diffuse pulmonary disease after initial total thyroidectomy and cervical lymph node dissection. He was weaned off oxygen in six weeks. The third patient is a five-year-old male who was treated with lenvatinib (14 mg/m2/day) for pulmonary disease progression 24 months after treatment with total thyroidectomy, cervical lymph node dissection, and RAI treatment. He was weaned off oxygen one day after starting lenvatinib. Two of the patients required dose adjustments secondary to proteinuria. Otherwise, all patients tolerated lenvatinib well. The first two patients remained clinically stable on lenvatinib 23 months and 11 months after initiation of therapy, respectively, and the third patient transitioned to a tumor-specific targeted therapy after one month. SUMMARY: Three pediatric patients are reported with metastatic PTC not amenable or refractory to RAI who achieved a response on lenvatinib. CONCLUSION: Lenvatinib therapy is well tolerated and demonstrated clinical activity in children with advanced PTC. Lenvatinib should be considered in children with PTC that is refractory or not amenable to conventional management.

Therapeutic response of metastatic angiomatoid fibrous histiocytoma carrying EWSR1-CREB1 fusion to the interleukin-6 receptor antibody tocilizumab.

Angiomatoid fibrous histiocytoma (AFH) is a rare soft tissue tumor that has been associated with EWSR1-CREB1 gene fusion. Outcome in patients with unresectable distant metastases is generally fatal. Interleukin-6 (IL-6) secretion has been described in tumors with EWSR1-CREB1 fusion, and may promote tumor growth due to autocrine stimulation. Tocilizumab is an IL-6 receptor antibody that has potential benefit as a targeted therapy in refractory neoplasms with IL-6 secretion. We describe a child with metastatic AFH with EWSR1-CREB1 fusion and elevated IL-6 whose disease progressed during treatment with traditional chemotherapeutic agents, but improved after targeted therapy with tocilizumab.

Erythropoietic Protoporphyria: Initial Diagnosis With Cholestatic Liver Disease.

The porphyrias are a group of rare metabolic disorders that result from defects in heme biosynthesis. Erythropoietic protoporphyria (EPP) is the most common inherited porphyria in children and is diagnosed in most individuals after the onset of cutaneous manifestations. Hepatobiliary disease affects the minority of individuals with EPP and usually manifests in patients with an established diagnosis of EPP. We report on a classic but rare case of EPP that masqueraded as cholestasis. An 8-year-old boy was referred to the Hepatology Clinic after an abrupt onset of jaundice with a longstanding history of dermatitis. The diagnosis of EPP was established with liver biopsy, which revealed dense, dark-brown pigment in hepatocytes and Kupffer cells that, on polarization, displayed bright-red birefringence and centrally located Maltese crosses. Plasma total porphyrins and erythrocyte protoporphyrin were elevated and confirmed a diagnosis of EPP. We hope to raise awareness of this diagnosis among pediatricians, hepatologists, and pathologists and increase the consideration of EPP in patients with cholestatic liver disease and chronic dermatitis.

Fundic Gland Polyps in the Pediatric Population: Clinical and Histopathologic Studies.

We retrospectively studied the clinical and histologic features of pediatric fundic gland polyps (FGPs) in 16 patients. FGPs had an endoscopic prevalence of 0.25% in 8527 pediatric gastric biopsies. Five patients had familial adenomatous polyposis (FAP). The median age of onset was 17.7 years in FAP and 17.3 years in sporadic patients. All syndromic patients were asymptomatic and FGPs were identified during surveillance for existing or concurrent colon polyps. They did not take antacids. In comparison, all 11 sporadic FGPs were identified during evaluation of symptomatic patients who had taken antacids (median duration 21 months). Syndromic FGPs can be multiple at single endoscopy and were more likely to recur, while sporadic FGPs were often single. None of the sporadic patients had recurrence of FGPs or a subsequent diagnosis of FAP during a median follow-up of 20.5 months. The dilated fundic glands were lined by parietal and chief cells only in a majority (22/41, 53.7%) of syndromic FGPs, while additional tall mucinous lining cells were found in all sporadic FGPs. Syndromic FGPs did not have parietal cell hypertrophy in the background oxyntic mucosa. Nuclear immunopositivity for beta-catenin was essentially absent in all the FGPs. In conclusion, FGPs were rare in pediatric patients. In syndromic patients, FGPs are asymptomatic and did not precede colon polyps. Prolonged antacid intake seems to be associated with development of sporadic FGPs. Cellular components of dilated fundic glands and background parietal cell hypertrophy can be useful features to eliminate concern for syndromic polyposis.