Search

Recurrent autoimmune hepatitis (rAIH) occurs in patients who undergo liver transplantation (LT) for AIH and de novo AIH (dAIH) is seen in patients who are transplanted for etiologies other than AIH. Whether these are distinct diseases with a similar phenotype remains understudied. The aim of this study was to identify clinical and immunologic factors affecting outcome in patients with dAIH and rAIH. A retrospective review of 387 LT patients from 1997 to 2014 was carried out, and they were followed until 2018. Patients with rAIH or dAIH were identified based on the pre-transplant diagnosis of AIH (or not) and characteristic histology. Liver biopsies were stained with H&E, B-cell marker CD20, and plasma cell marker CD138. Out of 387 patients, 31 were transplanted for AIH, and 8/31 developed rAIH. Of the remaining 356 patients, eight developed dAIH. Compared to the dAIH group, rAIH occurred in older patients, had an earlier onset in the allograft, and had higher IgG and serum ALT levels. It was most commonly seen in African American (AA) patients (87%). rAIH patients had significantly higher CD20 and CD138 positivity in liver biopsies. In addition, they had increased rejection episodes prior to the onset of recurrence, increased graft loss, and mortality. rAIH is a more aggressive disease, and has a preponderance of B cells and plasma cells in the liver tissue as compared to dAIH. The concurrent association with increased graft loss and patient mortality in rAIH warrants further investigations into B cell-targeted therapies.

Background: Right ventricular myocardial fatty infiltration has been observed in pediatric cardiac allografts with an associated decrease in graft life expectancy. A possible explanation included a...

Leydig cell nodular hyperplasia (LCNH) is a lesion that is less characterized than the familiar Leydig cell tumors. The paracrine effects of these lesions on adjacent gonadal stroma have not been widely documented. We present two cases of precocious puberty in pre-pubertal boys found to have a single LCNH with adjacent focal maturation of the seminiferous tubules. Blood tests showed elevated serum testosterone and dehydroepiandrosterone (DHEAS). Ultrasound revealed unilateral testicular enlargement with irregular echogenicity. Radical orchiectomy was performed. Histologically Leydig cell nodular proliferation without destruction of surrounding tubules was seen. Mature seminiferous tubules undergoing spermatogenesis were noted adjacent to the lesion, while away from the lesion seminiferous tubules were as expected in pre-pubescent boys. These cases emphasize the potential presence of both paracrine and endocrine effects in Leydig cell nodular hyperplasia. However, instances of the endocrine effects of hyperplastic Leydig cell lesions are more widely reported than the paracrine effects.

Bile duct paucity is the absence or marked reduction in the number of interlobular bile ducts (ILBD) within portal tracts. Its syndromic variant, Alagille syndrome (ALGS), is a multisystem disorder with effects on the liver, cardiovascular system, skeleton, face, and eyes. It is inherited as an autosomal dominant trait due to defects in NOTCH signaling pathway. ALGS is characterized by vanishing ILBD with subsequent chronic obstructive cholestasis in approximately 89% of cases. Cholestasis stimulates formation of new bile ductules through a process of neoductular reaction, making it difficult to evaluate the presence or absence of ILBD. Therefore, finding a method to differentiate clearly between ILBD and the ductular proliferation is essential for accurate diagnosis. A database search identified 28 patients with confirmed diagnosis of ALGS between 1992 and 2014. Additionally, 7 controls were used. A panel of two immunostains, cytokeratin 7 (CK7) and epithelial membrane antigen (EMA), was performed. CK7 highlighted the bile duct epithelium of ILBD and ductular proliferation, while EMA stained only the brush border of ILBD. In our ALGS group, the ratio of EMA-positive ILBD to identified portal tracts was 12.6% (range, 0%–41%). However, this same ratio was 95.0% (range, 90%–100%) among control cases ( P < 0.001). We propose a panel of two immunostains, CK7 and EMA, to differentiate ILBD from ductular proliferation in patients with cholestasis. With this panel, identification of bile duct paucity can be achieved. Additional studies, including molecular confirmation and clinical correlation, would provide a definitive diagnosis of ALGS.

During the age of enlightenment in the 18th century, radical changes were occurring in the Western world in science, medicine, philosophy, religion, and socioeconomic concepts. In medicine, major advances had already been underway since the days of Vesalius.

Malakoplakia, a rare granulomatous disease caused by impaired macrophage response, has been reported only rarely in children. We report 3 unique cases, with lesions occurring in unusual locations in children with primary immune deficiencies.

Intrathecal and systemic methotrexate (MTX), as well as cranial radiation, are effective modalities to prevent central nervous system relapse in childhood acute lymphoblastic leukemia. Leukoencephalopathy is a well-described adverse effect of MTX therapy and is associated with a wide range of neurological sequelae. Most recent studies of MTX-induced leukoencephalopathy have focused exclusively on imaging findings, particularly magnetic resonance imaging. Here we report a case of severe MTX-induced leukoencephalopathy with unique magnetic resonance imaging findings and pathologic correlation from a brain biopsy taken during a period of active neurological symptomatology.

Noniatrogenic neonatal gastric perforation is a rare and life-threatening condition whose etiology is often unclear. Interstitial cells of Cajal act as gastrointestinal pacemaker cells and express the proto-oncogene c-Kit. Six new cases were identified at our institution which presented with no mechanical, pharmacologic, or otherwise medical-related intervention prior to rupture. The number of interstitial cells of Cajal in nonnecrotic muscularis propria from five random high-power fields per specimen was compared using immunohistochemical stains for c-Kit. The authors show that a lack of interstitial cells of Cajal in the stomach musculature may be implicated in the development of noniatrogenic gastric perforation (p = 0.008). Further large-scale studies, including molecular and genetic analysis, may help to better understand this phenomenon.

Epstein-Barr virus (EBV) may present few or no symptoms in immunocompetent individuals; however, in immunocompromised patients as in the case of AIDS and post-transplant patients, the virus occasionally stimulates neoplastic transformations. Epstein-Barr virus may play a role in the development of smooth muscle tumors (SMT). In the case of Epstein-Barr associated smooth muscle tumors (EBV+SMT), the virus is thought to be the leading factor to the tumorigenic pathway. We report two pediatric patients (6 and 13 years old) who underwent liver transplantation and developed EBV+SMT in the colon and orbit. These two cases represent rare locations for this kind of lesion.

Bacterial infection of Salmonella enterica serotype Typhi is rare in the United States but endemic in many developing countries. Approximately 3-5% of patients become chronic asymptomatic carriers. We describe an atypical presentation of S. enterica serotype Typhi infection in a 10-year-old male, whose cholecystechtomy and bile culture revealed chronic carrier status despite negative stool tests and the absence of gallstones. The gallbladder showed marked thickening of the wall with an intense suppurative granulomatous reaction.

Colorectal adenocarcinoma (CRAC) is exceedingly rare in the pediatric population (fewer than 2 cases per 1 million children). There are 2 major categories of pediatric colorectal adenocarcinoma syndromes: polyposis-related and hereditary nonpolyposis colorectal cancer, also known as Lynch syndrome. Germ line mutations in DNA mismatch repair (MMR) genes (eg, MLH1, MSH2, PMS2, MSH6) have been established as the molecular genetic basis of Lynch syndrome. Another prognostic factor in adult CRAC is the reduced expression of epithelial cadherin (E-cadherin), which has been associated with poor outcome in some adult CRAC cases; however, its role in predicting prognoses in pediatric cases remains unclear. Seven pediatric patients with primary CRAC were reviewed. Available molecular genetic test results were evaluated, and immunohistochemical labeling for MMR proteins and E-cadherin were performed on 5 patients. Four of the 5 patients in our study with available paraffin blocks showed loss of MMR protein expression, consistent with Lynch syndrome. In cases stained for E-cadherin, 3 were strongly positive and 2 were weakly positive; however, with the small sample size and the relatively short follow-up period, an accurate correlation between E-cadherin and prognosis cannot be reached with any degree of certainty. Our findings highlight the importance of genetic testing for MMR gene mutations in children with colorectal cancer and suggest further investigation into the prognostic role of E-cadherin in pediatric CRAC.

Octamer4/3 is a POU transcription factor that regulates pluripotentiality in embryonic stem and germ cells and primordial germ cells. When expressed in post-embryonic life, Octamer4/3 may lead to malignant germ cell tumors (GCT). Thirty samples were selected for this study (26 GCT samples and 4 cryptorchid testes samples) and 16 non-GCT were used as controls. Samples were stained with an anti-Octamer4/3 antibody. All cases of GCT were positive for Octamer4/3, and the non-GCT were negative. This article focuses on pediatric populations where we found that Octamer4/3 immunostaining is a useful diagnostic tool in undifferentiated pediatric tumors.

Hepatic pulmonary fusion (HPF) is characterized by a fibrous connection between the liver and lung tissue. We present two cases of hepatic pulmonary fusion diagnosed with right diaphragmatic hernia and a third case with Pentalogy of Cantrell exhibiting complete agenesis of the diaphragm and finger-like projections of liver adhered to the right lung. It has been proposed that this anomaly is secondary to developmental failure of the mesoderm between days 14-18 after conception and is attributed to diaphragmatic maldevelopment. Understanding the molecular-genetic basis of diaphragmatic hernias may shed light on this unusual presentation and explain why other cases show no fusion.

Parasitic infections of the central nervous system (CNS) occur mostly in underdeveloped regions of the world. Neurocysticercosis (NC) occurs when the larval form of the T. solium tapeworm invades the CNS. Spinal cysticercosis is an extremely rare type of NC and occurs when the cyst occupies the subarachnoid space of the spinal column. Previous cases have been successfully treated through both surgical and medical means. The current case describes the symptoms, diagnosis, and treatment of a patient with this extremely uncommon manifestation of neurocysticercosis.

Rosai-Dorfman disease (RDD), or sinus histiocytosis with massive lymphadenopathy (SHML), is a rare idiopathic histiocytic disorder. The usual presentation of RDD is painless bilateral cervical lymphadenopathy. Extranodal RDD with lymphadenopathy occurs in almost 50% of patients but extranodal RDD, without lymphadenopathy, is very rare. Isolated RDD in the bone occurs in only 2% of patients but it is histologically similar to its nodal counterpart. There are only 14 previously reported cases of RDD in the bone without lymph node involvement in children. Here we describe two new patients--one with rib and lung involvement and the other with multi-osseous involvement.

Ciliated hepatic foregut cysts (CHFCs) are rare congenital legions that arise from the embryonic foregut. The cysts are formed during fetal development by evagination from their respective portions of the foregut, and are characterized by a ciliated epithelial lining. Approximately 100 cases of CHFC have been reported, of which only 13 were in children. Although CHFC is typically benign, malignant transformation to squamous cell carcinoma (SCC) has been reported in 3 cases. Survival rate after progression to malignancy is poor, as SCC in this setting is biologically aggressive. We present 4 new cases of CHFC in children between 5 months and 17 years old. Our cases are unusual, as some of the cysts exhibit multilocularity and biliary communication, and 2 of our patients were diagnosed under the age of 1. Additionally, 1 of the cysts was 19.3 cm in diameter, making it the largest reported CHFC to our knowledge. Ciliated hepatic foregut cysts should be included in the differential diagnosis of hepatic lesions.

Congenital infantile fibrosarcoma (CIFS) is a rare mesenchymal tumor that primarily presents in the soft tissue of the distal extremities and occasionally in unusual locations such as the lung and retroperitoneum. Herein, we report seven cases of unusual presentations of CIFS. These cases include three in the lungs, one in the retroperitoneum with cord compression, one in the posterior trunk, one in the heart, and one infratemporal involving the sphenoid bone. All tumors demonstrated CIFS's characteristic t(12;15)(p13;q25) and associated ETV6-NTRK3 gene fusion. One of the three lung cases was previously reported as primary bronchopulmonary fibrosarcoma (PBPF), but molecular analysis of the paraffin embedded tissue revealed the ETV6-NTRK3 gene fusion consistent with CIFS. We show that CIFS may occur in unusual sites including visceral locations, and we propose that neoplasms displaying the ETV6-NTRK3 gene fusion represent the visceral components of CIFS.

The pathogenesis of right ventricular fibrofatty changes can be broadly divided into genetic or acquired. The genetic cause is termed arrhythmogenic right ventricular dysplasia, an inherited cardiomyopathy characterized by fibrofatty replacement of the right ventricular myocardium, and represents an underdiagnosed cardiac entity leading to syncope, recurrent ventricular tachycardias, heart failure, and sudden death. Our study demonstrates that fibrofatty changes can also be seen in pediatric cardiac allografts. Conversely, fat replacement without fibrosis may be seen secondary to infectious myocarditis, chronic inflammation, and ischemia and as part of the aging process. We examined 29 failed cardiac allografts to identify the etiology of graft failure. In this study, 4 patients (13%) had severe right ventricular fibrofatty changes, and when compared with control patients, those with fibrofatty changes had a shorter interval from transplant to graft failure, 2.75 years vs 5.45 years ( P = 0.029). Neither body mass index nor other physiologic parameters found on electrocardiography, echocardiography, or cardiac catherization were different between groups. Furthermore, arrhythmias indicative of arrhythmogenic right ventricular dysplasia were not observed in the study group. This study suggests the fibrofatty infiltration in cardiac allografts is a clinically different entity from arrhythmogenic right ventricular dysplasia and has an unknown etiology. Our study findings suggest that identifying fibrofatty infiltrates in cardiac transplant patients during routine right ventricular biopsy can be a predictive factor for shortened life of the pediatric cardiac allograft.

Undifferentiated embryonal sarcoma (UES) of the liver is a primitive mesenchymal, malignant neoplasm occurring in children. The link between UES and mesenchymal hamartoma (MH) is controversial. Whether they share the same histiogenesis, representing 2 ends of a spectrum, or are distinct entities is unclear. The genetic aberrations of these neoplasms are not well understood, although a common breakpoint (19q13.4) was recently identified. The purpose of this study was to elucidate immunohistochemical markers that may establish a link between the 2 tumors by reviewing cases of UES and MH. Cases of UES from 1990 to 2008 were identified. Clinical demographics were reviewed. Hematoxylin and eosin staining and immunohistochemical staining for vimentin, alpha-1 antitrypsin, and alpha-fetoprotein were performed. Eleven children were diagnosed with UES. Five cases were seen arising in association with MH, and transitional zones were evident. The mean age at presentation was 10 years. To our knowledge, the 11-month-old patient is the youngest reported case of UES in concurrence with MH. All UES tumor cells were positive for vimentin, diastase-resistant periodic acid–Schiff stain, and alpha-1 antitrypsin. Chromosomal analysis of 3 UES cases, 2 arising with MH, showed complex karyotypes with no involvement of 19q13.4. We suggest a continuum between UES and MH. Although a chromosomal anomaly of 19q13.4 was not identified, a submicroscopic involvement of this locus cannot be excluded. Additionally, our analyses suggest that multiple chromosomal aberrations may be associated with the MH/UES spectrum.

Although Kawasaki disease (KD) was first discovered and identified in Japan by Kawasaki in the 1960s, fatal KD cases resulting from coronary artery aneurysms had been identified retrospectively in the West as early as 1871. Kawasaki initially postulated that this disease was a new, as yet unidentified, self-limiting illness with no fatal coronary sequelae. The connection between fatal cases, then diagnosed as infantile polyarteritis nodosa, was not made until the late 1970s. Kawasaki's thoughts were reinforced by an apparent absence of nonfatal cases in the West before 1967. Close examination of a 1948 autopsy report suggests that nonfatal cases of KD did indeed exist, at least in the United States, before its emergence in Japan in the early 1950s. These nonfatal cases of KD were misdiagnosed as Stevens-Johnson syndrome. The autopsy report reviewed in this article reinforces the likelihood that KD did occur in the United States before it was identified as Kawasaki disease in Japan.

Three cases of congenital immature intracranial teratomas were examined by autopsy. The fetuses were diagnosed prenatally as macrocephalic and hydrocephalic due to skull-occupying lesions. These fetuses were born alive at 32, 31, and 36 weeks gestation, respectively, via Cesarean section. Intracranial teratoma in the first case was diagnosed by MRI and in the second and third cases by ultrasound. All tumors were deemed to be unresectable. Congenital CNS teratoma should be considered in the differential diagnosis of fetuses diagnosed with macrocephaly or hydrocephaly.

Thoracoschisis is an extremely rare congenital birth defect in which intra-abdominal organs eviscerate through a defect in the thoracic wall(1). There are only seven previously reported pediatric cases and in each case, there is some diaphragmatic anomaly, suggesting that the defect took place before complete formation of the diaphragm. Our patient was referred to us from a local hospital immediately after delivery. The patient was born with a thoracoschisis of the left side below the 8(th) intercostal space. The thoracoschisis was repaired. Although there is a high prevalence of cardiac defects among thoracoschisis patients, this patient shows only small atrial septal defects.

Anti- N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis is a potentially fatal neurologic syndrome in which patients present with a spectrum of central nervous system deficits. Sixty percent of the cases can be attributed to the presence of tumors, most often ovarian teratomas. This report examines 6 pediatric patients who presented with neurologic deficits associated with the presence of such tumors. These cases illustrate a perplexing phenomenon, where benign teratomas could have a possible association with anti-NMDAR encephalitis. The purpose of this study was to compare the histology and immunohistochemistry of tumors associated with this syndrome to ovarian teratomas found in patients presenting with no neurologic symptoms. After obtaining institutional review board approval, 57 cases of ovarian teratomas were identified at our institution over 12 years. Six patients were identified with anti-NMDAR encephalitis. A panel of immunostains, including S100, GFAP, MAP2, and NeuN was applied to patients' tumor sections as well as the 6 controls from age-matched patients. No qualitative histologic or immunohistochemical differences were seen between the study cases and control group. Because no qualitative differences were identified between the study cases and the control group, testing of paired serum and cerebrospinal fluid remains the best method for diagnosis of anti-NMDAR encephalitis. Tumor banking with molecular analysis of ovarian teratomas, including whole-genome sequencing and comparative genomic hybridization between ovarian tissue saved from patients with and without anti-NMDAR encephalitis, is necessary to fully understand the etiopathogenesis of anti-NMDAR encephalitis.

Previously, we have shown that macrophage migration inhibitory factor (MIF) was highly elevated in the placental intervillous blood (IVB) of Plasmodium falciparum -infected women. Here, we compared the expression of MIF in placental tissues obtained from P. falciparum -infected and -uninfected women. Immunoperoxidase staining showed a consistent pattern of MIF expression in syncytiotrophoblasts, extravillous trophoblasts, IVB mononuclear cells, and amniotic epithelial cells, irrespective of their malaria infection status. Cytotrophoblast, villous stroma, and Hofbauer cells showed focal staining. Only amniotic epithelial and IVB mononuclear cells from P. falciparum -infected placentas exhibited significantly higher level of MIF expression than uninfected placentas. Stimulation of syncytilized human trophoblast BeWo cells with P. falciparum -infected erythrocytes that were selected to bind these cells resulted in significant increases in MIF secretion, whereas control erythrocytes, lipopolysaccharides, and synthetic β-hematin had minimal effect. These findings suggest that placental malaria modulates MIF expression in different placental compartments.

Nontuberculous mycobacterial (NTM) infections are serious, though rare, in patients with severe combined immunodeficiency who have received bone marrow transplants. A 5-year-old female patient underwent stem cell/bone marrow transplant with disseminated NTM. Real-time polymerase chain reaction (PCR) using a fluorescence resonance energy transfer (FRET) probe for detection and identification of NTM was performed. The FRET-based real-time PCR assay amplified mycobacterial DNA, and the postamplification melt curve analysis classified the organism as a NTM. The pyrosequence of the hypervariable region A definitively identified the infecting organism as Mycobacterium avium. Real-time PCR along with melt curve analysis and pyrosequencing provides faster, definitive identification of mycobacteria, as compared to bacterial culture. In this case report, we emphasize the importance of utilizing molecular means for fast and accurate diagnosis.

Ischemia-reperfusion injury (IRI) is a common clinical consequence of hepatic surgery, cardiogenic shock, and liver transplantation. A steatotic liver is particularly vulnerable to IRI, responding with extensive hepatocellular injury. Autophagy, a lysosomal pathway balancing cell survival and cell death, is engaged in IRI, although its role in IRI of a steatotic liver is unclear. The role of autophagy was investigated in high-fat diet (HFD)-fed mice exposed to IRI in vivo and in steatotic hepatocytes exposed to hypoxic IRI (HIRI) in vitro. Two inhibitors of autophagy, 3-methyladenine and bafilomycin A1, protected the steatotic hepatocytes from HIRI. Exendin 4 (Ex4), a glucagon-like peptide 1 analog, also led to suppression of autophagy, as evidenced by decreased autophagy-associated proteins [microtubule-associated protein 1A/1B-light chain 3 (LC3) II, p62, high-mobility group protein B1, beclin-1, and autophagy-related protein 7], reduced hepatocellular damage, and improved mitochondrial structure and function in HFD-fed mice exposed to IRI. Decreased autophagy was further demonstrated by reversal of a punctate pattern of LC3 and decreased autophagic flux after IRI in HFD-fed mice. Under the same conditions, the effects of Ex4 were reversed by the competitive antagonist exendin 9-39. The present study suggests that, in IRI of hepatic steatosis, treatment of hepatocytes with Ex4 mitigates autophagy, ameliorates hepatocellular injury, and preserves mitochondrial integrity. These data suggest that therapies targeting autophagy, by Ex4 treatment in particular, may ameliorate the effects of IRI in highly prevalent steatotic liver.

Giant cell myocarditis is a rare but often fatal form of myocarditis that often requires cardiac transplantation and has been associated with autoimmune diseases. We describe a 14-year-old female who developed painful proptosis and was diagnosed clinically and histologically with orbital myositis that improved with corticosteroid therapy. Approximately 2 months later, she developed abdominal pain, vomiting, weight gain, and fatigue. She was diagnosed with congestive heart failure and cardiomyopathy, and endomyocardial biopsy revealed giant cell myocarditis. She was treated with immunosuppressive agents and has responded well, without the need for cardiac transplantation. Three previous case reports have described an association between giant cell myocarditis and orbital myositis, but we present the first pediatric case report. We conclude that if orbital myositis is diagnosed in a patient, regardless of age, cardiac function should be closely monitored to detect myocarditis, which may affect the overall outcome.

Fetus-in-fetu is an unusual condition in which a vertebrate fetus is enclosed within the abdomen of another fetus. These occurrences are usually benign. This report describes an instance of malignant recurrence after resection of a fetus-in-fetu.

Studies indicate a close relationship between Yersinia and Crohn's disease in adults. Our study tested 77 colonic specimens from children with Crohn's disease for the presence of Yersinia DNA using a validated polymerase chain reaction (PCR) assay. Control cases included specimens from 45 ulcerative colitis patients and 10 appendicitis patients. The presence of Yersinia in Crohn's specimens was significant compared to the control specimens (9% vs. 0%; p = 0.0055). While our study supports the medical literature, future studies are needed to determine if the relationship between Crohn's disease and Yersinia is an initiating or mediating factor in the pathogenesis of pediatric Crohn's disease.

An improved method for long-term perfusion of the isolated human term placental lobule has been developed to investigate the maternofetal transfer of infectious agents, in particular the human immunodeficiency virus (HIV). The purpose of this paper is to describe those modifications that allow for substantially prolonged perfusions in in a biohazard environment. The method described has been adapted from previous models. The perfusion apparatus has been modified for use within a biohazard hood, and, intravenous bags contain the medium for circulation of perfusates in closed circuits. A Mera Silox-S 0.3 membrane oxygenator delivers more oxygen to the tissue, and, Electromedic Cardioplegia heat exchangers warm the perfusate prior to oxygenation. Viability criteria (glucose consumption, lactate production, de novo production of human placental lactogen (hPL), volume loss, flow, temperature, pressure, oxygen transfer, carbon dioxide production, absence of IgM transfer and light and electron microscopy) demonstrate that the placental tissue remains in a functional state throughout the perfusion. Oxygen and glucose consumption are both stable over time; lactate levels remain constant; and hPL continues to be produced. These significant modifications of the perfusion system have permitted the investigators to increase the duration of perfusion to 48 h while preserving normal metabolic function of ultrastructurally intact tissue as demonstrated by ultra structural observations. This perfusion model device provides biohazard precautions and may be applied to other studies of placental physiology.

We examined the association of placental malaria and mother-to-child transmission (MTCT) of HIV in a prospective community-randomized trial in Rakai District, Uganda. In the 746 HIV-positive mother-infant pairs, the MTCT rate was 20.4%. Placental malaria was more common in HIV-positive than HIV-negative women. After multivariate adjustment for HIV viral load, the risk of MTCT associated with placental malaria was 2.89 and with HIV viral load the risk was 2.85. Interventions to prevent malaria during pregnancy could potentially reduce MTCT.

Hepatopulmonary syndrome (HPS) is infrequently reported in children. Clinical-pathological findings in 10 HPS children were compared with non-HPS controls. Six patients had cirrhosis and four had noncirrhotic portal hypertension (NCPH) 40%. Polysplenia and abnormal venous malformations were exclusive to this group. This prevalence of NCPH with systemic venous anomalies suggests that HPS is associated with pulmonary vasoactive factors not cleared by the liver. Hepatopulmonary syndrome should be considered in any patient with hypoxemia and intrapulmonary shunting whether there is overt clinical liver disease or not.

Babesiosis is usually acquired from a tick bite or through a blood transfusion. We report a case of babesiosis in an infant for whom vertical transmission was suggested by evidence of Babesia spp. antibodies in the heel-stick blood sample and confirmed by detection of Babesia spp. DNA in placenta tissue.

Splenic cysts are rare lesions that can occur in parasitic and non-parasitic forms. Because they are uncommon, the classification, pathogenesis, and management techniques are still debated. The continual review of splenic cyst cases in the pediatric population is essential for establishing a clear diagnosis and course of treatment. This report presents 21 cases of pediatric splenic cysts observed at Children's Healthcare of Atlanta over an 18 year period (1993-2011). The cases include both parasitic and and nonparasitic cysts. The current splenic cyst classification and treatment methods are analyzed through a review of the current theories and based on our experiences.

Nonalcoholic fatty liver disease is an increasingly prevalent spectrum of conditions characterized by excess fat deposition within hepatocytes. Affected hepatocytes are known to be highly susceptible to ischemic insults, responding to injury with increased cell death, and commensurate liver dysfunction. Numerous clinical circumstances lead to hepatic ischemia. Mechanistically, specific means of reducing hepatic vulnerability to ischemia are of increasing clinical importance. In this study, we demonstrate that the glucagon-like peptide-1 receptor agonist Exendin 4 (Ex4) protects hepatocytes from ischemia reperfusion injury by mitigating necrosis and apoptosis. Importantly, this effect is more pronounced in steatotic livers, with significantly reducing cell death and facilitating the initiation of lipolysis. Ex4 treatment leads to increased lipid droplet fission, and phosphorylation of perilipin and hormone sensitive lipase – all hallmarks of lipolysis. Importantly, the protective effects of Ex4 are seen after a short course of perioperative treatment, potentially making this clinically relevant. Thus, we conclude that Ex4 has a role in protecting lean and fatty livers from ischemic injury. The rapidity of the effect and the clinical availability of Ex4 make this an attractive new therapeutic approach for treating fatty livers at the time of an ischemic insult.

Bartonella henselae, the etiologic agent of cat-scratch disease, causes a well-defined, self-limited syndrome of fever and regional lymphadenopathy in immunocompetent hosts. In immunocompromised hosts, however, B. henselae can cause severe disseminated disease and pathologic vasoproliferation known as bacillary angiomatosis (BA) or bacillary peliosis. BA was first recognized in patients infected with human immunodeficiency virus. It has become more frequently recognized in solid organ transplant (SOT) recipients, but reports of pediatric cases remain rare. Our review of the literature revealed only one previously reported case of BA in a pediatric SOT recipient. We herein present 2 pediatric cases, one of which is the first reported case of BA in a pediatric cardiac transplant recipient, to our knowledge. In addition, we review and summarize the literature pertaining to all cases of B. henselae-mediated disease in SOT recipients.

NUT midline carcinoma is a rare and aggressive tumor that has primarily been reported in children and young adults. The tumor is characterized by a rearrangement on the nuclear protein in testis (NUT) gene, located on chromosome 15q14, resulting in the BRD4-NUT fusion oncogene. This carcinoma most commonly presents in the midline and displays an invariably lethal clinical course. To highlight the imaging features of NUT midline carcinoma. IRB approval was obtained for chart review. We retrospectively reviewed the chart and imaging studies of three children. All three cases were diagnosed by karyotyping and confirmed by fluorescence in situ hybridization (FISH). Cross-sectional imaging including CT, MRI and, in one patient, PET was available for review. Two out of three children presented with midline and multifocal disease. The third case had a medial left thigh mass and no metastatic disease at initial presentation. The common imaging features include heterogeneous low density on CT and T1 hypointensity and low-level T2 hyperintensity on MRI with heterogeneous enhancement. All cases were confirmed pathologically and by molecular studies. NUT midline carcinoma usually presents in the midline, either in the head, neck or chest. We present three cases with the bulk of the tumor below the diaphragm, which is seen in the minority of patients with NUT midline carcinoma, according to the available literature. Metastatic disease is common at initial presentation and can be quite extensive. The most striking feature of this disease is its aggressive nature with exponential interval growth of tumor.

Mesenteric cysts, seen in all age groups, represent a rare cause of benign abdominal masses in children. We reviewed 21 patients with mesenteric/omental cysts. Gross and radiologic images, along with histologic sections, were reviewed to categorize the structures and determine the relationship to the mesentery and intestines. The cysts were composed of multi-loculated dilated channels at the serosal surface consistent with lymphangioma. Most treatment was simple excision, infrequently with intestinal resection. Nineteen patients did well after surgery. One patient developed short-gut syndrome after massive bowel resection, and one patient died immediately after birth due to massive fetal hydrops and heart failure.

Background. Involvement of the thymus during human immunodeficiency virus (HIV) infection may impair production of naive lymphocytes leading to more rapid depletion, but the characteristics of primary strains in the thymus are not well studied because of the unavailability of tissue in living individuals. Methods. We studied the characteristics of HIV type 1 (HIV-1) in a 5-year old perinatally infected child with thymitis and compared the genomic sequences of the HIV-1 C2-V5 region of the env gene in the thymic tissue and peripheral blood. Results. The thymus harbored predominantly viral sequences close to the founder HIV-1 variant that circulated in the blood at 2 and 3 months of age, whereas the peripheral blood virus at 5 years of age had evolved extensively. Viral sequences from circulating CD8' T cells at 5 years of age phylogenetically clustered with those from the thymic tissue. Conclusions. These results indicate the existence of a distinct thymic viral reservoir and suggest that circulating CD8 + T cells were infected in the thymus, presumably at the CD4 + CD8 + thymocyte stage. They also demonstrate that not all thymic HIV infections will necessarily lead to severe thymic dysfunction. The characteristics of the virus strain seeding the thymus may dictate the rate of disease progression.

Previous studies have suggested that immune mechanisms contribute to lung injury in cystic fibrosis (CF); however, there have been no comprehensive studies of immunofluorescent staining patterns in CF lung tissue. We performed immunofluorescence (IF) studies for immunoglobulins, C3, and fibrinogen on autopsy frozen lung tissue from 21 CF patients. Results were compared with lung findings in patients without CF. In CF-derived lung tissue fibrinogen was ubiquitous along the alveolar wall, alveolar space, and interstitium. Free immunoglobulin G (IgG) and IgA coated the alveolar surface segmentally in 14 and 6 cases, respectively. Unequivocal interstitial deposits were infrequent and IgM was present in blood vessels in one patient only. Intra-alveolar and interstitial inflammatory cells demonstrated cytoplasmic IgG, IgA, and IgM, respectively, in 18, 14, and 6 patients. C3 was seen only segmentally along the alveolar wall in two patients and in blood vessels in one. Antinuclear antibody (ANA) staining of interstitial cells for C3 and immunoglobulins was seen in five patients, four of whom had interstitial pneumonitis. Insignificant amounts of alveolar or interstitial fibrinogen and immunoglobulins in inflammatory cells were seen in controls in the absence of lung inflammation. The IF patterns were similar in the inflammatory lesions of CF and control specimens. The IF patterns observed in CF lung tissue are consistent with nonspecific vascular leakage and chronic inflammation with little evidence of immune complex deposition in the interstitium or blood vessels. This study confirms previous reports of ANA activity in CF patients, although the significance of this finding is unknown.

NUT midline carcinoma (NMC) is a rare and aggressive malignant epithelial tumor defined by rearrangement of the NUT gene on chromosome 15. In two thirds of cases, NUT is involved in a balanced translocation with BDR4 on chromosome 19, while in the remaining cases, NUT is rearranged with variant fusion partners such as BRD3. These undifferentiated tumors primarily affect midline structures, usually in the upper aerodigestive tract and mediastinum. Most reported cases have followed a rapidly lethal clinical course. We report the clinical and pathological findings of NMC in the youngest patients identified so far. The 1st case involves a newborn who presented with a supraorbital mass and extensive multiorgan involvement, including the spine, lungs, liver, pancreas, adrenal glands, and subcutaneous tissue. The 2nd patient was a 2-year-old male with an abdominal mass involving the liver and pancreas with pulmonary metastasis. Histopathological analysis of both tumors showed undifferentiated malignant neoplasms, and immunohistochemistry showed positivity for epithelial markers. Both tumors demonstrated t(15;19), and immunohistochemistry with NUT monoclonal antibodies and fluorescent in situ hybridization confirmed NUT rearrangement. The patients died from disease at 1 and 2 months postpresentation. Thus far, 25 cases have been reported, including our 2 current cases. Presentation ages range from 0 to 78 years (mean, 23 years). Herein, we report the 2 youngest reported cases of NMC, including the 1st congenital case and the 1st case arising within the liver/pancreas. Increased awareness and further molecular studies are required for a better understanding of NMC pathobiology and improved therapeutic outcomes.

Congenital diaphragmatic hernia (CDH) is a defect seen in approximately 1 in 3500 live births. A complication of CDH is the herniation of abdominal contents into the chest cavity through the defect, which may prevent normal intrauterine development of the lungs. The resultant pulmonary hypoplasia and pulmonary hypertension causes respiratory distress in the newborn, usually requiring some form of intervention before the defect is surgically corrected (Embryology for Surgeons. Baltimore, MD: Williams & Wilkins; 1994:491-539). Extracorporeal membrane oxygenation, which involves cannulation of the superior vena cava (SVC), is often used to manage these infants. However, the mediastinal shift that often occurs with CDH can cause an abnormal acute angulation of the SVC, which during cannulation can result in trauma and possible perforation of the SVC. We present 2 autopsy cases where the infants accidentally died as a result of extracorporeal membrane oxygenation cannulation.

Hepatopulmonary syndrome (HPS) is a triad of liver dysfunction, hypoxemia, and intrapulmonary vascular dilatation. We describe the prevalence and clinical features of HPS at a pediatric liver transplant center. Patients referred to Children's Healthcare of Atlanta/Emory University transplant program from February 1999 to May 2005 were reviewed. Oxygen saturation in room air was screened by percutaneous pulse oximetry. HPS cases were compared with similar age non-HPS recipients (n = 38) to determine differences in clinical characteristics, Pediatric End-Stage Liver Disease (PELD) scores, and posttransplantation survival. Of 211 patients referred and 114 patients transplanted, 7 met criteria for HPS (3.3% and 6.1%, respectively). Patients with HPS had lower PELD score (-0.4 +/- 5.9 vs. 11 +/- 11; P = 0.01) and total bilirubin (1.7 +/- 1.1 vs. 11.2 +/- 10.1; P = 0.02) at the time of transplantation. Four of 7 patients with HPS had polysplenia/interrupted inferior vena cava (PS/IVC) compared with 0 of 38 age-matched controls (P = 0.0002). Three patients with HPS did not have cirrhosis; 2 of these 3 had PS/IVC. All HPS cases normalized room air oxygen saturation by 6 months, and survival after transplantation in HPS cases was 100%. Marked hepatic synthetic or biochemical dysfunction may not be present, and cirrhosis is not a requirement for the development of HPS in children. HPS in children is frequently associated with PS/IVC. Histologic evidence of abnormal intrahepatic portal vein flow and the demonstration of portosystemic communications at any level should be sought in children presenting with unexplained intrapulmonary vascular dilatation. Liver transplantation for HPS in childhood may be appropriate even in the absence of cirrhosis.

Anaplastic large cell neuroblastomas (ALCNB) are a subset of undifferentiated neuroblastomas with marked pleomorphic and anaplastic features that render them diagnostically challenging. We reviewed the records of all patients diagnosed with ALCNB at Children's Healthcare of Atlanta (Egleston Children's Hospital) for their clinical, biologic, and pathologic characteristics and their treatment outcomes. From 1998 to 2006, 7 patients were diagnosed with ALCNB. All patients presented with abdominal-pelvic masses, 3 of them of adrenal origin and 2 with thoracic extension, with clinical stages 3 or 4, and were considered to have high-risk disease. The N-MYC oncogene was amplified in 3 cases and catecholamines were elevated in 5 of 6 patients tested. All pretreatment tumors demonstrate pleomorphic, anaplastic morphology with bizarre mitoses admixed with undifferentiated but monomorphic cells with minimal if any neuropil or neuro-ganglionic differentiation. Immunohistochemical markers for neuron specific enolase (NSE) and synaptophysin were strongly positive in all specimens and chromogranin in 4 of 5. Interestingly, all tumors showed strong Fli-1 nuclear positivity despite a negative CD-99 stain. However, reverse transcription polymerase chain reaction or fluorescent in-situ hybridization testing for Ewing sarcoma transcripts was negative in 4 available specimens. This same Fli-1 antibody had tested negative on 30 conventional neuroblastomas, indicating a peculiar cross reactivity with this subset of ALCNB. Posttreatment biopsies showed maturation changes to more conventional neuroblastoma histology in 5 of the 7 cases. Follow-up ranged from 9 months to 4 years from diagnosis (median: 25 months). Five patients are still alive after treatment, 1 died 9 months after diagnosis, and another patient refused high-risk therapy and progressed and died 9 months from diagnosis. Anaplastic large cell neuroblastomas are a subset of undifferentiated neuroblastomas characterized by the absence or marked paucity of histologic clues for the diagnosis of neuroblastoma. Although all these tumors are strongly positive for NSE and synaptophysin, they also show Fli-1 positivity. However, they are negative by molecular testing for EWS transcripts, and they are immunohistochemically negative for CD99. The true neuroblastic nature of these tumors is supported by the N-MYC oncogene amplification in some of them, catecholamine production, immunohistological reactivity, and their posttherapy maturation to a more recognizable neuroblastic morphology. Although follow-up is still somewhat limited, the response and survival of the patients in our institution is better than a previous European study that indicated an aggressive clinical behavior of these tumors, although treatment modalities were not described in that report. Further study of this variant of neuroblastoma with more patients is required to determine optimal therapy, more accurately predict outcome, and to ascertain if ALCNB are a distinct biologic group of neuroblastomas.

BACKGROUND: Bilateral microtia with aural atresia is rare. Rhabdomyomatous hamartomata containing salivary tissue, situated bilaterally and symmetrically simulating the palatine (faucial) tonsils, has apparently not been reported. We present the combination of these findings in two unrelated patients. CASES: In the first case, the patient was exposed prenatally to 13-cis-retinoic acid (isotretinoin) and has typical features of this exposure, including bilateral microtia with aural atresia and bilateral 7th nerve palsies. Due to symptoms of obstructive sleep apnea, patient 1 had a “tonsillectomy” and adenoidectomy. Histopathologic studies demonstrated rhabdomyomatous hamartomata containing salivary and striated muscle tissue in place of the palatine tonsils. In the second case, the patient had been prenatally exposed to alcohol, cocaine, and marijuana. He has been noted to have developmental delay and behavioral issues in addition to bilateral microtia with aural atresia. “Tonsillectomy” and adenoidectomy were performed to alleviate chronic upper respiratory infections and snoring. Again, histopathologic studies of the tissue submitted as “tonsil” demonstrated rhabdomyomatous hamartomata containing salivary and muscle tissue. Although an extended banded karyotype and subtelomere panel were normal, a genetic etiology for the second patient's features cannot be excluded. CONCLUSIONS: We hypothesize that the findings of bilateral microtia with aural atresia and rhabdomyomatous hamartomata containing salivary and muscle tissue in the area of the palatine tonsils may represent a newly recognized association, which may have a teratogenic and/or genetic etiology. Birth Defects Research (Part A), 2007. © 2006 Wiley-Liss, Inc.

We describe a case of an inflammatory pseudotumor of the spleen in a 5-year-old boy, found incidentally during a physical examination. The boy underwent a hemisplenectomy. The problems in differentiating this disease from lymphoma of the spleen before surgery and the advantages of hemisplenectomy are discussed. This rare disease has previously been described in the spleen in only 28 cases, the youngest being a 16-year-old patient.

1but the biological basis for this link is unknown. We report two cases of Langerhans-cell histiocytosis arising in the context of precursor T-lymphoblastic leukaemia/lymphoma. The Langerhans-cell histiocytosis cells and the precursor T-lymphoblastic leukaemia/lymphoma cells had identical rearrangements of the gene for T-cell receptor � , confirming a clonal relation between the two neoplastic diseases. In April, 1996, a 5-year-old boy presented with a mediastinal mass and a white-cell count of 2·9� 10 9 /L. Bone-marrow aspiration showed precursor T-cell acute lymphoblastic leukaemia; cerebrospinal fluid was negative. He had a complete response to the BerlinFrankfurt-Munster middle-risk schedule. However, from August, 1998, to October, 1998, he developed multiple penile lesions and a biopsy sample showed Langerhans-cell histiocytosis. Between 1998 and 2002 he received several chemotherapeutic regimens and radiotherapy (total dose 44·8 Gy), without a sustained complete response. Regimens included: etoposide and prednisolone; combinations of topical chlormethine, indometacin, betamethasone-depot, vinblastine, thalidomide, etanercept, and intralesional methylprednisolone; mercaptopurine, vinblastine, and 500 mg/m 2 metho

We present a case of an infant with Down syndrome (trisomy 21) who was affected by alveolar capillary dysplasia and other complications including endocardial cushion defect, hypothyroidism, and intrauterine growth restriction. The patient was the product of a third pregnancy to a 33-year-old woman with no significant risk factors. The child lived for 3 months, during which he developed intractable dyspnea, hypoxemia, and cardiac dysfunction and he eventually died from septicemia and multiorgan failure. In addition to the facial phenotypic features and cardiac anomalies, the autopsy revealed the characteristic microscopic pulmonary findings of alveolar capillary dysplasia with misalignment of pulmonary veins. This appears to be the first reported case of this anomaly associated with trisomy 21. In addition to the many reasons for pulmonary hypertension that occur in children with trisomy 21, alveolar capillary dysplasia may have to be included in the differential diagnosis although it appears to be a rare association.

Livin is a recently identified member of the Inhibitor-of-Apoptosis protein (IAP) family of antiapoptosis proteins, and expression has been reported in melanoma and some types of carcinoma. We evaluated livin expression in paraffin-embedded tumor tissue from 68 patients with neuroblastoma (NB) and 7 NB cell lines by immunoperoxidase using an anti-livin monoclonal antibody. Eighteen (26.5%) of the 68 NB tumor tissues showed high livin expression, 36 (53%) showed low-intermediate expression, and 14 (20.5%) were negative. Similarly, 4 NB cell lines showed high livin expression, and 3 showed intermediate expression. In primary NB tissue, livin was observed mainly in tumor neuropil, an extension of tumor cell cytoplasm, and the cytoplasm itself. By reverse transcriptase–polymerase chain reaction, livin expression was confirmed in all 7 NB lines and in frozen tissue from 1 of 3 primary tumors examined to date, in agreement with immunohistochemical data; both livin α and β isoforms were detected. In the NB cases, we further analyzed the correlation between livin expression and clinical and biological features with established prognostic significance (i.e., age at diagnosis, stage, histology, and MYCN oncogene status), and patients' outcome. Livin expression alone did not appear to have an effect on survival; however, patients with high livin expression and amplified MYCN had significantly decreased survival compared with patients lacking both markers or with either of these markers alone. These results suggest that (a) livin is expressed in primary and cultured neuroblastoma cells and (b) high livin expression may identify a subset of neuroblastoma patients with a particularly poor prognosis among those with MYCN amplified tumors.

Reports indicate peripheral eosinophilia (PE) and gastrointestinal eosinophilic inflammation can occur after pediatric liver transplantation. The incidence of these conditions, potential risk factors, and the impact of PE and gastrointestinal eosinophilic inflammation on liver transplant outcome were determined in this pediatric liver transplant program. Medical records of liver transplant recipients from 1 to 97 and from 12 to 99 were reviewed. Fifty-seven transplants on 54 patients were performed during the study period. Fifty-three patients were evaluated; all had normal pre-transplantation peripheral eosinophil counts. PE of10% developed in 28% of patients. Using this definition, all such identified patients had absolute eosinophil counts of350/mm3. History of immediate hypersensitivity did not differ between patients with or without eosinophilia. Gastrointestinal endoscopy and biopsy was performed in 23 patients with gastrointestinal complaints. Of those, six had eosinophilic gastroenteritis and all six had PE. Compared with patients without eosinophilia, those with PE were younger at the time of transplantation (p0.05), had more frequent rejection (p0.01), were more commonly managed with tacrolimus-based immunosuppression (p0.001), and experienced more frequent episodes of detectable EBV viral load (p0.04). Patients with eosinophilic gastroenteritis were more frequently retransplanted (p0.006). PE associated with symptomatic eosinophilic gastroenteritis is common after pediatric liver transplantation. Age at transplant, frequency of rejection episodes, tacrolimus-based immunosuppression, and EBV viral load may be associated with the development of this condition. There may be higher rates of graft loss in such patients. Whether innate immune responsiveness or an acquired immune dysregulation accounts for these findings merits further evaluation.