Regulated GATA1 expression as a universal gene therapy for Diamond-Blackfan anemia.

Gene therapy using hematopoietic stem and progenitor cells is altering the therapeutic landscape for patients with hematologic, immunologic, and metabolic disorders but has not yet been successfully developed for individuals with the bone marrow failure syndrome Diamond-Blackfan anemia (DBA). More than 30 mutations cause DBA through impaired ribosome function and lead to inefficient translation of the erythroid master regulator GATA1, providing a potential avenue for therapeutic intervention applicable to all patients with DBA, irrespective of the underlying genotype. Here, we report the development of a clinical-grade lentiviral gene therapy that achieves erythroid lineage-restricted expression of GATA1.

Clinical and immunophenotype correlating with response to immunotherapy in paediatric patients with primary liver carcinoma. A case series.

Background: Paediatric hepatocellular carcinomas (HCC) traditionally arise in the context of a normal structural and functional liver and carry a dismal prognosis. While chemotherapy is the frontline standard, there is emerging interest in the study of immunotherapies for paediatric patients with relapsed/refractory disease. There is limited data to support whether immunotherapies will be of utility in this patient population.

Splenic Lymphatic Malformation With Papillary Endothelial Proliferation: A Rare Histologic Variant or a Unique Entity?

Lymphatic malformations (LMs) are congenital anomalies of the lymphatic system due to abnormalities that occur during the development of the lymphovascular system. Also known as lymphangiomas, they are usually multifocal, affect multiple organ systems, and are seen in a variety of developmental or overgrowth syndromes. Splenic lymphangiomas are uncommon and usually occur in the context of multiorgan lymphangiomatosis.

Spectrum of Liver Pathology in Dyskeratosis Congenita.

Dyskeratosis congenita (DC) is a rare multisystemic disorder associated with defective telomere maintenance. Frequent clinical manifestations of DC include reticular skin pigmentation, dystrophic nails, oral leukoplakia, and bone marrow failure. Hepatic disturbances are reported to occur in 7% of DC patients.

A multi-disciplinary team approach to pediatric malignant mandibular tumors.

Objective: Mandibular tumors in the pediatric population are rare. These malignancies are variable in their histology, and combined with their rarity, has made it difficult to describe their clinical course, and treatment guidelines. The aim of this paper is to describe the experience of Boston Children's Hospital, a pediatric tertiary referral center, with treating malignant mandibular malignancies, as well as provide multi-disciplinary team approach in managing this clinical entity.

Kaposiform Lymphangiomatosis: Pathologic Aspects in 43 Patients.

Kaposiform lymphangiomatosis is an uncommon generalized lymphatic anomaly with distinctive clinical, radiologic, histopathologic, and molecular findings. Herein, we document the pathology in 43 patients evaluated by the Boston Children's Hospital Vascular Anomalies Center from 1999 to 2020. The most frequent presentations were respiratory difficulty, hemostatic abnormalities, and a soft tissue mass.

Pediatric Acute Liver Failure: A Clinicopathological Perspective.

Pediatric acute liver failure (PALF) is a life-threatening disorder characterized by acute hepatocellular injury occurring in children without recognized underlying liver disease. The clinicopathologic evaluation of PALF requires a different approach from that in adults. The diagnostic considerations differ depending on the age, personal and family history, geographical region, and clinical presentation.

Prenatal diagnosis of rapidly enlarging choledochal cyst with gastric outlet obstruction.

Choledochal cysts are congenital malformations of the biliary tract that involve aberrant configurations of the pancreaticobiliary ductal system. The pathology exists on a spectrum from fusiform dilation of the common bile duct to multiple dilations involving the intra- and extrahepatic bile ducts with potential risks of malignant transformation and hepatic fibrosis. Advancements in ultrasound technology have increased the incidence of prenatal diagnosis of choledochal cysts.

Hemolysis in Early Infancy: Still a Cause of Cholestatic Neonatal Giant Cell Hepatitis.

Before the prophylactic use of anti-D antibodies in pregnancy, hemolytic anemia of the newborn was the most common cause of hyperbilirubinemia. Nowadays, given the rarity of hemolytic anemia of the newborn, hepatobiliary abnormalities, perinatal infections, and metabolic disorders have become the most common conditions in the differential diagnosis of neonatal cholestasis. Here, we report 3 instances of cholestatic giant cell hepatitis in 3 infants who had Coombs' positive hemolysis due to ABO incompatibility in 1, Rh incompatibility in another, and combined ABO and Rh incompatibility in the third.

Giant Cell Myocarditis in Children: Elusive Giant Cells Might Not Be the Only Clue.

Giant cell myocarditis (GCM) is a form of fulminant myocarditis that is rapidly progressive and frequently lethal even in children. Over the course of 20 years, a definitive histopathologic diagnosis of GCM has been made at our institution in only two pediatric patients, and in neither instance was the diagnosis of GCM rendered on initial cardiac biopsy. We present the two patients and highlight the similarities in their clinical presentation and their challenging and inconclusive- albeit histologically similar- initial cardiac biopsy findings.

Cardiomyopathy: Consequences of Impaired Autophagy in the Heart.

Background Human mutations in the X-linked lysosome-associated membrane protein-2 () gene can cause a multisystem Danon disease or a primary cardiomyopathy characterized by massive hypertrophy, conduction system abnormalities, and malignant ventricular arrhythmias. We introduced an mutation (denoted L2) causing human cardiomyopathy, into mouse gene, to elucidate its consequences on cardiomyocyte biology. This mutation results in deletion of 41 amino acids, compatible with presence of some defective LAMP2 protein.

Accuracy of Cardiac Magnetic Resonance Imaging in Diagnosing Pediatric Cardiac Masses: A Multicenter Study.

Background: After diagnosis of a cardiac mass, clinicians must weigh the benefits and risks of ascertaining a tissue diagnosis. Limited data are available on the accuracy of previously developed noninvasive pediatric cardiac magnetic resonance (CMR)-based diagnostic criteria.

Objectives: The goals of this study were to: 1) evaluate the CMR characteristics of pediatric cardiac masses from a large international cohort; 2) test the accuracy of previously developed CMR-based diagnostic criteria; and 3) expand diagnostic criteria using new information.

Fibrolamellar carcinoma: An entity all its own.

Fibrolamellar carcinoma (FLC) is a rare malignant entity arising from the liver and primarily affecting patients in late adolescence and young adulthood. FLC tumors are characterized by their unique histologic features and an only recently discovered genomic alteration: a chimeric fusion protein found in nearly all tumors. The rarity of these tumors coupled with the only recent acknowledgement of this genomic abnormality has likely led to disease under-recognition and de-prioritization of collaborative efforts aimed at establishing an evidence-guided standard of care.

Undifferentiated Embryonal Sarcoma of the Liver With Rhabdoid Morphology Mimicking Carcinoma: Expanding the Morphologic Spectrum or a Distinct Variant?

Undifferentiated embryonal sarcoma of the liver (UESL) is a rare aggressive neoplasm that occurs predominantly in children. Like mesenchymal hamartoma of the liver (MHL), UESL harbors recurrent rearrangements involving 19q13.3 and 19q13.

Liver Pathology, Including MOC31 Immunohistochemistry, in Congenital Tufting Enteropathy.

Congenital tufting enteropathy (CTE) is a rare heritable cause of intractable diarrhea due to EPCAM mutation. Pathologic findings include intestinal villous atrophy, tufted discohesive tear-drop-shaped epithelium, and a normal brush border. In affected patients, absent intestinal epithelial cell adhesion molecule (EpCAM) expression results in loss of MOC31 immunostaining.

Desmoid tumors of the head and neck in the pediatric population: Has anything changed?

Introduction: Pediatric head and neck desmoid tumors are rare neoplasms that can cause significant morbidity due to infiltration of vital anatomic structures. The goal of this study is to review presentation, evaluation, and management of these tumors.

Methods: Retrospective study of children with head and neck desmoid tumors treated from 1999 to 2018 and literature review.

Ganglioneuromas are driven by activated AKT and can be therapeutically targeted with mTOR inhibitors.

Peripheral sympathetic nervous system tumors are the most common extracranial solid tumors of childhood and include neuroblastoma, ganglioneuroblastoma, and ganglioneuroma. Surgery is the only effective therapy for ganglioneuroma, which may be challenging due to the location of the tumor and involvement of surrounding structures. Thus, there is a need for well-tolerated presurgical therapies that could reduce the size and extent of ganglioneuroma and therefore limit surgical morbidity.

Making the most of small samples: Optimization of tissue allocation of pediatric solid tumors for clinical and research use.

Introduction: Tissue from pediatric solid tumors is in high demand for use in high-impact research studies, making the allocation of tissue from an anatomic pathology laboratory challenging. We designed, implemented, and assessed an interdepartmental process to optimize tissue allocation of pediatric solid tumors for both clinical care and research.

Methods: Oncologists, pathologists, surgeons, interventional radiologists, pathology technical staff, and clinical research coordinators participated in the workflow design.

LIN28B regulates transcription and potentiates MYCN-induced neuroblastoma through binding to ZNF143 at target gene promotors.

LIN28B is highly expressed in neuroblastoma and promotes tumorigenesis, at least, in part, through inhibition of microRNA biogenesis. Here, we report that overexpression of either wild-type (WT) LIN28B or a LIN28B mutant that is unable to inhibit processing increases the penetrance of MYCN-induced neuroblastoma, potentiates the invasion and migration of transformed sympathetic neuroblasts, and drives distant metastases in vivo. Genome-wide chromatin immunoprecipitation coupled with massively parallel DNA sequencing (ChIP-seq) and coimmunoprecipitation experiments show that LIN28B binds active gene promoters in neuroblastoma cells through protein-protein interaction with the sequence-specific zinc-finger transcription factor ZNF143 and activates the expression of downstream targets, including transcription factors forming the adrenergic core regulatory circuitry that controls the malignant cell state in neuroblastoma as well as and that are involved in neuronal cell adhesion and migration.

Imaging features of pathologically proven pediatric splenic masses.

Splenic masses present a diagnostic challenge to radiologists and clinicians alike, with a relative paucity of data correlating radiologic findings to pathological diagnosis in the pediatric population. To illustrate splenic mass imaging findings and approximate lesion prevalence, we retrospectively reviewed all splenectomies and splenic biopsies for splenic masses at a single academic pediatric hospital over a 10-year period in patients 18 years and younger. A total of 31 splenic masses were analyzed.