In Utero Enzyme-Replacement Therapy for Infantile-Onset Pompe's Disease.

Patients with early-onset lysosomal storage diseases are ideal candidates for prenatal therapy because organ damage starts in utero. We report the safety and efficacy results of in utero enzyme-replacement therapy (ERT) in a fetus with CRIM (cross-reactive immunologic material)-negative infantile-onset Pompe's disease. The family history was positive for infantile-onset Pompe's disease with cardiomyopathy in two previously affected deceased siblings. After receiving in utero ERT and standard postnatal therapy, the current patient had normal cardiac and age-appropriate motor function postnatally, was meeting developmental milestones, had normal biomarker levels, and was feeding and growing well at 13 months of age.

ALK-positive histiocytosis: a new clinicopathologic spectrum highlighting neurologic involvement and responses to ALK inhibition.

ALK-positive histiocytosis is a rare subtype of histiocytic neoplasm first described in 2008 in 3 infants with multisystemic disease involving the liver and hematopoietic system. This entity has subsequently been documented in case reports and series to occupy a wider clinicopathologic spectrum with recurrent KIF5B-ALK fusions. The full clinicopathologic and molecular spectra of ALK-positive histiocytosis remain, however, poorly characterized. Here, we describe the largest study of ALK-positive histiocytosis to date, with detailed clinicopathologic data of 39 cases, including 37 cases with confirmed ALK rearrangements. The clinical spectrum comprised distinct clinical phenotypic groups: infants with multisystemic disease with liver and hematopoietic involvement, as originally described (Group 1A: 6/39), other patients with multisystemic disease (Group 1B: 10/39), and patients with single-system disease (Group 2: 23/39). Nineteen patients of the entire cohort (49%) had neurologic involvement (7 and 12 from Groups 1B and 2, respectively). Histology included classic xanthogranuloma features in almost one-third of cases, whereas the majority displayed a more densely cellular, monomorphic appearance without lipidized histiocytes but sometimes more spindled or epithelioid morphology. Neoplastic histiocytes were positive for macrophage markers and often conferred strong expression of phosphorylated extracellular signal-regulated kinase, confirming MAPK pathway activation. KIF5B-ALK fusions were detected in 27 patients, whereas CLTC-ALK, TPM3-ALK, TFG-ALK, EML4-ALK, and DCTN1-ALK fusions were identified in single cases. Robust and durable responses were observed in 11/11 patients treated with ALK inhibition, 10 with neurologic involvement. This study presents the existing clinicopathologic and molecular landscape of ALK-positive histiocytosis and provides guidance for the clinical management of this emerging histiocytic entity.

Synoptic Reporting in Clinical Placental Pathology: A Preliminary Investigation Into Report Findings and Interobserver Agreement.

INTRODUCTION: Placental pathology is key for investigating adverse pregnancy outcomes, however, lack of standardization in reporting has limited clinical utility. We evaluated a novel placental pathology synoptic report, comparing its robustness to narrative reports, and assessed interobserver agreement. METHODS: 100 singleton placentas were included. Histology slides were examined by 2 senior perinatal pathologists and 2 pathology residents using a synoptic report (32 lesions). Historical narrative reports were compared to synoptic reports. Kappa scores were calculated for interobserver agreement between senior, resident, and senior vs resident pathologists. RESULTS: Synoptic reporting detected 169 (51.4%) lesion instances initially not included in historical reports. Amongst senior pathologists, 64% of all lesions examined demonstrated fair-to-excellent agreement (Kappa ≥0.41), with only 26% of Kappas ≥0.41 amongst those examined by resident pathologists. Well-characterized lesions (e.g., chorioamnionitis) demonstrated higher agreement, with lower agreement for uncommon lesions and those previously shown to have poor consensus. DISCUSSION: Synoptic reporting is one proposed method to address issues in placenta pathology reporting. The synoptic report generally identifies more lesions compared to the narrative report, however clinical significance remains unclear. Interobserver agreement is likely related to differential in experience. Further efforts to improve overall standardization of placenta pathology reporting are needed.

Evaluating the Prognostic Implication of the Collins Histology Scoring System in a Pediatric Eastern Ontario Population With Eosinophilic Esophagitis.

INTRODUCTION: Collins et al developed a histology scoring system (EoE HSS) to assess multiple pathologic features. The aim of this study is to identify if the EoE HSS can better detect endoscopic and symptom improvement vs the Peak Eosinophilic Count (PEC). METHODS: A retrospective chart review was performed for patients during 2014-2016. All patients ≤18 years old with a diagnosis of EoE and whose records included initial and follow-up upper gastrointestinal endoscopies were included. Severity and extent of endoscopic features were scored using 8 parameters, from normal to maximum change for each location of the esophageal biopsy. RESULTS: Forty patients with EoE were included in the study, of which 35 (87.5%) patients demonstrated symptom and 25 (62.5%) endoscopic improvement at the time of follow-up. In the proximal esophagus, the EoE HSS outperformed the change in eosinophil count of the Children's Hospital of Eastern Ontario (CHEO) practice in predicting endoscopic improvement by 16.8% when examining the change in grade and 17.1% when examining the change in stage scores. CONCLUSIONS: At our institution, adoption of the EoE HSS in assessing biopsies of EoE patients might be warranted, compared to the traditional practice. However, a bigger sample size may give a more robust difference in all locations.

Workload Measurement in Subspecialty Placental Pathology in Canada.

BACKGROUND: Workload measurement is important to help determine optimal staffing and workload distribution for pathology laboratories. The Level 4 Equivalent (L4E) System is the most widely used Anatomical Pathology (AP) workload measurement tool in Canada. However, it was initially not developed with subspecialties in mind. METHODS: In 2016, a Pan-Canadian Pediatric-Perinatal Pathology Workload Committee (PCPPPWC) was organized to adapt the L4E System to assess Pediatric-Perinatal Pathology workload. Four working groups were formed. The Placental Pathology Working Group was tasked to develop a scheme for fair valuation of placental specimens signed out by subspecialists in the context of the L4E System. Previous experience, informal time and motion studies, a survey of Canadian Pediatric-Perinatal Pathologists, and interviews of Pathologists' Assistants (PA) informed the development of such scheme. RESULTS: A workload measurement scheme with average L4E workload values for examination and reporting of singleton and multiple gestation placentas was proposed. The proposal was approved by the Canadian Association of Pathologist - Association canadienne des pathologistes Workload and Human Resources Committee for adoption into the L4E System. CONCLUSION: The development of a workload measurement model for placental specimens provides an average and fair valuation of these specimen types, enabling its use for resource planning and workload distribution.

An unusual case of pediatric embryonal rhabdomyosarcoma with subsequent diagnosis of neurofibromatosis type 1.

A 10-month-old girl presented with a 4-month history of a rapidly growing lesion on the lower lip. Initial assessment and Doppler ultrasound supported a diagnosis of pyogenic granuloma. However, emergent biopsy revealed an embryonal rhabdomyosarcoma, a highly malignant tumor commonly associated with cancer-susceptible syndromes including neurofibromatosis type 1 (NF1). Despite having no apparent clinical features of NF1 at initial presentation, she was later found to have multiple café-au-lait spots and a subsequent diagnosis of NF1 was made.

Porokeratotic eccrine ostial and dermal duct nevus associated with an 11 megabase 3p deletion.

Porokeratotic eccrine ostial and dermal duct nevus (PEODDN) is a rare eccrine hamartoma; the etiology is incompletely understood. A patient presented with congenital, widespread PEODDN. Clinical assessment, histopathologic, cytogenetic, and molecular genetic investigations on affected cells were pursued. Histopathology confirmed PEODDN, and chromosomal microarray on affected tissues identified a mosaic 3p26.3p25.3 deletion in affected tissues. This 11Mb deletion encompasses 47 OMIM genes. We propose that this and other chromosomal deletions may be implicated in some cases of PEODDN, suggesting locus heterogeneity and underscoring the importance of incorporating cytogenetic and molecular investigations into the multidisciplinary care of individuals with suspected mosaic genetic skin disorders.

Examining the Relationship Between Gastroschisis and Placental Fetal Vascular Malperfusion.

INTRODUCTION: Gastroschisis is a congenital malformation characterized by intestinal herniation through an abdominal wall defect. Despite its unknown pathogenesis, known risk factors include maternal smoking, alcohol use, and young maternal age. Previous work has shown that gastroschisis is associated with placental delayed villous maturation, and the goal of this study was to assess for additional associated placental pathologies that may help clarify the pathogenesis of gastroschisis. METHODS: We conducted a retrospective slide review of 29 placentas of neonates with gastroschisis. Additionally, we reviewed pathology reports from one control group of 30 placentas with other congenital malformations. Gross and histological data were collected based on a standardized rubric. RESULTS: Gastroschisis was associated with increased placental fetal vascular malperfusion (FVM) in 62% of cases (versus 0% of controls, p < 0.0001). It was also associated with increased placental villous maldevelopment in 76% of cases (versus 3% of controls, p < 0.0001). CONCLUSION: Our study demonstrates an association between gastroschisis and FVM. While FVM could be the consequence of vascular disruption due to the ventral location of gastroschisis, it could also reflect estrogen-induced thrombosis in early pregnancy. Further research is needed to separate these possibilities and determine the cause of the placental FVM observed in gastroschisis.

Risk of Lower Birth Weight and Shorter Gestation in Oocyte Donation Pregnancies Compared With Other Assisted Reproductive Technology Methods: Systematic Review.

OBJECTIVE: Oocyte donation (OD) is associated with an increased risk of pregnancy-induced hypertension, but the evidence of an association between OD and infant outcomes, including birth weight and gestational age, is conflicting. This study sought to determine the associations between oocyte donation and birth weight or gestational age compared with other forms of autologous oocyte assisted reproductive technology (ART). METHODS: Medline, Embase, and the CENTRAL Trials Registry of the Cochrane Collaboration were searched using a comprehensive search strategy. Studies of women over 24 weeks gestation compared infant outcomes among OD pregnancies versus other ART. Study quality was assessed, and a meta-analysis of mean birth weight and gestational age was conducted using a random effects model. RESULTS: Nineteen studies were included. Four studies showed a significant association between OD and lower birth weights, and five studies found significant differences in gestational age between OD and autologous oocyte ART. The pooled difference in birth weight means between OD and autologous ART was -42 (-88, 4) . The pooled difference in gestational age was -0.4 weeks (-0.8, 0.0 weeks). CONCLUSION: A high degree of interstudy heterogeneity exists, and the association between OD and infant outcomes remains unclear.

Early Onset Allergic Proctitis in a Preterm Neonate-A Case Report and Review of the Literature.

Cow's milk protein allergy/intolerance (CMPA/CMPI) is a common entity in the pediatric population with a nonspecific presentation ranging from gastrointestinal symptoms to systemic manifestations. Most infants with CMPI are term, and symptoms often appear in the week following the introduction of cow's milk-based formula. There is typically a significant delay in the onset of milk allergy in premature infants compared to full term. We report a rare case of a premature neonate who presented with symptoms of CMPA within the first 2 days of life.

Sclerosing Pneumocytoma of the Lungs Arising in a Child With PTEN Mutation.

We report a rare case of sclerosing pneumocytoma occurring in a child with PTEN mutation. A 13-year-old female presented to the emergency department of an adult hospital following 2 to 3 days of upper respiratory tract infection symptoms. A primary lung lesion was discovered during her initial chest X-ray to rule out pneumonia. The patient underwent an uneventful thoracoscopic right upper lobe segmentectomy. The pathology demonstrated a sclerosing pneumocytoma of the lung. She tested positive for PTEN hamartoma tumor syndrome with a pathogenic variant at c.388 C > T. The PTEN mutation was also identified in the sclerosing pneumocytoma. Further study of PTEN mutation in sclerosing pneumocytoma is warranted.

Atypical Hepatic Mesenchymal Hamartoma: Histologic Appearance, Immunophenotype, and Molecular Findings.

Hepatic mesenchymal hamartoma is a rare benign neoplasm principally encountered in young children. Its origin is unknown. We report an unusual hepatic mesenchymal hamartoma in a 7-month-old girl, including histopathologic findings, immunophenotype, and karyotype. Chromosomal microarray analysis of tumoral tissue and circulating lymphocytes found 4 copies of a segment at 1q44 and fluorescence in situ hybridization indicated tandem triplication, ascribed to expansion of a paternal tandem duplication. This genetic abnormality may have played a role in pathogenesis.

Intrauterine Interventions for the Treatment of Twin Anemia-Polycythemia Sequence: A Systematic Review.

BACKGROUND: Twin anemia-polycythemia sequence (TAPS) is a complication of monochorionic, multiple gestation pregnancies in which blood shunting through placental anastomoses results in chronic anemia in one fetus and chronic polycythemia in another. The outcomes of different treatment modalities for TAPS are not well known. OBJECTIVE: To determine the outcomes of the intrauterine interventions used to treat TAPS. STUDY DESIGN: A systematic literature search of MEDLINE, EMBASE, and CENTRAL was performed in June 2016. Primary outcomes were mortality, morbidity, and adverse perinatal outcomes. Data were summarized in the form of weighted means, and statistical difference was determined. RESULTS: Twenty-one articles were identified for inclusion in this review and were composed of 105 cases of TAPS. In the cases presented in the literature, there was no statistically significant difference in mortality, morbidity, or emergent Caesarean section rates between expectant management, intrauterine transfusion (IUT), and laser ablation therapy. Laser ablation therapy and IUT were found to have a significantly lower rate of adverse perinatal outcomes when compared to expectantly managed cases. CONCLUSIONS: The literature looking into the treatment of TAPS is very limited, with no randomized controlled trials and only one includable comparative study. Based on the data in the case report and case study literature, there is no mortality difference between any of the treatment modalities. Expectant management may be associated with an increase in adverse perinatal outcomes when compared to laser therapy and IUT. More comparative studies are needed to assist clinicians in adopting an evidence-based approach to the treatment of TAPS.

Investigating the link of ACAD10 deficiency to type 2 diabetes mellitus.

The Native American Pima population has the highest incidence of insulin resistance (IR) and type 2 diabetes mellitus (T2DM) of any reported population, but the pathophysiologic mechanism is unknown. Genetic studies in Pima Indians have linked acyl-CoA dehydrogenase 10 (ACAD10) gene polymorphisms, among others, to this predisposition. The gene codes for a protein with a C-terminus region that is structurally similar to members of a family of flavoenzymes-the acyl-CoA dehydrogenases (ACADs)-that catalyze α,ß-dehydrogenation reactions, including the first step in mitochondrial FAO (FAO), and intermediary reactions in amino acids catabolism. Dysregulation of FAO and an increase in plasma acylcarnitines are recognized as important in the pathophysiology of IR and T2DM. To investigate the deficiency of ACAD10 as a monogenic risk factor for T2DM in human, an Acad-deficient mouse was generated and characterized. The deficient mice exhibit an abnormal glucose tolerance test and elevated insulin levels. Blood acylcarnitine analysis shows an increase in long-chain species in the older mice. Nonspecific variable pattern of elevated short-terminal branch-chain acylcarnitines in a variety of tissues was also observed. Acad10 mice accumulate excess abdominal adipose tissue, develop an early inflammatory liver process, exhibit fasting rhabdomyolysis, and have abnormal skeletal muscle mitochondria. Our results identify Acad10 as a genetic determinant of T2DM in mice and provide a model to further investigate genetic determinants for insulin resistance in humans.

Dermal non-neural granular cell tumor in a 3-year-old child.

Dermal non-neural granular cell tumors, also known as primitive polypoid granular cell tumors, are a rare group of distinct cutaneous non-neural granular cell tumors. Pediatric cases are rare, and to the best of our knowledge, we report the youngest patient with dermal non-neural granular cell tumors.

Pediatric Blastic Plasmacytoid Dendritic Cell Neoplasm: A Systematic Literature Review.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare aggressive hematologic malignancy characterized by frequent skin involvement that most commonly affects older patients. BPDCN is known to have a poor prognosis. Our objective was to assess if outcome and disease prognosis were independently influenced by age when evaluated with clinical presentation, sex, and treatment regimens. We conducted a systematic review to identify BPDCN cases, to compare pediatric BPDCN cases with adult cases. A total of 125 publications were identified detailing 356 cases. Including 1 pediatric case from our institution, 74 were children, and 283 were adults aged 19 or over. Age was shown to be an independent prognostic factor predictive of more favorable outcomes across measures including initial response to therapy, likelihood of relapse, and overall survival at follow-up. The distribution of affected organs at diagnosis was similar across children and adults and type of clinical presentation did not disproportionately influence 1 age group's prognosis over the other. Acute lymphoblastic leukemia-type chemotherapy regimens were shown to be superior to other chemotherapy regimens (acute myeloid leukemia, lymphoma, acute lymphoblastic leukemia/lymphoma, other, or none) in inducing complete remission. Allogeneic stem cell transplantation was shown to increase mean survival time. Future research may be directed toward elucidating the further morphologic, cytogenetic, and cytochemical differences between younger and older BPDCN patients.

Oocyte donation pregnancies and the risk of preeclampsia or gestational hypertension: a systematic review and metaanalysis.

The purpose of this study was to determine whether pregnancies that were achieved via oocyte donation, compared with pregnancies achieved via other assisted reproductive technology methods or natural conception, demonstrate increased risk of preeclampsia or gestational hypertension. Comparative studies of pregnancies that were achieved with oocyte donation vs other methods of assisted reproductive technology or natural conception with preeclampsia or gestational hypertension were included as 1 of the measured outcomes. Abstracts and unpublished studies were excluded. Two reviewers independently selected studies, which were assessed for quality with the use of methodological index for non-randomized studies, and extracted the data. Statistical analysis was conducted. Of the 523 studies that were reviewed initially, 19 comparative studies met the predefined inclusion and exclusion criteria and were included in the metaanalysis, which allowed for analysis of a total of 86,515 pregnancies. Our pooled data demonstrated that the risk of preeclampsia is higher in oocyte-donation pregnancies compared with other methods of assisted reproductive technology (odds ratio, 2.54; 95% confidence interval, 1.98-3.24; P < .0001) or natural conception (odds ratio, 4.34; 95% confidence interval, 3.10-6.06; P < .0001). The risk of gestational hypertension was also increased significantly in oocyte donation pregnancies in comparison with other methods of assisted reproductive technology (odds ratio, 3.00; 95% confidence interval, 2.44-3.70; P < .0001) or natural conception (odds ratio, 7.94; 95% confidence interval, 1.73-36.36; P = .008). Subgroup analysis that was conducted for singleton and multiple gestations demonstrated a similar risk for preeclampsia and gestational hypertension in both singleton and multiple gestations. This metaanalysis provides further evidence that supports that egg donation increases the risk of preeclampsia and gestational hypertension compared with other assisted reproductive technology methods or natural conception.

Fetal segmental spinal dysgenesis and unusual segmental agenesis of the anterior spinal artery.

Segmental spinal dysgenesis (SSD) is a rare congenital spinal abnormality characterized by segmental dysgenesis or agenesis of the thoracolumbar or lumbar spine, congenital kyphosis, and abnormal configuration of the underlying spinal cord. A unique feature of SSD is that the vertebrae are present above and below the defect, and there is often a lower cord segment in the caudal spinal canal. We report a fetal MRI case of SSD with postmortem and neuropathological correlations. Our report confirms already published findings including the presence of a neurenteric cyst but is the first to document anterior spinal artery segmental agenesis in SSD.

Placental Pathology and Pregnancy Complications.

Placental pathology assessment following delivery provides an opportunity to identify the presence and type of disease that can mediate major obstetrical complications, especially in cases where the fetus is growth-restricted, born premature, or stillborn, or if the mother suffers from severe hypertensive morbidities [...].

Impact of villitis of unknown etiology and adverse acute neonatal outcomes in Eastern Ontario.

INTRODUCTION: Villitis of unknown etiology (VUE) is a histopathological lesion associated with adverse neonatal outcomes. We seek to define the obscure relationship between the severity and distribution of VUE and adverse neonatal outcomes. METHODS: A retrospective chart review was conducted of pathologic findings from singleton placentas diagnosed with VUE between 2013 and 2019. Control placentas were matched 1:1 for gestational age and presence/absence of fetal IUGR. Neonatal outcomes of interest included: newborn resuscitation, NICU admission, Apgar scores and cord blood acidosis. Odds ratio and 95 % confidence intervals were calculated with controls as the reference. RESULTS: 452 placentas were included. 35 % of pregnancies were complicated by IUGR. When analyzed by severity (low-grade: OR = 4.75 [2.86-8.14]; high-grade: OR = 4.76 [2.71-8.79]) and distribution (focal: OR = 5.24 [2.87-10.17]; multifocal: OR = 4.90 [2.90-8.59]), VUE was significantly associated with need for newborn resuscitation. No other neonatal outcomes of interest were significantly associated with VUE diagnosis. DISCUSSION: We determined a statistically significant association between VUE severity and distribution and the need for newborn resuscitation. VUE lesions were not associated with any additional neonatal outcomes of interest. Further studies with larger sample sizes are required to confirm these associations for obstetric and neonatal case management.