Clinical Features of Children With Serology Negative, Biopsy Positive Celiac Disease.

The prevalence of pediatric serological negative celiac disease (SNCD) is poorly described, with few recognized clinical predictors beyond immunoglobulin A (IgA) deficiency or reduced gluten intake. The purpose of this retrospective review was to describe the prevalence of SNCD at the Stollery Children's Hospital and identify clinical features to help in recognition of these cases. Patients with a positive biopsy and negative serology (SNCD) were compared to those with positive biopsy and serology. SNCD diagnosis required clinical correlation and either confirmatory genetics or follow up endoscopy on a gluten-free diet. Of the 424 patients who met celiac disease (CD) criteria, 4.7% (n = 20) fulfilled our criteria for SNCD. There was a significant difference in the rates of IgA deficiency between the 2 groups, but no other clinical features were found that allowed for ready identification of SNCD patients.

Mechanistic understanding of the combined immunodeficiency in complete human CARD11 deficiency.

BACKGROUND: Germline pathogenic variants impairing the caspase recruitment domain family member 11 (CARD11)-B cell chronic lymphocytic leukemia/lymphoma 10 (BCL10)-MALT1 paracaspase (MALT1) (CBM) complex are associated with diverse human diseases including combined immunodeficiency (CID), atopy, and lymphoproliferation. However, the impact of CARD11 deficiency on human B-cell development, signaling, and function is incompletely understood. OBJECTIVES: This study sought to determine the cellular, immunological, and biochemical basis of disease for 2 unrelated patients who presented with profound CID associated with viral and fungal respiratory infections, interstitial lung disease, and severe colitis. METHODS: Patients underwent next-generation sequencing, immunophenotyping by flow cytometry, signaling assays by immunoblot, and transcriptome profiling by RNA-sequencing. RESULTS: Both patients carried identical novel pathogenic biallelic loss-of-function variants in CARD11 (c.2509C>T; p.Arg837∗) leading to undetectable protein expression. This variant prevented CBM complex formation, severely impairing the activation of nuclear factor-κB, c-Jun N-terminal kinase, and MALT1 paracaspase activity in B and T cells. This functional defect resulted in a developmental block in B cells at the naive and type 1 transitional B-cell stage and impaired circulating T follicular helper cell (cTFH) development, which was associated with impaired antibody responses and absent germinal center structures on lymph node histology. Transcriptomics indicated that CARD11-dependent signaling is essential for immune signaling pathways involved in the development of these cells. Both patients underwent hematopoietic stem cell transplantations, which led to functional normalization. CONCLUSIONS: Complete human CARD11 deficiency causes profound CID by impairing naive/type 1 B-cell and cTFH cell development and abolishing activation of MALT1 paracaspase, NF-κB, and JNK activity. Hematopoietic stem cell transplantation functionally restores impaired signaling pathways.

Malignant Mesothelioma With EWSR1-ATF1 Fusion in Two Adolescent Male Patients.

Malignant mesothelioma is a neoplasm of serosal surfaces, most commonly affecting the pleura. The peritoneum, pericardium, and tunica vaginalis are less frequently involved. Malignant mesothelioma with EWSR1-ATF1 fusion in young adults was recently reported in the literature. Here, we present two pediatric cases of EWSR1-ATF1 translocation-associated malignant mesothelioma in the peritoneum and pericardium respectively. Both cases lacked a known exposure history. Microscopy in both cases showed predominantly epithelioid morphology with ample eosinophilic cytoplasm, and immunohistochemistry was positive for pan-keratin, calretinin, and WT1. Both cases showed EWSR1-ATF1 gene rearrangement by RNA sequencing, which was instrumental in confirming the diagnosis of malignant mesothelioma and to exclude more common pediatric sarcomas, especially in the context of limited sampling.

The novel p.Ser263Phe mutation in the human high-affinity choline transporter 1 (CHT1/SLC5A7) causes a lethal form of fetal akinesia syndrome.

A subset of a larger and heterogeneous class of disorders, the congenital myasthenic syndromes (CMS) are caused by pathogenic variants in genes encoding proteins that support the integrity and function of the neuromuscular junction (NMJ). A central component of the NMJ is the sodium-dependent high-affinity choline transporter 1 (CHT1), a solute carrier protein (gene symbol SLC5A7), responsible for the reuptake of choline into nerve termini has recently been implicated as one of several autosomal recessive causes of CMS. We report the identification and functional characterization of a novel pathogenic variant in SLC5A7, c.788C>T (p.Ser263Phe) in an El Salvadorian family with a lethal form of a congenital myasthenic syndrome characterized by fetal akinesia. This study expands the clinical phenotype and insight into a form of fetal akinesia related to CHT1 defects and proposes a genotype-phenotype correlation for the lethal form of SLC5A7-related disorder with potential implications for genetic counseling.

COQ4 mutations cause a broad spectrum of mitochondrial disorders associated with CoQ10 deficiency.

Primary coenzyme Q10 (CoQ10) deficiencies are rare, clinically heterogeneous disorders caused by mutations in several genes encoding proteins involved in CoQ10 biosynthesis. CoQ10 is an essential component of the electron transport chain (ETC), where it shuttles electrons from complex I or II to complex III. By whole-exome sequencing, we identified five individuals carrying biallelic mutations in COQ4. The precise function of human COQ4 is not known, but it seems to play a structural role in stabilizing a multiheteromeric complex that contains most of the CoQ10 biosynthetic enzymes. The clinical phenotypes of the five subjects varied widely, but four had a prenatal or perinatal onset with early fatal outcome. Two unrelated individuals presented with severe hypotonia, bradycardia, respiratory insufficiency, and heart failure; two sisters showed antenatal cerebellar hypoplasia, neonatal respiratory-distress syndrome, and epileptic encephalopathy. The fifth subject had an early-onset but slowly progressive clinical course dominated by neurological deterioration with hardly any involvement of other organs. All available specimens from affected subjects showed reduced amounts of CoQ10 and often displayed a decrease in CoQ10-dependent ETC complex activities. The pathogenic role of all identified mutations was experimentally validated in a recombinant yeast model; oxidative growth, strongly impaired in strains lacking COQ4, was corrected by expression of human wild-type COQ4 cDNA but failed to be corrected by expression of COQ4 cDNAs with any of the mutations identified in affected subjects. COQ4 mutations are responsible for early-onset mitochondrial diseases with heterogeneous clinical presentations and associated with CoQ10 deficiency.

Microscopic Polyangiitis with Spinal Cord Involvement: A Case Report and Review of the Literature.

BACKGROUND: Microscopic polyangiitis (MPA) is an ANCA-associated vasculitis (AAV; ANCA denotes antineutrophil cytoplasmic antibody) that causes necrotizing inflammation of small blood vessels. Renal and pulmonary manifestations are common whereas central nervous system (CNS) involvement, and in particular spinal disease, is rare. METHODS: We reviewed a case of MPA presenting with spinal intradural hemorrhage and intracerebral hemorrhage. We also summarized all reported cases of AAV with spinal cord involvement in the literature (database search included MEDLINE, Embase, Scopus, and Proquest with no date or language restriction). RESULTS: We reviewed 20 cases of AAV with spinal cord involvement (12 granulomatosis with polyangiitis [GPA], 4 eosinophilic granulomatosis with polyangiitis, 2 MPA, and 2 cases diagnosed as AAV only) and reported demographic information, clinical features, methods of diagnosis, treatment, and patient outcome. Although CNS involvement has been associated with a poor prognosis, 14 of 18 cases that reported outcome data achieved remission during follow-up. Death occurred in 3 patients diagnosed with GPA and in 1 patient with MPA. Our patient with MPA deteriorated rapidly despite use of prednisone and died. CONCLUSIONS: AAV can present with brain and spinal cord involvement, even in the absence of systemic disease. CNS disease may be responsive to immunosuppressive therapy (e.g., steroids and cyclophosphamide) in several of the cases reviewed.

Pulmonary interstitial glycogenosis associated with pulmonary hypertension and hypertrophic cardiomyopathy.

A neonate with pulmonary interstitial glycogenosis, pulmonary hypertension, and hypertrophic cardiomyopathy is described. The fatal outcome for this patient contrasts with the reported favorable prognosis associated with isolated pulmonary interstitial glycogenosis. To the authors' knowledge, the association of pulmonary interstitial glycogenosis and hypertrophic cardiomyopathy has not been reported previously. The authors have broadened the phenotype of pulmonary interstitial glycogenosis and demonstrate the diagnostic value of lung biopsy in cases of unexplained neonatal pulmonary hypertension.

Lafora Disease and Alpha-Synucleinopathy in Two Adult Free-Ranging Moose (Alces alces) Presenting with Signs of Blindness and Circling.

Lafora disease is an autosomal recessive glycogen-storage disorder resulting from an accumulation of toxic polyglucosan bodies (PGBs) in the central nervous system, which causes behavioral and neurologic symptoms in humans and other animals. In this case study, brains collected from two young adult free-ranging moose (Alces alces) cows that were seemingly blind and found walking in circles were examined by light and electron microscopy. Microscopic analysis of the hippocampus of the brain revealed inclusion bodies resembling PGBs in the neuronal perikaryon, neuronal processes, and neuropil. These round inclusions measuring up to 30 microns in diameter were predominantly confined to the hippocampus region of the brain in both animals. The inclusions tested α-synuclein-negative by immunohistochemistry, α-synuclein-positive with PAS, GMS, and Bielschowsky's staining; and diastase-resistant with central basophilic cores and faintly radiating peripheral lines. Ultrastructural examination of the affected areas of the hippocampus showed non-membrane-bound aggregates of asymmetrically branching filaments that bifurcated regularly, consistent with PGBs in both animals. Additionally, α-synuclein immunopositivity was noted in the different regions of the hippocampus with accumulations of small granules ultrastructurally distinct from PGBs and morphologically compatible with alpha-synucleinopathy (Lewy body). The apparent blindness found in these moose could be related to an injury associated with secondary bacterial invasion; however, an accumulation of neurotoxicants (PGBs and α-synuclein) in retinal ganglions cells could also be the cause. This is the first report demonstrating Lafora disease with concurrent alpha-synucleinopathy (Lewy body neuropathy) in a non-domesticated animal.

The role of histopathology in diagnosing protracted diarrhea of infancy.

Protracted diarrhea is used to describe infants with loose and frequent stools of sufficient severity to require nutritional support, most commonly parenteral nutrition. Despite similar clinical presentations, the causes of protracted diarrhea in infants are varied and diverse in management and prognosis. The following cases represent the two more common causes of protracted diarrhea in young infants in the developed world - allergic and autoimmune enteropathy. Both patients demonstrate diagnostic challenges related to clinical and/or laboratory features. These cases illustrate the important role histological assessment plays in determining the correct diagnosis, treatment course and prognosis in infants with protracted diarrhea.

Duodenal Bulb Histology in Paediatric Celiac Disease: A Case-Control Study.

BACKGROUND: Controversy exists about optimal methods for duodenal biopsy in diagnosis of celiac disease (CD), in terms of both number of samples and anatomic location. The reliability of duodenal bulb biopsy has been questioned given that normal bulb architecture may mimic disease. However, multiple studies have reported patients with CD have histopathological lesions limited to proximal changes in the duodenal bulb alone. METHODS: We retrospectively compared duodenal and duodenal bulb histology in a population of paediatric patients with CD and compared with a population of nonceliac controls at Stollery Children's Hospital, 2010 to 2012. RESULTS: Fifty-seven paediatric patients diagnosed with CD and 16 nonceliac controls were included in the study. Fifty-three celiac patients (93.0%) had histopathology consistent with CD (modified Marsh score of 3A, 3B or 3C) in the duodenal bulb. The modified Marsh classification differed significantly between duodenum and duodenal bulb in nine celiac patients (15.8%). Of these, five (8.8%) had Marsh 3 in the bulb and Marsh 0 in the distal duodenum. Among controls, no patients had villous atrophy in either the distal duodenum or duodenal bulb, and all patients had a modified Marsh score of 0 at both sites. CONCLUSIONS: The results of this study reinforce that duodenal bulb samples are critically important for diagnosing CD in paediatric patients. We suggest that duodenal bulb samples be submitted in separate containers from distal duodenal samples to facilitate accurate interpretation. In contrast to prior reports, we found villous blunting and intraepithelial lymphocytosis are actually uncommon findings in paediatric patients with nonceliac gastrointestinal disorders.

Left hypoplastic lung and hemoptysis-rare familial unilateral pulmonary vein atresia.

Unilateral pulmonary vein atresia (UPVA) is a rare congenital vascular malformation with obliteration of the pulmonary vein. We present a case series of three siblings with variable presentation of UPVA. We suggest a dominant genetic cause based on different paternity. Identifying genetic etiology would contribute to early diagnosis and screening.

Esophageal mucoceles causing airway obstruction as a complication of esophageal diversion: two rare pediatric cases and a review of the literature.

An esophageal mucocele causing airway obstruction is an exceptionally rare complication of esophageal diversion in children. In this instance, they are fluid-filled dilatations of the esophageal remnant following bipolar exclusion of the thoracic esophagus. Only six pediatric cases have been reported previously in the literature. We present two consecutive cases of esophageal mucoceles causing respiratory distress in children following surgical exclusion of the esophagus. Bronchoscopy followed by imaging (computerized tomography or magnetic resonance imaging) was used to reach the diagnosis. Complete resection of the thoracic esophagus was required in both patients. Esophageal mucoceles can occur many years after esophageal exclusion, and the clinical features are often non-specific. Furthermore, complex co-morbidities may mask the underlying etiology of the respiratory distress, thus the diagnosis may be difficult to delineate. A high degree of suspicion, clinical awareness, and the use of the proper diagnostic tools, are essential for a diagnosis of mucoceles in children with a past history of esophageal exclusion.

GNE Myopathy With Novel Mutations and Pronounced Paraspinal Muscle Atrophy.

GNE myopathy is characterized by distal muscle weakness, and caused by recessive mutations in GNE. Its onset is characteristically in young adulthood, although a broad spectrum of onset age is known to exist. A large number of mutations in GNE are pathogenic and this clinical phenotype can be difficult to differentiate clinically from other late-onset myopathies. We describe two families with novel mutations in GNE, and describe their clinical and MRI features. We also describe the presence of striking paraspinal muscle involvement on MRI of the lumbar spine, which is an under-recognized feature of GNE myopathy.

A duplication of the mouth associated with a dysontogenic cyst: a case report and discussion of theories of origin.

IMPORTANCE Diprosopus is a medical condition that refers to full or partial craniofacial duplication. A particular subset of this condition, duplication of the mouth, is an exceedingly rare condition, with 7 reported cases in the medical literature. The embryogenesis and mechanism of disease are not well understood. The objective of this report was to describe a case of partial facial duplication with a discussion of the previous literature, leading to a proposed theory of embryogenesis for this rare anomaly. OBSERVATIONS We present a rare case of duplication of the mouth associated with an intraoral dysontogenic cyst, which presented with upper airway obstruction. The diagnostic and management strategies are discussed, as well as the histopathological features and theories of embryogenesis. CONCLUSIONS AND RELEVANCE On the basis of our findings, we propose the mechanism of origin for duplication of the mouth to be duplication of the first branchial arch. This case offers a deeper understanding of the mechanism of this disease than previously reported. Additional basic science and clinical research is needed to corroborate this theory.

Immunohistochemical expression of endothelial nitric oxide synthase and C-kit in the placenta of complete hydatidiform mole.

Complete hydatidiform mole is an abnormal conceptus characterized by hydropic villi accompanied by proliferating trophoblasts. Its pathogenesis is largely unknown. Endothelial nitric oxide synthase is induced by vascular endothelial growth factor and has been implicated in the pathogenesis of preeclampsia and other physiologic conditions in the placenta. C-kit is the tyrosine kinase receptor and is involved in tumor formation elsewhere in the body. Using standard immunohistochemical protocols, we studied the expression of C-kit and endothelial nitric oxide synthase in the placenta of 10 patients with complete hydatidiform mole. Cytoplasmic and nuclear staining with endothelial nitric oxide synthase was identified in the cytotrophoblast and intermediate trophoblast layers in all cases, with high staining in 7/10 and 6/8 cases, respectively. Minimal staining is identified in the syncytiotrophoblast layer. Hofbauer stromal cells were identified in 9 cases and showed low staining intensity in 7/9 cases. Cytoplasmic C-kit staining was diffuse and of low intensity. The cytotrophoblast, the syncytiotrophoblast, intermediate trophoblast, and the stromal cells had low C-kit staining intensity in 8/10, 8/10, 7/9, and 5/9 cases. These results indicate that C-kit and endothelial nitric oxide are expressed in the placentas of complete hydatidiform mole and may play a role in the pathogenesis of trophoblastic proliferation in this condition.

Familial gigantiform cementoma with brittle bone disease, pathologic fractures, and osteosarcoma: a possible explanation of an ancient mystery.

We describe four individuals of an African-American family with a predominantly diaphyseal bone disease associated with familial gigantiform cementoma (FGC), a disorder typically seen in Caucasians. The mother and her children presented with deformities of the jaws, abnormalities of the long bones, and pre-pubertal pathologic fractures. The index patient carried the diagnosis of osteosarcoma (OS). In addition, we provide a possible explanation for the jaw abnormalities of King Tutankhamen's father in the 18th dynasty in Egypt around 1350 BC.

Expression of c-kit in Ewing family of tumors: a comparison of different immunohistochemical protocols.

Ewing sarcoma is a small round blue cell tumor with a high incidence of metastasis and poor survival. The tyrosine kinase receptor, c-kit, is a growth factor receptor that is expressed in a variety of tumors including Ewing sarcoma. Blockade of c-kit by imatinib mesylate (Gleevec; Novartis Pharmaceuticals Corp, East Hanover, NJ) has been successfully used in the treatment of chronic myelogenous leukemia and gastrointestinal tumors. Detection of c-kit expression in Ewing sarcoma indicates a possible role of c-kit in tumor progression and a potential use of anti-c-kit therapy in Ewing sarcoma. Ki-67 is a proliferation marker found at all stages of the cell cycle. Expression of c-kit and Ki-67 was studied in 17 patients with Ewing sarcoma. Sections from paraffin-embedded tumor samples were immunostained, using standard immunohistochemical protocols, with c-kit and Ki-67 monoclonal antibodies, polyclonal c-kit antibody without antigen retrieval, and c-kit polyclonal antibody with antigen retrieval. Eleven out of 17 cases (65%) stained with c-kit monoclonal antibody; the staining was diffuse in 6/17 (35%) cases. C-kit expression did not correlate with Ki-67 proliferation rates. Using the polyclonal c-kit-antibody without antigen retrieval methods, c-kit expression was demonstrated in 1/11 (9%) cases. Incorporating antigen retrieval methods, c-kit expression increased to 53%. Concordance between monoclonal antibodies in detecting c-kit expression was observed in 12/17 cases (71%). We conclude that c-kit is variably expressed in Ewing sarcoma, using either monoclonal or polyclonal antibodies. Detection of c-kit expression in Ewing sarcoma improves with the use of antigen retrieval methods.

Clinico-pathologic conference: 18-month old boy with fever and severe respiratory infection.

An 18-month-old boy with severe combined immunodeficiency (SCID) due to an IL2-y-receptor defect had a successful engraftment following a related mismatched allogenic bone transplant. He subsequently developed post-transplantation lymphoproliferative disorder, with severe respiratory infection which resulted in death. The case presentation is followed by a discussion with differential diagnosis of the clinical findings, and then by a discussion of the pathology found and the implications of this diagnosis.