Normalization Time of Celiac Serology in Children on a Gluten-free Diet.

OBJECTIVES: Response to a gluten-free diet (GFD) in children with celiac disease is determined by symptom resolution and normalization of serology. We evaluated the rate of normalization of the transglutaminase (TTG) and antiendomysial (EMA) for children on a GFD after diagnosis. METHODS: Celiac serologies were obtained over 3.5 years after starting a GFD in 228 newly diagnosed children with biopsy-proven celiac disease. Patients were classified into categories based on serology (group A, TTG ≥10 × upper limit of normal [ULN] and EMA ≥ 1:80; group B, TTG ≥10 × ULN and EMA ≤ 1:40; and group C, TTG <10 × ULN) and by severity of histologic injury at diagnosis. RESULTS: In children with the highest serology at diagnosis (group A), 79.7% had an abnormal TTG at 12 months after diagnosis (mean TTG 12 months, 68.8 ±â€Š7.3, normal <20 kU/L). At 2 years, an abnormal TTG persisted in 41.7%. In contrast, only 35% of children with the lowest serology at diagnosis (group C) displayed an abnormal TTG at 12 months (mean TTG 14.3 ±â€Š1.9 kU/L). In those with the most severe mucosal injury, Marsh 3C, 74.2% and 33.2% had an abnormal TTG at 1 and 2 years. CONCLUSIONS: Normalization of celiac serology took >1 year in approximately 75% of GFD-compliant children with the highest celiac serology or most severe mucosal injury at diagnosis. Clinicians must consider serology and histology at diagnosis to properly evaluate response to GFD.

Evaluation of the ESPGHAN Celiac Guidelines in a North American Pediatric Population.

OBJECTIVES: We retrospectively examined the performance of the tissue transglutaminase (TTG), endomysial antibody (EMA) tests, and the ESPGHAN (European Society of Paediatric Gastroenterology, Hepatology and Nutrition) nonbiopsy criteria in a pediatric population. METHODS: Consecutive celiac serologies and corresponding intestinal biopsy results were obtained on children <18 years old over 3.5 years. Patients were classified into three categories: positive TTG, negative TTG, and IgA deficiency. RESULTS: Of the 17,505 patients with celiac serology performed, 775 had a positive TTG, 574 with a negative TTG were biopsied, and 25 were IgA deficient. Of the patients with a TTG ≥10 × upper limit of normal (ULN), positive EMA, and symptoms, 98.2% had biopsies consistent with celiac disease (CD). Four human leukocyte antigen (HLA) DQ2/DQ8-positive patients who met the ESPGHAN nonbiopsy criteria did not have CD. In the group with a TTG 3-10 × ULN, 75.7% EMA-positive patients and only 40% EMA-negative patients had CD (P<0.001). Of those with a TTG 1-3 × ULN, 52.2% EMA-positive patients vs. only 13.3% EMA-negative patients had CD (P<0.01). Of the patients with bulbar and duodenal biopsies, 9.8% had CD confined only in the bulb, especially those with a low titer TTG (P<0.01). CD prevalence in our cohort was 34.6%. Sensitivity, specificity, and positive predictive value of the TTG were 98.7%, 86.4%, and 79.4%, respectively. CONCLUSIONS: The TTG is a very sensitive screen for CD, but positive predictive value improves with a positive EMA titer. To apply the new ESPGHAN guidelines, clinicians must understand the performance of their celiac serology tests.

Congenital heart defects and major structural noncardiac anomalies in Alberta, Canada, 1995-2002.

BACKGROUND: Although the majority of congenital heart defects (CHDs) occur in isolation, a significant number occur with noncardiac anomalies. This study determined the proportion of noncardiac anomalies among CHD cases in Alberta. METHODS: Records of infants and children born in Alberta between January 1, 1995, to December 31, 2002, were searched using multiple sources of ascertainment in addition to the Alberta Congenital Anomalies Surveillance System (ACASS) (Alberta Health and Wellness, 2012). Each case was assigned to one CHD category and was further categorized into one of the following groups: isolated CHD, syndromes, chromosomal, associations and sequences, teratogens, Mendelian, neoplasia, heterotaxy, multiple minor anomalies, and multiple major anomalies. RESULTS: Of all 3751 CHD cases (prevalence 12.42/1000 total births: confidence interval, 12.03-12.83), 75% were isolated, 10% had a chromosomal etiology, and 9% had multiple major anomalies. All other categories accounted for <2% each. The most commonly associated major noncardiac anomalies were musculoskeletal (MSK) (24%) followed by anomalies of the urinary tract (14%), gastrointestinal system (GI) (11%), and central nervous system (CNS) (11%). CONCLUSIONS: This is both a population-based and clinical study using a classification scheme that could help to determine possible etiologic factors contributing to CHD. By eliminating known etiologies such as chromosomal and single gene, future studies can focus on the remainder to evaluate possible preventive measures. The most commonly associated major noncardiac anomalies involve the MSK system, followed by the urinary, GI, and CNS systems.

Folic acid fortification and the birth prevalence of congenital heart defect cases in Alberta, Canada.

BACKGROUND: Congenital heart defects (CHDs) are the most common type of congenital anomaly. The precise etiology is unknown and the development of successful primary prevention strategies is challenging. Folic acid may have a protective role; however published results have been inconsistent. This study examines the impact of mandatory folic acid fortification (FAF) on the prevalence of CHDs. METHODS: CHD cases were ascertained using the Alberta Congenital Anomalies Surveillance System, Pediatric Cardiology Clinics, Pathology, and hospital records. The birth prevalence and odds ratios (OR) of isolated CHD cases (i.e., without noncardiac anomalies) were calculated comparing pre-FAF (1995-1997) with post-FAF (1999-2002). RESULTS: The prevalence of isolated CHD cases remained relatively unchanged when pre-FAF (9.34, 95% confidence interval [CI] 8.79-9.92) was compared with post-FAF (9.41, 95% CI, 8.93-9.91). Left ventricular outflow tract obstruction (LVOTO) decreased post-FAF (OR, 0.76; 95% CI, 0.61-0.94). Coarctation of the aorta contributed to this decline (OR, 0.55; 95% CI, 0.32-0.92). Atrial septal defect (ASD) (OR, 1.42; 95% CI, 1.13-1.80) and ASD with ventricular septal defect (OR, 1.52; 95% CI, 1.10-2.10) increased post-FAF. The remaining types of CHDs were unchanged. CONCLUSION: FAF alone does not have an impact on the prevalence of CHDs as a group and the majority of selected types of CHDs in Alberta. The decrease in LVOTO, particularly coarctation of the aorta, may be due to FAF or other environmental factors. The increase in ASD and ASD with ventricular septal defect may reflect an increase in diagnosis and ascertainment.

Congenital heart defect case ascertainment by the Alberta Congenital Anomalies Surveillance System.

BACKGROUND: Congenital heart defects (CHDs) are the most common type of congenital anomaly, with a wide range of reported birth prevalence estimates. This quality assurance study describes CHD case ascertainment by the Alberta Congenital Anomalies Surveillance System (ACASS). METHODS: ACASS data for CHD cases were compared with additional sources including the two Pediatric Cardiology clinics in Alberta, the Alberta Children's Hospital Department of Pathology, and hospital records. Cases included live births, stillbirths, and fetal deaths at less than 20 weeks' gestation born in Alberta, Canada, between 1995 and 2002. The birth prevalence of cases and chi-square linear trend analyses were calculated for specific types of heart defects for the total study period. RESULTS: The ascertainment of CHD cases by ACASS was 45%. The total prevalence of CHD cases was 5.59 per 1000 total births (TBs; 95% confidence interval [CI], 5.32-5.86) when ACASS was the only data source and increased to 12.42 per 1000 TBs (95% CI, 12.03-12.83) when all data sources were used. Although the total prevalence of CHD cases remained stable during 1995 to 2002, the prevalence of atrial septal defect (ASD) and cases with an ASD and ventricular septal defect (VSD) significantly increased. The prevalence of left ventricular outflow tract obstruction cases significantly decreased during the study period. CONCLUSIONS: Pediatric cardiology clinics are worth including as additional ascertainment sources to contribute to more accurate prevalence estimates. The significant increases of ASD and cases with both an ASD and VSD may reflect differences in diagnostic and ascertainment practices.

Kabuki syndrome and Crohn disease in a child with familial hypocalciuric hypercalcemia.

BACKGROUND: Familial hypocalciuric hypercalcemia (FHH) results from a mutation of the calcium sensing receptor (CASR) gene and typically presents as asymptomatic hypercalcemia with inappropriately low urinary calcium excretion and normal or mildly elevated levels of parathyroid hormone. OBJECTIVE: To describe a case of FHH associated with Kabuki syndrome and Crohn disease. METHOD: Genomic DNA was screened for CASR mutations and a retrospective chart review was performed. RESULTS: Heterozygosity was observed in exon 3, which encodes a portion of the extra-cellular domain. Sequencing revealed a n.476T>G nucleotide transversion, predicting a non-conservative substitution of arginine for leucine at codon 159 (p.L159R). CONCLUSION: An association between Kabuki syndrome and autoimmune disease has been described in the literature, which may explain the connection between Kabuki syndrome and Crohn disease. However, it remains unclear if there is a link between FHH, Kabuki syndrome and Crohn disease in this case.

Motor neuron degeneration in a 20-week male fetus: spinal muscular atrophy type 0.

BACKGROUND: Neuropathological changes in degenerating motor neurons are well documented in the term neonate with spinal muscular atrophy, but not at midgestation. METHODS: Postmortem neuropathological examination was performed in a 20-week male fetus with a hypoplastic left cardiac anomaly. RESULTS: Selective degeneration of spinal and hypoglossal motor neurons was an incidental finding. Degenerating motor neurons were not immunoreactive with neuronal nuclear antigen (NeuN) or neuron-specific enolase (NSE), as were the normal motor neurons. Synaptophysin reactivity was reduced around the soma of degenerating normal motor neurons. Ubiquitin and tau were expressed in degenerating motor neurons. Gliosis, inflammation and microglial activation were lacking in the ventral horns of the spinal cord. Laryngeal striated muscle was unaltered for age. No cerebral malformations or hypoxic-ischaemic changes were found. CONCLUSION: This case represents an early motor neuronal degeneration and corresponds to the recently described "type 0" spinal muscular atrophy. Lack of contractures is attributed to the early fetal age, since most muscular growth occurs in the second half of gestation.

Comparison of Presentation, Course, and Outcome of Congenital and Acquired Cytomegalovirus Infection in Twins.

Background Cytomegalovirus (CMV) is one of the most common causes of serious viral intrauterine infections. It is universally distributed among the human population with an average incidence of 0.15 to 2%. Indeed, at least half of the women in the reproductive age have evidence of prior CMV infection. Epidemiology and Pathogenicity However, it is not a usual practice to screen asymptomatic pregnant woman or neonates for CMV. Even if a mother developed a primary CMV infection during pregnancy, up to 90% of the newborns with congenital CMV will be asymptomatic at the time of birth. Only 5 to 7% of the infected babies will be acutely symptomatic, and the typical clinical presentation includes intrauterine growth restriction, microcephaly, various cutaneous manifestations (including petechiae and purpura), hematological abnormalities (particularly resistant thrombocytopenia), hepatosplenomegaly, chorioretinitis, hepatitis, etc. In contrast, acquired CMV infection is extremely unlikely to cause any serious sequelae for the infant. Cases We present a case of congenital and acquired CMV infection in twins with a focus of dissimilarity in presentation, clinical course, and outcome.

Noonan syndrome in a premature infant with hypertrophic cardiomyopathy and death in infancy.

We report an extremely premature infant with Noonan syndrome who developed rapidly progressive obstructive hypertrophic cardiomyopathy, which contributed to the death of the infant. The complications of prematurity combined with progressive, severe hypertrophic cardiomyopathy associated with Noonan syndrome lead to a poor prognosis.

The pathology of rotavirus-associated deaths, using new molecular diagnostics.

Rotavirus, the most common cause of severe, dehydrating gastroenteritis among children worldwide, annually causes approximately 500,000 deaths among children aged <5 years. The primary site of rotavirus infection is the small intestine. Pathologic investigations of patients who died of rotavirus infection are limited to data from a few reported autopsies, and dehydration with electrolyte imbalance is believed to be the major cause of death. Several recent reports suggest that children who died during a rotavirus illness were viremic before death, because rotavirus was detected at several extraintestinal sites. We report 3 rotavirus-associated deaths among children, 2 of whom had evidence of rotavirus genome in extraintestinal tissues detected by use of novel molecular diagnostic methods. The part played by rotavirus in fatal cases is unclear and requires additional investigation of diarrhea-associated deaths, because a better understanding might alter the approach to treatment and the need for antiviral therapy.

Periostin is upregulated in coronary arteriopathy in Kawasaki disease and is a potential diagnostic biomarker.

Periostin was upregulated 11-fold in acute and chronic Kawasaki disease coronary arteries compared with controls (P = 0.003). Kawasaki disease patients had significantly elevated serum periostin values compared with febrile controls (P = 0.0086). There was no relationship between serum periostin values and age, gender or acute phase reactants; there was a relationship between serum periostin and maximal coronary artery Z scores that did not reach significance (P = 0.08). Periostin may prove to be useful as a component of a future diagnostic biomarker panel for Kawasaki Disease.

Fetal opercular cavernous angioma causing cerebral cleft: contralateral primitive vascular anomaly and subicular dysgenesis.

We describe a 22-week female fetus after pregnancy was terminated because of fetal magnetic resonance imaging showing a large left cerebral hemispheric cleft suggestive of porencephaly or schizencephaly. Postmortem examination revealed a large cavernous angioma of the left opercular region with evidence of previous hemorrhage and extensive cerebral infarction. In the right hemisphere, another vascular malformation within the frontal germinal matrix consisted of an aggregate of primitive vessels not yet canalized. Selective dysgenesis of the right subiculum also was demonstrated. This case illustrates not only a severe encephaloclastic effect of cavernous angioma in fetal brain but also the importance of fetal autopsy to help correlate and explain fetal neuroimaging. Potential future prenatal treatment of fetal angiomata requires precise in utero diagnosis.

Alpers syndrome: the natural history of a case highlighting neuroimaging, neuropathology, and fat metabolism.

Mitochondrial diseases are increasingly being recognized as causes of encephalopathy and intractable epilepsy. There is no gold-standard test for diagnosing mitochondrial disease, and the current diagnosis relies on establishing a consistent pattern of evidence from clinical data, neuroimaging, tissue biopsy, and biochemical, genetic, and other investigations. Experience in the diagnosis and treatment of patients with certain forms of mitochondrial disease, such as Alpers syndrome, is largely gained from case reports or small case series. The authors describe a case of Alpers syndrome due to POLG1 mutations, including serial neuroimaging and pathological investigations, to illustrate two main points: (1) Unique characteristics evident on serial diffusion-weighted imaging can be a valuable indicator of Alpers syndrome; and (2) abnormal lipid metabolism can be present in Alpers syndrome, which may need to be considered when using a ketogenic diet.

Subscapular tumoral calcinosis in a toddler: case report.

Tumoral calcinosis is uncommon in toddlers, and rare within the subscapular area. Although typically benign, tumoral calcinosis is often incorrectly diagnosed prior to biopsy. We present a case of subscapular tumoral calcinosis in a 16-month old girl and discuss the radiological findings on X-ray, ultrasound, computed tomography and magnetic resonance imaging, including the first description of T1-weighted post contrast imaging, which demonstrate the fibrotic components of tumoral calcinosis.

Three linked vasculopathic processes characterize Kawasaki disease: a light and transmission electron microscopic study.

BACKGROUND: Kawasaki disease is recognized as the most common cause of acquired heart disease in children in the developed world. Clinical, epidemiologic, and pathologic evidence supports an infectious agent, likely entering through the lung. Pathologic studies proposing an acute coronary arteritis followed by healing fail to account for the complex vasculopathy and clinical course. METHODOLOGY/PRINCIPAL FINDINGS: Specimens from 32 autopsies, 8 cardiac transplants, and an excised coronary aneurysm were studied by light (n=41) and transmission electron microscopy (n=7). Three characteristic vasculopathic processes were identified in coronary (CA) and non-coronary arteries: acute self-limited necrotizing arteritis (NA), subacute/chronic (SA/C) vasculitis, and luminal myofibroblastic proliferation (LMP). NA is a synchronous neutrophilic process of the endothelium, beginning and ending within the first two weeks of fever onset, and progressively destroying the wall into the adventitia causing saccular aneurysms, which can thrombose or rupture. SA/C vasculitis is an asynchronous process that can commence within the first two weeks onward, starting in the adventitia/perivascular tissue and variably inflaming/damaging the wall during progression to the lumen. Besides fusiform and saccular aneurysms that can thrombose, SA/C vasculitis likely causes the transition of medial and adventitial smooth muscle cells (SMC) into classic myofibroblasts, which combined with their matrix products and inflammation create progressive stenosing luminal lesions (SA/C-LMP). Remote LMP apparently results from circulating factors. Veins, pulmonary arteries, and aorta can develop subclinical SA/C vasculitis and SA/C-LMP, but not NA. The earliest death (day 10) had both CA SA/C vasculitis and SA/C-LMP, and an "eosinophilic-type" myocarditis. CONCLUSIONS/SIGNIFICANCE: NA is the only self-limiting process of the three, is responsible for the earliest morbidity/mortality, and is consistent with acute viral infection. SA/C vasculitis can begin as early as NA, but can occur/persist for months to years; LMP causes progressive arterial stenosis and thrombosis and is composed of unique SMC-derived pathologic myofibroblasts.

Synaptophysin immunoreactivity in the human hippocampus and neocortex from 6 to 41 weeks of gestation.

To assess the synaptic vesicle protein synaptophysin as a potential marker for maturation in the human fetal brain, synaptophysin immunoreactivity (sIR) was prospectively studied in postmortem sections of 162 normal human fetal and neonatal brains of both sexes from 6 to 41 weeks' gestational age. There was a consistent temporal and spatial pattern of sIR in the hippocampus and cerebral neocortex. In the rostral hippocampus, sIR was first apparent in the molecular zone of the dentate gyrus at 12 weeks, followed by CA2 at 14 weeks, CA3 and CA4 at 15 to 16 weeks, and CA1 at 19 weeks; it was incomplete until 26 weeks. In frontal neocortex, sIR developed in a laminar pattern above and below the cortical plate as early as 12 weeks, around Cajal-Retzius neurons of the molecular zone at 14 weeks, surrounding pyramidal neurons of Layers 5 and 6 at 16 weeks, and at the surface of neuronal somata in Layers 2 and 4 at 22 weeks. At 33 weeks, Layers 2 and 4 still had less sIR than other layers. Uniform sIR among all cortical layers was evident at 38 weeks. Ascending probable thalamocortical axons were reactive as early as 12 weeks and were best demonstrated by 26 weeks, after which increasing sIR in the neuropil diminished the contrast. The sIR was preserved for more than 96 hours postmortem, even in severely autolytic brains. We conclude that synaptophysin is a reliable marker in human fetal brain and that sIR provides the means for objective assessment of cerebral maturation in normal brains and to enable interpretation of abnormal synaptic patterns in pathological conditions.