Subcutaneous nodules following vaccination.

Five patients presented to surgical clinics at our institution with subcutaneous nodules of the upper arm or thigh present for 6-18 months. Excisional or fine-needle biopsy was performed due to diagnostic uncertainty and parental concern. Histopathological examination revealed these to be cutaneous lymphoid hyperplasia in reaction to vaccine components. Nodular reactions with this histopathological pattern are well recognised within vaccine-related literature, but less commonly recognised in patients presenting to general paediatric or surgical clinics. This article reviews literature on delayed-onset nodule formation after vaccination and recommends observation and reassurance as mainstays of management of this largely benign entity.

Paternal mosaicism for a novel PBX1 mutation associated with recurrent perinatal death: Phenotypic expansion of the PBX1-related syndrome.

Autosomal dominant (de novo) mutations in PBX1 are known to cause congenital abnormalities of the kidney and urinary tract (CAKUT), with or without extra-renal abnormalities. Using trio exome sequencing, we identified a PBX1 p.(Arg107Trp) mutation in a deceased one-day-old neonate presenting with CAKUT, asplenia, and severe bilateral diaphragmatic thinning and eventration. Further investigation by droplet digital PCR revealed that the mutation had occurred post-zygotically in the father, with different variant allele frequencies of the mosaic PBX1 mutation in blood (10%) and sperm (20%). Interestingly, the father had subclinical hydronephrosis in childhood. With an expected recurrence risk of one in five, chorionic villus sampling and prenatal diagnosis for the PBX1 mutation identified recurrence in a subsequent pregnancy. The family opted to continue the pregnancy and the second affected sibling was stillborn at 35 weeks, presenting with similar severe bilateral diaphragmatic eventration, microsplenia, and complete sex reversal (46, XY female). This study highlights the importance of follow-up studies for presumed de novo and low-level mosaic variants and broadens the phenotypic spectrum of developmental abnormalities caused by PBX1 mutations.

Pseudodiastrophic dysplasia expands the known phenotypic spectrum of defects in proteoglycan biosynthesis.

BACKGROUND: Pseudodiastrophic dysplasia (PDD) is a severe skeletal dysplasia associated with prenatal manifestation and early lethality. Clinically, PDD is classified as a 'dysplasia with multiple joint dislocations'; however, the molecular aetiology of the disorder is currently unknown. METHODS: Whole exome sequencing (WES) was performed on three patients from two unrelated families, clinically diagnosed with PDD, in order to identify the underlying genetic cause. The functional effects of the identified variants were characterised using primary cells and human cell-based overexpression assays. RESULTS: WES resulted in the identification of biallelic variants in the established skeletal dysplasia genes, B3GAT3 (family 1) and CANT1 (family 2). Mutations in these genes have previously been reported to cause 'multiple joint dislocations, short stature, and craniofacial dysmorphism with or without congenital heart defects' ('JDSCD'; B3GAT3) and Desbuquois dysplasia 1 (CANT1), disorders in the same nosological group as PDD. Follow-up of the B3GAT3 variants demonstrated significantly reduced B3GAT3/GlcAT-I expression. Downstream in vitro functional analysis revealed abolished biosynthesis of glycosaminoglycan side chains on proteoglycans. Functional evaluation of the CANT1 variant showed impaired nucleotidase activity, which results in inhibition of glycosaminoglycan synthesis through accumulation of uridine diphosphate. CONCLUSION: For the families described in this study, the PDD phenotype was caused by mutations in the known skeletal dysplasia genes B3GAT3 and CANT1, demonstrating the advantage of genomic analyses in delineating the molecular diagnosis of skeletal dysplasias. This finding expands the phenotypic spectrum of B3GAT3-related and CANT1-related skeletal dysplasias to include PDD and highlights the significant phenotypic overlap of conditions within the proteoglycan biosynthesis pathway.

Paediatric acute lymphoblastic leukaemia causing acute leukaemic occlusion of the proximal middle cerebral artery: Treatment with endovascular thrombectomy.

Optimal treatment for ischaemic stroke in paediatric acute lymphoblastic leukaemia (ALL) is unclear. We describe an ischaemic stroke in an adolescent with ALL who underwent successful endovascular thrombectomy following leukaemic arterial occlusion. Endovascular thrombectomy should be considered in paediatric ALL patients with acute ischaemic stroke and large vessel occlusion.

Familial GATA6 mutation causing variably expressed diabetes mellitus and cardiac and renal abnormalities.

A 26-year-old man presented with a combination of permanent neonatal diabetes due to pancreatic aplasia, complex congenital heart disease, central hypogonadism and growth hormone deficiency, structural renal abnormalities with proteinuria, umbilical hernia, neurocognitive impairment and dysmorphic features. His older brother had diabetes mellitus due to pancreatic hypoplasia, complex congenital heart disease, hypospadias and umbilical hernia. Their father had an atrial septal defect, umbilical hernia and diabetes mellitus diagnosed incidentally in adulthood on employment screening. The proband's paternal grandmother had a congenital heart defect. Genetic testing of the proband revealed a novel heterozygous missense variant (Chr18:g.19761441T>C, c.1330T>C, p.Cys444Arg) in exon 4 of GATA6, which is class 5 (pathogenic) using American College of Medical Genetics and Genomics guidelines and is likely to account for his multisystem disorder. The same variant was detected in his brother and father, but not his paternal grandmother. This novel variant of GATA6 likely occurred de novo in the father with autosomal dominant inheritance in the proband and his brother. The case is exceptional as very few families with monogenic diabetes due to GATA6 mutations have been reported to date and we describe a new link between GATA6 and renal pathology. Learning points: Monogenic diabetes should be suspected in patients presenting with syndromic features, multisystem congenital disease, neonatal-onset diabetes and/or a suggestive family history. Recognition and identification of genetic diabetes may improve patient understanding and empowerment and allow for better tailored management. Identification of a genetic disorder may have important implications for family planning.

Retrospective analysis of South Australian pediatric oral and maxillofacial pathology over a 16-year period.

AIM: The epidemiological features and distribution of pediatric oral and maxillofacial pathology in South Australia, Australia, is unknown. The medical and dental specialties involved in the management of oral and maxillofacial pathology is also unknown. The aim of the present study was to audit oral and maxillofacial pathology specimens submitted for diagnosis in a pediatric tertiary-referral hospital setting. METHODS: Histopathology records were retrieved from the Women's and Children's Hospital, Adelaide over a 16-year period. Age, sex, histopathological diagnosis, location of the lesion, and department involved were recorded. Lesions were classified into 12 categories. RESULTS: A total of 676 lesions involving the oral and maxillofacial region were collected from patients aged 0-18 years. The mean age was 8.71 years. Diagnosis was not significantly associated with sex (P = 0.123). A total of 97.37% of cases were benign, with connective tissue and salivary gland lesions most frequently biopsied and more frequently biopsied by medical departments. Mucoceles (19.23%) were most commonly diagnosed, followed by dentigerous cysts (5.62%). The Department of Paediatric Dentistry submitted most specimens, followed by the Department of Otolaryngology, the Australian Craniofacial Unit, and the Departments of Paediatric Surgery and Plastics. CONCLUSION: The present study provides valuable understanding into the epidemiological features of, and the specialties involved in, oral and maxillofacial histopathology in an Australian pediatric population.

Histological analysis of 41 dentigerous cysts in a paediatric population.

BACKGROUND: Dentigerous cysts are usually of developmental nature but may be of inflammatory origin especially in paediatric populations. It is important to understand the histological features of dentigerous cysts to enable accurate diagnosis. The aim of this study is to present epidemiological, clinical features and histopathological features of dentigerous cysts seen in a paediatric tertiary referral hospital. METHOD: The medical, radiographic and histopathology records of the Department of Pathology, Women's and Children's Hospital, Adelaide, Australia, during January 1998 to December 2013 were reviewed for patients with dentigerous cysts. All cases were re-examined by a specialist oral pathologist, consultant paediatric pathologist and paediatric dentistry registrar. RESULTS: Forty-one cases of dentigerous cysts were found. Patients in the permanent dentition were most frequently affected. Male predilection was observed (male:female 2.42:1). The posterior mandible was the most frequently affected region (63.42%) although maxillary canines were the teeth most commonly associated with dentigerous cysts (29.27%). The majority of cases were incidental findings. Squamous epithelium showing pseudoepitheliomatous hyperplasia (46%) was frequently observed and was significantly present with thicker epithelium (P < 0.0001) and an acute and chronic inflammatory infiltrate (P < 0.001). Inflammatory infiltrate was seen in 75.6% of cases. CONCLUSIONS: The current study provides increased knowledge of the histological features of dentigerous cysts in a large retrospective series of paediatric patients and provides further evidence regarding the frequency of inflammatory dentigerous cysts.

Pemphigus Vulgaris and Eosinophilic Esophagitis in a 13-Year-Old Boy: Case Report and Review of the Literature.

This case report presents a 13-year-old boy referred to the Department of Paediatric Dentistry, Women's and Children's Hospital, Adelaide, South Australia, Australia, with a 5-week history of severe oral ulcerations and significant weight loss of unknown origin. The diagnosis of pemphigus vulgaris was made after histologic and immunofluorescent examination of an intraoral deep incisional biopsy, with eosinophilic esophagitis also diagnosed during the initial upper gastrointestinal endoscopy. The association between pemphigus vulgaris and eosinophilic esophagitis in this case, although previously unreported, is explicable on the basis of dysregulation of desmoglein 1 (DSG1). This case report identifies a new clinical association that could help clinicians identify further such cases and provides insight into the pathogenesis of both conditions.

Occult Adrenocortical Carcinoma and Unexpected Early Childhood Death.

A four-year-old previously well boy collapsed unexpectedly and was taken immediately to hospital, where he developed seizures and cardiogenic shock with lethal, rapidly progressing multi-organ failure. At autopsy, the height was >90th percentile and there were indications of early virilization. Internally, a friable tumor of the left adrenal gland was identified that had invaded the left renal vein and inferior vena cava. Histology revealed typical features of an adrenocortical carcinoma with aggregated trabeculae of cells containing abundant eosinophilic cytoplasm and large pleomorphic nuclei. There was strong positive cytoplasmic staining for inhibin; mitochondria were shown on electron microscopy to contain prominent electron-dense granules. Death was due to massive pulmonary tumor embolism. Although adrenocortical carcinomas are very rare and are more commonly found in adults, the current case demonstrates that they may also occur in childhood and be responsible for unexpected death by the very unusual mechanism of tumor embolism.

Recurrent chronic histiocytic intervillositis with intrauterine growth restriction, osteopenia, and fractures.

Chronic histiocytic intervillositis (CHI) is characterized by the presence of histiocytes within the intervillous space of the placenta. The pathogenesis is unclear but available evidence supports an alloimmune mechanism on the basis of the presence in maternal blood of HLA antibodies directed against paternal HLA antigens. CHI has a high risk of recurrence and of abnormal perinatal outcomes. Little is known about the effects of CHI on the developing fetus, in particular on the growth and development of the skeleton. We have studied a woman whose third pregnancy was terminated after ultrasonography showed severe intrauterine growth restriction, raising the possibility of a lethal skeletal dysplasia. Postmortem radiographs showed multiple fractures and other signs of osteogenesis imperfecta (OI). However, bone histology was not typical of OI and no abnormalities were identified by sequencing OI genes. The subsequent pregnancy was also severely growth restricted and was terminated. The placenta showed chronic histiocytic intervillositis, which, on retrospective review, had also been present in her second and third pregnancies. Her fifth pregnancy was again associated with intrauterine growth restriction and CHI but resulted in a premature birth. CHI can be associated with radiographic features that mimic OI and should be considered when fetal fractures occur in the context of recurrent miscarriage, fetal death in utero, and intrauterine growth restriction. The correct diagnosis can be made by histopathology of the placenta, supported by bone histology and normal results of molecular studies for OI. © 2016 Wiley Periodicals, Inc.

Renal tubular epithelial vacuoles-a marker for both hyperlipidemia and ketoacidosis at autopsy.

Review of 15 cases of nephrotic syndrome found that eight had significant hyperlipidemia with serum cholesterol levels ranging between 10.59 and 18.60 mmol/L (mean 12.88) and serum triglyceride levels between 2.30 and 9.92 mmol/L (mean 4.58); all of these cases displayed basal lipid vacuolization. Seven of the 15 study cases had normal-mild hyperlipidemia with serum cholesterol levels ranging between 4.71 and 7.54 mmol/L (mean 6.02) and serum triglyceride levels between 0.65 and 4.1 mmol/L (mean 1.57). Six of the seven cases had basal lipid vacuoles (86%). Of these, five cases were hyperlipidemic and one case had borderline hyperlipidemia with a serum cholesterol level of 4.71 mmol/L. Although hyperlipidemia was associated with renal tubular epithelial vacuolization, the vacuoles appeared morphologically different to those found in ketoacidosis. This study has shown that while hyperlipidemia in isolation may result in basal lipid vacuolization within renal tubular epithelial cells, the phenotype differs from that observed in ketoacidosis.

Two mature products of MIR-491 coordinate to suppress key cancer hallmarks in glioblastoma.

MIR-491 is commonly co-deleted with its adjacent CDKN2A on chromosome 9p21.3 in glioblastoma multiforme (GBM). However, it is not known whether deletion of MIR-491 is only a passenger event or has an important role. Small-RNA sequencing of samples from GBM patients demonstrated that both mature products of MIR-491 (miR-491-5p and -3p) are downregulated in tumors compared with the normal brain. The integration of GBM data from The Cancer Genome Atlas (TCGA), miRNA target prediction and reporter assays showed that miR-491-5p directly targets EGFR, CDK6 and Bcl-xL, whereas miR-491-3p targets IGFBP2 and CDK6. Functionally, miR-491-3p inhibited glioma cell invasion; overexpression of both miR-491-5p and -3p inhibited proliferation of glioma cell lines and impaired the propagation of glioma stem cells (GSCs), thereby prolonging survival of xenograft mice. Moreover, knockdown of miR-491-5p in primary Ink4a-Arf-null mouse glial progenitor cells exacerbated cell proliferation and invasion. Therefore, MIR-491 is a tumor suppressor gene that, by utilizing both mature forms, coordinately controls the key cancer hallmarks: proliferation, invasion and stem cell propagation.

Recalcitrant hypocalcaemia in autoimmune enteropathy.

Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy syndrome is a monogenic disorder associated with autoimmune destruction of both endocrine and nonendocrine tissues. The classic triad includes candidiasis, hypoparathyroidism, and Addison disease. Up to 25% of patients with autoimmune polyendocrinopathy candidiasis ectodermal dystrophy syndrome also have gastrointestinal manifestations, which can have an impact on the management of other aspects of the disease. The management of the case discussed was challenging because of the complex interplay between the manifestations and treatment of his hypoparathyroidism, Addison disease, and autoimmune enteropathy. Attempts at management of hypocalcemia were largely unsuccessful until the introduction of immunosuppressive therapy for autoimmune enteropathy. This case supports early consideration of immunosuppression in this condition.

Assessment of renal functional maturation and injury in preterm neonates during the first month of life.

Worldwide, approximately 10% of neonates are born preterm. The majority of preterm neonates are born when the kidneys are still developing; therefore, during the early postnatal period renal function is likely reflective of renal immaturity and/or injury. This study evaluated glomerular and tubular function and urinary neutrophil gelatinase-associated lipocalin (NGAL; a marker of renal injury) in preterm neonates during the first month of life. Preterm and term infants were recruited from Monash Newborn (neonatal intensive care unit at Monash Medical Centre) and Jesse McPherson Private Hospital, respectively. Infants were grouped according to gestational age at birth: ≤28 wk (n = 33), 29-31 wk (n = 44), 32-36 wk (n = 32), and term (≥37 wk (n = 22)). Measures of glomerular and tubular function were assessed on postnatal days 3-7, 14, 21, and 28. Glomerular and tubular function was significantly affected by gestational age at birth, as well as by postnatal age. By postnatal day 28, creatinine clearance remained significantly lower among preterm neonates compared with term infants; however, sodium excretion was not significantly different. Pathological proteinuria and high urinary NGAL levels were observed in a number of neonates, which may be indicative of renal injury; however, there was no correlation between the two markers. Findings suggest that neonatal renal function is predominantly influenced by renal maturity, and there was high capacity for postnatal tubular maturation among preterm neonates. There is insufficient evidence to suggest that urinary NGAL is a useful marker of renal injury in the preterm neonate.

Congenital cystic adenomatoid malformation with associated mucinous bronchioloalveolar carcinoma in a neonate.

Congenital cystic adenomatoid malformation (CCAM) of lung is a rare hamartomatous disorder characterized by abnormal branching morphogenesis of the lung. We report an unusual case of a 2-day-old male newborn with a pulmonary cystic lesion and lobectomy revealed a CCAM of the lung that has overlapping features of type 1 and type 2, complicating with multifocal mucinous bronchioloalveolar carcinoma (BAC). The case indicates that malignant transformation can occur in very early stage of the infancy in the patients with CCAM of lung.

IDH1/2 mutations target a key hallmark of cancer by deregulating cellular metabolism in glioma.

Isocitrate dehydrogenase (IDH) enzymes have recently become a focal point for research aimed at understanding the biology of glioma. IDH1 and IDH2 are mutated in 50%-80% of astrocytomas, oligodendrogliomas, oligoastrocytomas, and secondary glioblastomas but are seldom mutated in primary glioblastomas. Gliomas with IDH1/2 mutations always harbor other molecular aberrations, such as TP53 mutation or 1p/19q loss. IDH1 and IDH2 mutations may serve as prognostic factors because patients with an IDH-mutated glioma survive significantly longer than those with an IDH-wild-type tumor. However, the molecular pathogenic role of IDH1/2 mutations in the development of gliomas is unclear. The production of 2-hydroxyglutarate and enhanced NADP+ levels in tumor cells with mutant IDH1/2 suggest mechanisms through which these mutations contribute to tumorigenesis. Elucidating the pathogenesis of IDH mutations will improve understanding of the molecular mechanisms of gliomagenesis and may lead to development of a new molecular classification system and novel therapies.

When birth comes early: effects on nephrogenesis.

Preterm birth (birth prior to 37 completed weeks of gestation) may occur at a time when the infant kidney is very immature and nephrogenesis is often ongoing. In autopsied preterm human kidneys and in a baboon model of preterm birth it has been shown that nephrogenesis continues after preterm birth, with a significant increase in the number of glomerular generations and number of nephrons formed within the kidney after birth. Of concern, however, morphologically abnormal glomeruli (with a cystic Bowman's space) are often observed; the abnormal glomeruli are only located in the outer renal cortex, suggesting that it is the recently formed glomeruli (perhaps those formed in the extra-uterine environment) that are affected. The proportion of abnormal glomeruli within the renal cortex differs between infants with some kidneys appearing normal whereas others are severely affected. This suggests that it may be haemodynamic factors and/or factors in the neonatal care of the infant that lead to the glomerular abnormalities. Indeed, the haemodynamic transition at birth where there is a marked increase in systemic blood pressure and renal blood flow are likely to lead to injury of glomerular capillaries, although further studies are required to elucidate this. In order to optimize renal health at the beginning of life in the preterm infant, it is imperative in future studies to gain an understanding of the causes of the glomerular abnormalities in the preterm neonate.

Transcriptome and small RNA deep sequencing reveals deregulation of miRNA biogenesis in human glioma.

Altered expression of oncogenic and tumour-suppressing microRNAs (miRNAs) is widely associated with tumourigenesis. However, the regulatory mechanisms underlying these alterations are poorly understood. We sought to shed light on the deregulation of miRNA biogenesis promoting the aberrant miRNA expression profiles identified in these tumours. Using sequencing technology to perform both whole-transcriptome and small RNA sequencing of glioma patient samples, we examined precursor and mature miRNAs to directly evaluate the miRNA maturation process, and examined expression profiles for genes involved in the major steps of miRNA biogenesis. We found that ratios of mature to precursor forms of a large number of miRNAs increased with the progression from normal brain to low-grade and then to high-grade gliomas. The expression levels of genes involved in each of the three major steps of miRNA biogenesis (nuclear processing, nucleo-cytoplasmic transport, and cytoplasmic processing) were systematically altered in glioma tissues. Survival analysis of an independent data set demonstrated that the alteration of genes involved in miRNA maturation correlates with survival in glioma patients. Direct quantification of miRNA maturation with deep sequencing demonstrated that deregulation of the miRNA biogenesis pathway is a hallmark for glioma genesis and progression.