Chantal Bernard

ARHGDIA: a novel gene implicated in nephrotic syndrome

Background Congenital nephrotic syndrome arises from a defect in the glomerular filtration barrier that permits the unrestricted passage of protein across the barrier, resulting in proteinuria, hypoalbuminaemia, and severe oedema. While most cases are due to mutations in one of five genes, in up to 15% of cases, a genetic cause is not identified. We investigated two sisters with a presumed recessive form of congenital nephrotic syndrome. Methods and results Whole exome sequencing identified five genes with diallelic mutations that were shared by the sisters, and Sanger sequencing revealed that ARHGDIA that encodes Rho GDP (guanosine diphosphate) dissociation inhibitor α (RhoGDIα, OMIM 601925) was the most likely candidate. Mice with targeted inactivation of ARHGDIA are known to develop severe proteinuria and nephrotic syndrome, therefore this gene was pursued in functional studies. The sisters harbour a homozygous in-frame deletion that is predicted to remove a highly conserved aspartic acid residue within the interface where the protein, RhoGDIα, interacts with the Rho family of small GTPases (c.553_555del(p.Asp185del)). Rho-GTPases are critical regulators of the actin cytoskeleton and when bound to RhoGDIα, they are sequestered in an inactive, cytosolic pool. In the mouse kidney, RhoGDIα was highly expressed in podocytes, a critical cell within the glomerular filtration barrier. When transfected in HEK293T cells, the mutant RhoGDIα was unable to bind to the Rho-GTPases, RhoA, Rac1, and Cdc42, unlike the wild-type construct. When RhoGDIα was knocked down in podocytes, RhoA, Rac1, and Cdc42 were hyperactivated and podocyte motility was impaired. The probands fibroblasts demonstrated mislocalisation of RhoGDIα to the nucleus, hyperactivation of the three Rho-GTPases, and impaired cell motility, suggesting that the in-frame deletion leads to a loss of function. Conclusions Mutations in ARHGDIA need to be considered in the aetiology of heritable forms of nephrotic syndrome.

Kawasaki disease complicated by renal artery stenosis

We report the case of a child who developed severe renovascular hypertension six months after acute Kawasaki disease. The hypertension was well controlled with enalapril, but there was a gradual decrease in function of the affected kidney. The lesion, an ostial stenosis of the right main renal artery, was not amenable to percutaneous balloon angioplasty, so was treated with bypass surgery. Vasculitis is an important cause of renovascular hypertension in children. This case highlights the importance of regular blood pressure monitoring in children with a history of systemic vasculitis.

Guidelines from the Canadian Association of Pathologists for establishing a telepathology service for anatomic pathology using whole-slide imaging.

The use of telepathology for clinical applications in Canada has steadily become more attractive over the last 10 years, driven largely by its potential to provide rapid pathology consulting services throughout the country regardless of the location of a particular institution. Based on this trend, the president of the Canadian Association of Pathologists asked a working group consisting of pathologists, technologists, and healthcare administrators from across Canada to oversee the development of guidelines to provide Canadian pathologists with basic information on how to implement and use this technology. The guidelines were systematically developed, based on available medical literature and the clinical experience of early adopters of telepathology in Canada. While there are many different modalities and applications of telepathology, this document focuses specifically on whole-slide imaging as applied to intraoperative pathology consultation (frozen section), primary diagnosis, expert or second opinions and quality assurance activities. Applications such as hematopathology, microbiology, tumour boards, education, research and technical and/or standard-related issues are not covered.

The pitfalls of endotracheal intubation beyond the fistula in babies with type C esophageal atresia

The intraoperative management of a neonate with esophageal atresia (EA) and distal tracheoesophageal fistula (TEF) is a true anesthetic challenge. Pediatric anesthesia textbooks recommend a distal tracheal intubation beyond the fistula and spontaneous ventilation, if possible, until surgical control of the fistula is achieved to minimize gastric distention. A full-term neonate with Trisomy 21 presented with an EATEF and was transferred to the operating theater for repair after appropriate evaluation. After induction of anesthesia, a size 3.0 endotracheal tube was inserted orally with confirmation of its position by good air entry and chest movement bilaterally. After positioning for thoracotomy, the patient desaturated and became bradycardic with abdominal distention. Despite reintubation, gastric needle decompression, and bilateral pleural aspiration to exclude pneumothorax, cardiopulmonary resuscitation was unsuccessful and the child died. Autopsy revealed the endotracheal tube in the trachea with its distal end passing through a large distal TEF. Preoperative bronchoscopy may help the team to assess the size and location of the distal TEF and plan for the best anesthetic strategy. It may also be useful to confirm tube location after endotracheal intubation and intraoperatively in the event of cardiorespiratory instability.

Cow's-milk-induced allergic colitis in an exclusively breast-fed infant: diagnosed with ultrasound

Background. An exclusively breast-fed 8-week-old boy presented with irritability and non-bilious projectile vomiting. He was referred to our Medical Imaging Department to eliminate pyloric stenosis.¶Patient and methods. A diagnosis of colitis was strongly suggested by ultrasound. A more detailed history revealed that the patient also had episodes of colicky pain and bloody stools. An infectious colitis was subsequently excluded and rectal biopsy supported the diagnosis of allergic proctocolitis.¶Results. The infant responded well to the withdrawal of cows milk and dairy products from the maternal diet.¶Conclusion. Allergic proctocolitis should be included in the differential diagnosis of infants presenting with vomiting and/or bloody stools.

Spindle epithelial tumor with thymus-like elements of the thyroid: a multi-institutional case series and review of the literature

BACKGROUND/PURPOSE Spindle epithelial tumor with thymus-like elements (SETTLE) is a rare tumor of the thyroid observed in children and adolescents. We present a case series of 3 patients with SETTLE, focusing on the clinical and pathologic features of this rare tumor. METHODS Three male patients presented at ages 4.5, 6.5, and 7 years with a right thyroid mass. All were treated by standard hemithyroidectomy. None had evidence of distant metastases at presentation. The diagnosis of SETTLE was confirmed at the time of the initial operation in 2 of the 3 patients. RESULTS All patients had uneventful postoperative courses. Two patients remain disease-free 4 and 7 years postresection, respectively. One patient presented 10 years after resection with shortness of breath and hemoptysis secondary to multiple bilateral parenchymal lung metastases. This patient received chemotherapy against the epithelial components of the tumor with a 25% response based on imaging studies. CONCLUSION Spindle epithelial tumor with thymus-like elements is rare tumor that should be suspected if spindle elements are observed in the resected thyroid specimen. Because these patients may present with delayed metastases, follow-up is recommended. However, chemotherapy against specific tumor elements is only marginally effective.

Symptomatic splenic hamartoma with renal, cutaneous, and hematological abnormalities.

Background. There is a rare association between splenic hamartomas and hematological abnormalities with, to our knowledge, only 24 reported cases in the English literature.¶Patients and methods. We report a case of a splenic hamartoma in a 14-year-old boy associated with membranoproliferative glomerulonephritis, multiple lobular capillary hemangiomas of the skin, hypertension, and anemia. Following imaging with ultrasonography, MRI, and nuclear scans, a hamartoma was suspected, but malignancy could not be excluded. The lesion was removed by partial splenectomy, and pathological examination confirmed the presence of a red pulp splenic hamartoma.¶Results. The renal, hematological, and dermatological abnormalities resolved following removal of the splenic hamartoma. This is the first reported case of a splenic hamartoma associated with renal, cutaneous, and hematological abnormalities and only the second reported case of a symptomatic splenic hamartoma treated by partial splenectomy.

Acute tubular dysfunction with Fanconi syndrome: a new manifestation of mitochondrial cytopathies.

S b es itochondrial diseases are a heterogeneous group of energy metabolism disorders hat can affect almost any organ. Kidney disease s well-known in patients with mitochondrial isorders, most commonly manifesting as proxial tubulopathy with chronic tubular acidosis, ypically a minor feature in pediatric patients ith severe involvement of brain, liver, heart, or ther organs. Other renal presentations inlude chronic tubulointerstitial nephropathy, rogressive glomerular diseases, and nephrotic yndrome. Acute, severe, and fluctuant tubular ysfunction has not been previously described.

Neonatal Hypoxic-Ischemic Injury: Sonography and Dynamic Color Doppler Sonography Perfusion of the Brain and Abdomen With Pathologic Correlation

OBJECTIVE The purpose of this article is to describe the role of cerebral and abdominal sonography with color Doppler sonography, including assessment of multiorgan tissue perfusion, in neonates with hypoxic-ischemic injury. CONCLUSION Bedside sonography and color Doppler sonography of the brain and abdominal organs can provide reliable and comprehensive information in asphyxiated neonates with hypoxic-ischemic injury. This article, which includes pathologic correlation, illustrates the major sonographic findings in this critical population.

High level of apoptosis and low AKT activation in mass screening as opposed to standard neuroblastoma

Sartelet H, Ohta S, Barrette S, Rougemont A‐Laure, Brevet M, Regairaz M, Harvey I, Bernard C, Fabre M, Gaboury L, Oligny L L, Bosq J, Valteau‐Couanet D & Vassal G
(2010) Histopathology56, 607–616