Congenital hyperinsulinism: current trends in diagnosis and therapy

Congenital hyperinsulinism (HI) is an inappropriate insulin secretion by the pancreatic β-cells secondary to various genetic disorders. The incidence is estimated at 1/50, 000 live births, but it may be as high as 1/2, 500 in countries with substantial consanguinity. Recurrent episodes of hyperinsulinemic hypoglycemia may expose to high risk of brain damage. Hypoglycemias are diagnosed because of seizures, a faint, or any other neurological symptom, in the neonatal period or later, usually within the first two years of life. After the neonatal period, the patient can present the typical clinical features of a hypoglycemia: pallor, sweat and tachycardia. HI is a heterogeneous disorder with two main clinically indistinguishable histopathological lesions: diffuse and focal. Atypical lesions are under characterization. Recessive ABCC8 mutations (encoding SUR1, subunit of a potassium channel) and, more rarely, recessive KCNJ11 (encoding Kir6.2, subunit of the same potassium channel) mutations, are responsible for most severe diazoxide-unresponsive HI. Focal HI, also diazoxide-unresponsive, is due to the combination of a paternally-inherited ABCC8 or KCNJ11 mutation and a paternal isodisomy of the 11p15 region, which is specific to the islets cells within the focal lesion. Genetics and 18F-fluoro-L-DOPA positron emission tomography (PET) help to diagnose diffuse or focal forms of HI. Hypoglycemias must be rapidly and intensively treated to prevent severe and irreversible brain damage. This includes a glucose load and/or a glucagon injection, at the time of hypoglycemia, to correct it. Then a treatment to prevent the recurrence of hypoglycemia must be set, which may include frequent and glucose-enriched feeding, diazoxide and octreotide. When medical and dietary therapies are ineffective, or when a focal HI is suspected, surgical treatment is required. Focal HI may be definitively cured when the partial pancreatectomy removes the whole lesion. By contrast, the long-term outcome of diffuse HI after subtotal pancreatectomy is characterized by a high risk of diabetes, but the time of its onset is hardly predictable

Carcinomes rénaux à stroma léiomyomateux et carcinomes papillaires à cellules claires (étude anatomo-pathologique et cytogénétique comparative de deux nouvelles entités de carcinomes à cellules rénales)

Le carcinome rénal à stroma léiomyomateux (CSL) est une nouvelle entité rare, méconnue, semblant se rapprocher du carcinome papillaire à cellules claires (CPCC), une autre entité récente. L objectif de notre travail a été de décrire et comparer une série de 15 cas de CSL à une série de 24 cas de CPCC. Les CSL et CPCC surviennent chez les sujets d âge moyen. Un contexte d insuffisance rénale chronique est plus fréquemment retrouvé dans les CPCC. Un contexte génétique différent a été identifié: une Sclérose tubéreuse de Bourneville dans 26% des cas de CSL et une maladie de Von Hippel Lindau dans 16% des CPCC. La taille des tumeurs n excède pas 5 cm. Un cas de métastase ganglionnaire a été identifié parmi les CSL. Sur le plan microscopique, l architecture est tubulo-papillaire. Les kystes sont plus fréquents dans les CPCC. Les ascensions nucléaires sont rares dans les CSL mais le grade nucléaire est plus élevé. L abondance du stroma musculaire lisse est une caractéristique des CSL. Les deux entités partagent une expression forte de la CK7 couplée à la négativité de la racémase. La CKHPM+ est positive et hétérogène dans les deux tumeurs. En revanche l expression du CD10 est plus discriminante avec 84% des CSL qui expriment le CD10 tandis que les CPCC restent majoritairement négatifs (62,5%). L étude en hybridation génomique comparative de 10 cas de CSL n a pas retrouvé d anomalies récurrentes, ni d anomalies sur les chromosomes 3p, 7 et 17. Notre étude a permis de souligner les points communs entre ces deux entités. L existence de contextes génétique différents incite à poursuivre les études moléculaires afin de déterminer d éventuels liens entre ces deux tumeurs rénales.PARIS6-Bibl.Pitié-Salpêtrie (751132101) / SudocSudocFranceF

The surgical management of atypical forms of congenital hyperinsulinism

Beyond the 2 classical forms of congenital hyperinsulinism, focal and diffuse, we report our experience on the surgical treatment of atypical forms. We define 2 subtypes among these atypical forms of hyperinsulinism: in case of a giant focal form the surgical strategy is the same as in focal forms. In case of hyperinsulinism caused by a mosaic, our experience suggests the benefit of a limited resection from the tail to the body of the pancreas. © 2011 Elsevier Inc

Le cancer du rein sporadique du sujet jeune : étude des particularités cliniques et anatomopathologiques d’une cohorte bicentrique

The epidemiology of kidney cancer is evolving with a net increase in the incidence of renal tumors, globally, and in young people in particular. OBJECTIVE: To evaluate the incidence and clinical and pathological characteristics of sporadic renal tumors in young subjects and their risk factors. MATERIAL AND METHODS: A retrospective study aimed at collecting clinical, epidemiological and anatomopathological information from the 118 patients aged 18 to 40 treated for a sporadic kidney tumor in two Parisian university hospital centers between 2003 and 2013. RESULTS: Our study showed a very significant increase in the incidence of renal tumors in our 11 years of decline (P=6.10-15). The mode of discovery also seems to have evolved with a majority of tumors (67 %), due to the considerable growth of imaging in recent decades. We also showed a different pathological distribution compared to the literature with a significant increase in the number of papillary tumors (16.9 %) and chromophobes (15.2 %), in addition to a decrease in the number of carcinomas (43.2 %) as well as the appearance of a new pathological entity of particular clinical severity: renal carcinoma related to translocation Xp11.2 (15.3 %) (P<10-5). Among the risk factors, hypertension seems to be a definite risk factor while tobacco and obesity do not have a significant influence. CONCLUSION: Our study showed a marked increase in the incidence of renal tumors with specific clinical and epidemiological features in a population of young subjects. The role and importance of oncogenetic management as well as the study of environmental factors could lead to the identification of new risk factors and corollary to their prevention

Unique Transcriptomic Profile of Collecting Duct Carcinomas Relative to Upper Tract Urothelial Carcinomas and other Kidney Carcinomas

International audienceCollecting duct carcinoma (CDC) is a kidney cancer subtype that is thought to arise from principal cells in distal parts of the collecting ducts. Some studies suggested an overlap of CDC with upper tract urothelial carcinoma (UTUC), making the pathological diagnosis challenging. Herein, we performed for the first time transcriptome sequencing of CDC and compared them to UTUC and renal cell carcinoma subtypes. We discovered that CDC displays a unique transcriptomic signature among kidney cancer subtypes, with a putative cell of origin in the distal convoluted tubules. Hierarchical unsupervised clustering reveals that the CDC signature is closer to that of other RCC subtypes than to UTUC, which is similar to that of bladder carcinoma. CDC is characterized by a metabolic shift, with impairment of oxidoreductase activity, pyruvate metabolism and the tricarboxlyic acid cycle, as well as an immunogenic response consistent with increased tumor infiltrating lymphocytes, particularly within metastatic cases. In addition, pathways differentially altered between CDC and UTUC point to a basal-like phenotype of CDC in contrast to the luminal-like signature of UTUC. We conclude that CDC harbors a pathognomonic transcriptomic signature characterized by immunogenic and a metabolic aberrations, indicating that targeting these processes might provide therapeutic options for patients

FGF10 Signaling differences between type I pleuropulmonary blastoma and congenital cystic adenomatoid malformation.

International audienceBACKGROUND: Type I pleuropulmonary blastoma (PPB) and congenital cystic adenomatoid malformation of the lung (CCAM) are cystic lung diseases of childhood. Their clinical and radiological presentations are often similar, and pathologic discrimination remains difficult in many cases. As a consequence, type I PPB and CCAM are frequently confused, leading to delayed adequate management for type I PPB. Recent studies have suggested a role for fibroblast growth factor (FGF) 10 signal pathway in CCAM pathogenesis. The objective of our study was to determine whether FGF10 signaling differs between CCAM and type I PPB. METHODS: Immunohistochemical studies were performed for expression of FGF10, its receptor FGFR2b, and its inhibitor sonic hedgehog (SHH) in focal type I PPB (n=6), CCAM type I (n=7), CCAM type II (n=7), and control lungs (n=5). RESULTS: FGF10, FGFR2b, and SHH expressions differed markedly between type I PPB and both types of CCAM. Type I and type II CCAM cystic walls expressed FGF10, FGFR2b, and SHH, whereas staining was absent or poor in type I PBB cystic walls. Expression of FGF10, FGFR2b, and SHH did not differ between CCAM cystic walls and control airway walls. CONCLUSIONS: These findings show that immunohistochemistry with FGF10, FGFR2b, or SHH could be useful in differentiating CCAM from type I PPB, when a child presents with a focal cystic lung lesion. The absence of strong expression of FGF10, FGFR2b, and/or SHH makes the diagnosis of CCAM very doubtful

MYO5B and BSEP contribute to cholestatic liver disorder in Microvillous Inclusion Disease.

International audience: Background and aims: Microvillous Inclusion Disease (MVID) is a congenital disorder of the enterocyte related to mutations in the MYO5B gene, leading to intractable diarrhea indicating intestinal transplantation (ITx). Among our cohort of 28 MVID patients, 8 developed a cholestatic liver disease akin to progressive familial intrahepatic cholestasis (PFIC). Our aim was to investigate the mechanisms by which MYO5B mutations affect hepatic biliary function and lead to cholestasis in MVID patients. Methods: Clinical, biological features and outcome were reviewed. Pre-transplant liver biopsies were analyzed by immunostaining and electron microscopy. Results: Cholestasis occurred before (n=5) or after (n=3) ITx and was characterized by intermittent jaundice, intractable pruritus, increased serum bile acid (BA) levels and normal gamma-glutamyl transpeptidase activity. Liver histology showed canalicular cholestasis, mild to moderate fibrosis and ultrastructural abnormalities of bile canaliculi. Portal fibrosis progressed in 5 patients. No mutation in ABCB11/BSEP or ATP8B1/FIC1 genes were identified. Immunohistochemical studies demonstrated abnormal cytoplasmic distribution of MYO5B, RAB11A and BSEP in hepatocytes. Interruption of enterohepatic BA cycling after partial external biliary diversion or graft removal proved the most effective to ensure long-term remission. Conclusion: MVID patients are at risk of developing a PFIC-like liver disease that may hamper outcome after ITx. Our results suggest that cholestasis in MVID patients results from: (i) impairment of the MYO5B/RAB11A apical recycling endosome pathway in hepatocytes (ii) altered targeting of BSEP to the canalicular membrane (iii) and increased ileal BA absorption. Because cholestasis worsens after ITx, indication of a combined liver-ITx should be discussed in MVID patients with severe cholestasis. Future studies will need to address more specifically the impact of MYO5B dysfunction in BA homeostasis. (Hepatology 2013;)