Hereditary pancreatitis in children: surgical implications with special regard to genetic background.

PURPOSE: Hereditary pancreatitis (HP) is the primary etiology of chronic pancreatitis during childhood, progressing through recurrent episodes of acute pancreatitis and finally leading to pancreatic insufficiencies. Hereditary pancreatitis is because of mutations of the cationic trypsinogen (PRSS1) gene. Some other genes, such as SPINK1 or CFTR, have been associated with familial idiopathic chronic pancreatitis. The aim of our study was to clearly define diagnostic and therapeutic strategies for HP patients, through an analysis of our study group and a review of the literature. METHODS: All children admitted from 1995 to 2007 with a final diagnosis of hereditary pancreatitis were restrospectively included in the study. We analyzed all medical records with special attention given to cases involving genetic screening (PRSS1, SPINK1, and CFTR genes). RESULTS: Ten children were included. Eight had HP with PRSS1 mutation, 2 of them without a familial history of chronic pancreatitis. The 2 others patients had SPINK1 mutations. Three HP patients were operated on for acute complications of pancreatitis and are well with a mean follow-up of 5.5 years. No patient had pancreatic insufficiencies or weight loss. CONCLUSIONS: Hereditary pancreatitis is associated with severe pancreatitis, with a greater risk of developing pancreatic cancer. It must therefore be diagnosed correctly and treated to prevent its considerable complications

In-vivo retroviral gene transfer to the liver is cancelled by an immune response against the corrected cells. Can it be avoided?

Highly efficient retroviral-mediated gene transfer into hepatocytes in vivo has been previously reported in rats, but some reports described transient expression of the transgene that may be related to induction of an immune response against the transgene product. To devise a surgical approach to circumvent this drawback, two-thirds partial hepatectomy was performed in Wistar male rats to induce the hepatocyte division required to achieve retrovirus integration. Delivery of amphotrophic retroviral vectors (RVV) encoding Escherichia coli beta-galactosidase was performed 24 h after partial hepatectomy. In a first group (n = 11), gene delivery was performed by peripheral injection of 2 ml retrovirus-containing medium. For the second group (n = 11), asanguineous perfusion of the regenerating liver after complete vascular exclusion was carried out with 20 ml viral solution. Liver biopsies were performed sequentially in each group. In the first group, beta-galactosidase was expressed at day 7 in 7 +/- 6.3% of hepatocytes and the labeled hepatocytes had disappeared in less than 4 weeks. Polymerase chain reaction experiments demonstrated the elimination of the transduced cells and the appearance of antibodies against beta-galactosidase. Of the 11 rats in the second group, 8 were still able to express beta-galactosidase more than 6 weeks after asanguineous perfusion with no detectable antibody response. Asanguineous perfusion of the regenerating liver with RVV after complete vascular exclusion enabled long-term expression in rats and avoided the immune response present after peripheral delivery in most animals. These results suggest that the immune reaction is secondary to viral infection of antigen presenting cells. Asanguineous perfusion could thus be a way to perform gene therapy for inherited liver diseases without immunosuppressive therapy

Follow-up and surgical management of Peutz-Jeghers syndrome in children.

BACKGROUND: Peutz-Jeghers syndrome (PJS) is an autosomal dominant syndrome with an increased risk of polyposis complications and intestinal and extraintestinal tumours. METHODS: During the last 15 years, we reviewed a series of 11 children with PJS, with special attention to evolution and follow-up. Diagnosis was based on at least 1 hamartomatous polyp associated with 2 of the 3 following criteria: family record of PJS, polyposis localised on small bowel, and mucocutaneous pigmentation. Diagnosis of PJS also could be raised by a single genetic analysis of STK11 gene. RESULTS: Median age at beginning of symptoms was 6 years old. Seven of the 11 children had genetic tests, which were positive for STK11 gene mutation. Among the 10 children presenting with gastrointestinal complications, 8 were operated on, 6 had at least 1 small bowel resection, and 4 had repeat surgery for recurrent intussusceptions. In case of complications leading to a surgical procedure, we performed intraoperative enteroscopy to remove all large polyps. To prevent any polyposis complications, we suggest a complete check-up of polyposis topography with some of the new endoscopic tools, either double-balloon endoscopy or videocapsule endoscopy. CONCLUSIONS: Children with PJS have a high risk of numerous laparotomies due to polyps\u27 complications. Therefore, a screening of intestinal polyposis by videocapsule endoscopy is recommended, as well as a screening of the most frequent sites of cancers for the patient\u27s whole life. During any abdominal procedure, they should have an intraoperative endoscopy, this management allowing an increased time interval between 2 laparotomies

Disorders of sex development: insights from targeted gene sequencing of a large international patient cohort

BACKGROUND: Disorders of sex development (DSD) are congenital conditions in which chromosomal, gonadal, or phenotypic sex is atypical. Clinical management of DSD is often difficult and currently only 13% of patients receive an accurate clinical genetic diagnosis. To address this we have developed a massively parallel sequencing targeted DSD gene panel which allows us to sequence all 64 known diagnostic DSD genes and candidate genes simultaneously. RESULTS: We analyzed DNA from the largest reported international cohort of patients with DSD (278 patients with 46,XY DSD and 48 with 46,XX DSD). Our targeted gene panel compares favorably with other sequencing platforms. We found a total of 28 diagnostic genes that are implicated in DSD, highlighting the genetic spectrum of this disorder. Sequencing revealed 93 previously unreported DSD gene variants. Overall, we identified a likely genetic diagnosis in 43% of patients with 46,XY DSD. In patients with 46,XY disorders of androgen synthesis and action the genetic diagnosis rate reached 60%. Surprisingly, little difference in diagnostic rate was observed between singletons and trios. In many cases our findings are informative as to the likely cause of the DSD, which will facilitate clinical management. CONCLUSIONS: Our massively parallel sequencing targeted DSD gene panel represents an economical means of improving the genetic diagnostic capability for patients affected by DSD. Implementation of this panel in a large cohort of patients has expanded our understanding of the underlying genetic etiology of DSD. The inclusion of research candidate genes also provides an invaluable resource for future identification of novel genes.Stephanie Eggers ... Elizabeth M. Thompson, Jennifer Couper, Anne Baxendale, Jozef Gecz ... et al