Peutz-Jeghers syndrome is caused by mutations in a novel serine threonine kinase.

Peutz-Jeghers (PJ) syndrome is an autosomal-dominant disorder characterized by melanocytic macules of the lips, multiple gastrointestinal hamartomatous polyps and an increased risk for various neoplasms, including gastrointestinal cancer. The PJ gene was recently mapped to chromosome 19p13.3 by linkage analysis, with the highest lod score at marker D19S886. In a distance of 190 kb proximal to D19S886, we identified and characterized a novel human gene encoding the serine threonine kinase STK11. In a three-generation PJ family, we found an STK11 allele with a deletion of exons 4 and 5 and an inversion of exons 6 and 7 segregating with the disease. Sequence analysis of STK11 exons in four unrelated PJ patients has identified three nonsense and one acceptor splice site mutations. All five germline mutations are predicted to disrupt the function of the kinase domain. We conclude that germline mutations in STK11, probably in conjunction with acquired genetic defects of the second allele in somatic cells, cause the manifestations of PJ syndrome.

Typical signs of acute appendicitis in ultrasonography mimicked by other diseases?

BACKGROUND: The diagnosis of acute appendicitis in pediatric patients is difficult. There are patients with positive ultrasonography without clinical or histological confirmation of acute appendicitis. It is essential to recognise these patients to avoid unnecessary surgery. METHODS: During 1 year, we compared the patients with 'false-positive' ultrasonography with those with 'true-positive' and those with 'true-negative' ultrasonography. RESULTS: Eighty-two patients were admitted to our inpatient ward for suspected appendicitis. Ultrasonography was performed on 68 patients. In sixteen cases, the ultrasonography showed typical signs of acute appendicitis though the patients turned out to be negative for acute appendicitis either by an observation period (n = 13) or by negative histology (n = 3). We could not find any significant differences between the groups in terms of age, gender or laboratory inflammation markers, though the latter tended to be elevated in patients with confirmed appendicitis. CONCLUSIONS: There are patients with clearly visible typical signs of acute appendicitis that do not need surgery and cannot be distinguished from others by age, gender or laboratory values. In conclusion, the clinical presentation still is the determining indicator for need of surgery. The underlying cause of the visible changes of the appendiceal area remains unclear, but there are several presumptions.

High proportion of large genomic deletions and a genotype phenotype update in 80 unrelated families with juvenile polyposis syndrome.

BACKGROUND: In patients with juvenile polyposis syndrome (JPS) the frequency of large genomic deletions in the SMAD4 and BMPR1A genes was unknown. METHODS: Mutation and phenotype analysis was used in 80 unrelated patients of whom 65 met the clinical criteria for JPS (typical JPS) and 15 were suspected to have JPS. RESULTS: By direct sequencing of the two genes, point mutations were identified in 30 patients (46% of typical JPS). Using MLPA, large genomic deletions were found in 14% of all patients with typical JPS (six deletions in SMAD4 and three deletions in BMPR1A). Mutation analysis of the PTEN gene in the remaining 41 mutation negative cases uncovered a point mutation in two patients (5%). SMAD4 mutation carriers had a significantly higher frequency of gastric polyposis (73%) than did patients with BMPR1A mutations (8%) (p<0.001); all seven cases of gastric cancer occurred in families with SMAD4 mutations. SMAD4 mutation carriers with gastric polyps were significantly older at gastroscopy than those without (p<0.001). In 22% of the 23 unrelated SMAD4 mutation carriers, hereditary hemorrhagic telangiectasia (HHT) was also diagnosed clinically. The documented histologic findings encompassed a wide distribution of different polyp types, comparable with that described in hereditary mixed polyposis syndromes (HMPS). CONCLUSIONS: Screening for large deletions raised the mutation detection rate to 60% in the 65 patients with typical JPS. A strong genotype-phenotype correlation for gastric polyposis, gastric cancer, and HHT was identified, which should have implications for counselling and surveillance. Histopathological results in hamartomatous polyposis syndromes must be critically interpreted.

Chance fracture--a rare injury in pediatric patients?

We report on a 9-year-old girl who was involved in a car accident. She suffered severe polytrauma with torn abdominal muscles, rupture of the mesenteric arteries, bowel and bladder, hematoma at the right colonic flexure and disruption of the intervertebral ligaments L2/L3, including the intervertebral disc, typical of Chance fracture. The abdominal bleeding was stopped, the bowel resected and the fracture fixed by internal fixation. The patient developed a postoperative enterocutaneous fistula in the right flank and paraplegia. She underwent three laparotomies with ileostomy and closure of the fistula. Two years later, she has normal bowel movement, the wounds are closed, the internal fixation has been removed, she is able to walk with crutches and suffers from a mild bladder dysfunction. Chance fracture is a typical fracture in adults involved in motor vehicle accidents. In the last 10 years, there have only been four case reports describing this fracture in children under the age of 10. All of these individuals were involved in a car accident and had been fixed with a lap belt. With the increasing use of lap belts, this fracture has to be considered even in young children. Mild clinical symptoms can be associated with severe intra-abdominal injuries.

Experience of 49 longitudinal intestinal lengthening procedures for short bowel syndrome.

PATIENTS, METHODS AND RESULTS: Forty-nine patients with a mean age of 25 months underwent a longitudinal intestinal lengthening procedure for short bowel syndrome (SBS) in our institution. Indications for the operation were dependence on parenteral nutrition in spite of adequate conservative management. The small bowel was lengthened from a mean of 27 cm to a mean of 51 cm. There was no intraoperative mortality. The following early complications occurred in our early series: ischemia of a short bowel segment of 2 cm, requiring resection in two patients, insufficiency of the longitudinal anastomosis in two patients and an intra-abdominal abscess in one. Four of 9 non-survivors died of liver failure and 3 of sepsis. Follow-up showed that 19 patients were weaned from parenteral nutrition after a mean of 9.1 months. Long-term complications encountered were dismotility with malabsorption due to bacterial overgrowth caused by progressive dilatation of the bowel, d-lactic acidosis, cholelithiasis and urolithiasis. CONCLUSIONS: A longitudinal intestinal lengthening procedure is an effective and safe surgical approach for SBS, provided it is performed in time, the patient's preoperative condition is optimized and technical surgical details are taken into account.

Switching CAR T cells on and off: a novel modular platform for retargeting of T cells to AML blasts.

The adoptive transfer of CD19-specific chimeric antigen receptor engineered T cells (CAR T cells) resulted in encouraging clinical trials in indolent B-cell malignancies. However, they also show the limitations of this fascinating technology: CAR T cells can lead to even life-threatening off-tumor, on-target side effects if CAR T cells crossreact with healthy tissues. Here, we describe a novel modular universal CAR platform technology termed UniCAR that reduces the risk of on-target side effects by a rapid and reversible control of CAR T-cell reactivity. The UniCAR system consists of two components: (1) a CAR for an inert manipulation of T cells and (2) specific targeting modules (TMs) for redirecting UniCAR T cells in an individualized time- and target-dependent manner. UniCAR T cells can be armed against different tumor targets simply by replacement of the respective TM for (1) targeting more than one antigen simultaneously or subsequently to enhance efficacy and (2) reducing the risk for development of antigen-loss tumor variants under treatment. Here we provide 'proof of concept' for retargeting of UniCAR T cells to CD33- and/or CD123-positive acute myeloid leukemia blasts in vitro and in vivo.

Immunolocalization of beta catenin in intestinal polyps of Peutz-Jeghers and juvenile polyposis syndromes.

AIM: To examine the membranous and nuclear distribution of beta catenin in the epithelial cells of gut polyps from Peutz-Jeghers syndrome and juvenile polyposis in comparison with other types of polyps and tumours. METHODS: Immunohistochemistry for beta catenin and proliferation markers was performed on conventional paraffin sections. Immunohistological staining was carried out on Peutz-Jeghers syndrome polyps from four different families, on juvenile polyposis polyps from two different families, on solitary juvenile polyps, and on hyperplastic polyps. The immunohistochemistry was evaluated qualitatively in relation to defined areas of the polyps. RESULTS: All polyps from the hamartomatous polyposis syndromes (Peutz-Jeghers syndrome and juvenile polyposis) showed nuclear localization of beta catenin in some epithelial cell nuclei. In Peutz-Jeghers syndrome polyps beta catenin positive nuclei were seen at the base of the deep crypt infoldings. In juvenile polyposis polyps and in some solitary juvenile polyps they were found in irregularly distributed cryptal epithelial cells corresponding to the proliferative compartments. Normal mucosa of the gut and hyperplastic polyps of the colon do not show nuclear staining for beta catenin. CONCLUSIONS: The dysregulation of cellular beta catenin distribution is not only a phenomenon of adenoma formation and adenoma progression in the colon--it is at least focally present in polyps of the hamartomatous type and is related to the proliferation zones of these polyps. The nuclear translocation of beta catenin most probably reflects a disturbed beta catenin metabolism. In view of the different functions of beta catenin during development and cell differentiation, the nuclear translocation of beta catenin is likely to be an important factor in enhanced cell proliferation which escapes local control mechanisms.

Polyvinylchloride infusion lines expose infants to large amounts of toxic plasticizers.

PURPOSE: The purpose of this study was to evaluate whether infusion lines are able to leach plasticizers in substantial amounts and thus be a candidate substance for hepatotoxic effects during long-term total parenteral nutrition (TPN). METHODS: TPN solutions, blood products, and selected drugs typical for preterm infants concerning amount, content, and infusion time were perfused through common polyvinylchloride (PVC) infusion lines. Concentration of diethylhexyl-phthalate (DEHP) before and after perfusion was determined by gas chromatography/mass spectrometry. RESULTS: Daily quantities of DEHP by 24-hour infusions were Lipid emulsion 20%: 10185.6 microg; aminoacid/glucose-solution: 116.2 microg; midazolaminfusion for sedation: 26.4 microg; fentanyl for sedation: 132.5 microg; propofol for sedation: 6561.0 microg. The amount of DEHP by single doses of blood products (20 mL) were packed red blood cells: 144-608 microg; platelet rich plasma: 928 microg; and fresh frozen plasma: 552-8108 microg. The dose of DEHP for a typical preterm neonate requiring TPN and additional therapy like sedation or blood products is at minimum 10 mg and can easily reach 20 mg/d. CONCLUSION: This large amount of DEHP is especially disturbing, because it effects the most vulnerable patients (neonates). Whether there is a relation to TPN-induced hepatobiliary dysfunction remains to be elucidated and is under investigation. With respect to recent literature, a biological effect of these doses must be assumed.

Long-term total parenteral nutrition-induced hepatobiliary dysfunction in a rabbit model.

BACKGROUND/PURPOSE: Currently, the reason for hepatobiliary dysfunction associated with long-term total parenteral nutrition (TPN) is much debated and still unclear. No agreement can be achieved about whether bacteriotoxins and sepsis, enteral starvation, consequences of abdominal operations, or the TPN solution itself is the real cause for the disease. Animal models were criticized for their short period of TPN and their failure to demonstrate cholestasis and bile duct proliferation. The aim of this study was to establish an animal model for long-term TPN in which the same alterations of the hepatobiliary system as observed in humans could be produced. METHODS: In this model, rabbits could be kept for the first time under continuous TPN for 4 weeks. Three serial liver biopsy sections were taken operatively from each animal and biochemical analyses were performed four times. A control group of enterally fed rabbits underwent exactly the same procedure in respect to operations and handling, so that differences in macroscopical, biochemical, and histological changes between both groups could be attributed exclusively to TPN. RESULTS: Only in the TPN group gallbladder distension developed in all animals after 1 week. After 3 and 4 weeks, viscous dark bile, sludge and stones, a slight rise in direct bilirubin, and a decline in plasma albumin and alkaline phosphatase was noted. In both groups liver biopsy results showed a similar degree of mild portal inflammation and single-cell necrosis at equivalent time points. These changes could be caused by antiseptics, antibiotics, anesthesia, and operations. Although mild to moderate proliferative changes and no hydropic degeneration developed in the control group during the same time, the TPN group generated marked proliferative and degenerative changes. We noted as early as 1 week after starting TPN a severe hydropic degeneration in 90% of the animals. Fibrosis and bile duct proliferation increased from a slight degree after 1 week up to a moderate to severe degree after 3 and 4 weeks, respectively. CONCLUSIONS: The hepatobiliary alterations associated with TPN in children, which cannot be separated clinically from consequences of multiple other factors, can almost identically be reproduced in our rabbit model as a clear consequence of TPN. Furthermore, the hydropic degeneration of the liver cells begins in zone 3 and is an early predominant feature of hepatobiliary dysfunction in rabbits and infants. It must be rated as a response to a direct cytotoxic effect on the liver cell.

Is there a correlation between organochlorine compounds and undescended testes?

Some pesticides and synthetic chemicals are known to act as hormonal modulators, often possessing oestrogenic activity (xenooestrogens). They are persistent and accumulate in fatty tissue. Aim of our study is to address the question, whether a selection of such compounds is to be found in the fatty tissue of children undergoing surgical procedures and whether there are differences in values obtained from patients with or without undescended testes. Fat samples of 48 patients, 18 of whom had undescended testes, were examined by high-resolution gas chromatography and mass spectrometry for DDT and metabolites, polychlorinated biphenyls (PCB), toxaphenes, hexachlorocyclohexane (HCH), chlorinated cyclodienes and chlorinated benzenes. We were able to find accumulation of all substances in every patient. Statistical analysis revealed a highly significant difference between patients from the control group and those from the undescended testes group for two compounds, namely heptachloroepoxide (HCE) and hexachlorobenzene (HCB), increased values being found in the patients with undescended testes. Since the aetiology of this entity is unknown in most of the cases, prenatal exposure to exogenous oestrogens is an attractive and plausible hypothesis. In order to confirm this, some questions will have to be answered in further studies: effect of exposure to xenooestrogens during a specific period of development, probable role of other substances with proven or suspected hormonal activity, potential synergism of such compounds and differences in individual susceptibility.

[Overflow incontinence--a rare manifestation of Peutz-Jeghers syndrome]. / Uberlaufinkontinenz--seltene Erscheinungsform des Peutz-Jeghers-Syndroms.

We present the case of a 12-year-old girl with Peutz-Jeghers syndrome (PJS). Enormous polyps of the transverse colon intussuscepting into the rectum turned out to be the rate cause of overflow incontinence. Although she presented all the signs of PJS at infancy, diagnosis was made only after a period of nine years, implying a lack of follow-up. We emphasize that when polyps occur in children, a complete examination is required, and once the diagnosis of Peutz-Jeghers syndrome is established, frequent endoscopic follow-up and resection of polyps are necessary.

Transanal pull-through procedure for Hirschsprung's disease: a 5-year experience.

BACKGROUND/PURPOSE: Transanal endorectal pull-through (TEPT) has become a widely used approach for the treatment of Hirschsprung's Disease. The technique is safe and, according to previous reports, it has a good clinical outcome. In this study our experience with TEPT in the early postoperative period is evaluated. METHODS: The clinical course of 34 children (28 boys and 6 girls) who underwent one-stage pull-through operation according to De la Torre for Hirschsprung's disease from January 2003 to December 2007 was reviewed. Their ages ranged from 2 months to 4 years. Complications occurring within the first four weeks after operation were analyzed. RESULTS: Eight of 34 children (24 %) had early complications in the form of dehiscences of the anastomosis. Two children (6 %) had symptomatic anastomotic dehiscences. One child had an almost full retraction of the colon that had to be pulled down and resutured. One child developed a retrorectal abscess three weeks postoperatively due to anastomotic leakage. The dehiscences of 6 children (18 %) were asymptomatic. These dehiscences were detected only with standardized routine examination. The dehiscences healed uneventfully after resuturing. Two other patients (6 %) developed an anastomotic stricture that could be treated with rectal dilatations. Four children (12 %) showed a single episode of postoperative enterocolitis. CONCLUSION: The rate of early clinical and particularly subclinical complications such as anastomotic dehiscences after TEPT is higher than previously estimated. Patients should be monitored carefully during the early postoperative period. Severe complications can only be avoided with a thorough examination. Early resuturing of dehiscences might be helpful to prevent hazardous sequelae.

Double ileoileal intussusception caused by a giant polypoid mass of heterotopic pancreas in a child.

UNLABELLED: Heterotopic pancreatic tissue has been found in several abdominal and intrathoracic locations. In the ileum, it is a rare, usually asymptomatic, incidental finding. CONCLUSION: A unique case of a recurrent ileoileal intussusception in an 11-year-old girl is presented caused by a giant polypoid mass composed of ectopic pancreatic tissue that remained undetected during several diagnostic tests during two previous admissions and laparoscopic abdominal exploration.

Coincidence of congenital cystic adenomatoid malformation and extralobar sequestration of the lung in a newborn.

We present a rare case of coincidence of an extralobar sequestration with a congenital cystic adenomatoid malformation of the lung in a newborn. The symptoms, diagnostic features, and therapy are described and the etiology and classification are briefly discussed.

[Peutz-Jeghers syndrome. Cases at the Mannheim clinic over 25 years]. / Peutz-Jeghers-Syndrom. Beobachtungen am Klinikum Mannheim über 25 Jahre.

Observations in our clinic and others reviewed in the literature result in a new picture of the Peutz-Jeghers syndrome. It turns out to be a hereditary polypose syndrome which is hard to define. The tendency to malignant degeneration of polyps and development of associated neoplasms is almost impossible to forecast. In addition operations frequently involve complications and often need to be repeated more than once. Radical removal of all polyps must be the aim of treatment; the patients must then be closely followed up by clinical examination, endoscopy and radiology to avoid complications of regrowth and to make sure degeneration and associated neoplasms are detected at an early stage.

Large, septated ileal duplication cyst in a 4-year old, simulating the urinary bladder.

A 4-year-old boy presented with acute abdominal pain and a 1-year history of intermittent umbilical complaints. Ultrasonographic examination demonstrated a large cyst in the lower abdomen divided by a thin membrane. With micturition, impaired bladder function was expected. Initial suprapubic drainage produced 1,000 ml dark-brown liquid. Laparotomy revealed an ileal duplication cyst. Preoperative computed tomography and laparoscopy with the cyst drained did not further clarify the diagnosis.

[Value of anorectal manometry in assessment of constipation in childhood]. / Stellenwert der anorektalen Manometrie bei der Abklärung der Obstipation im Kindesalter.

We studied retrospectively 210 anorectal manometries of constipated children. Of the 87 patients with an anal fissure or a functional constipation, 83 had normal sphincter relaxation. All of the 23 patients with Hirschsprung's disease lacked the sphincter relaxation, as well as 22 of the patients with a dysganglionosis. Eleven patients with innervation defects showed pathologic sphincter contractions. Anorectal manometry is a valuable tool to differentiate between innervation defects and constipation of other etiologies.

Long-term total parenteral nutrition and cholecystostomy tube in a rabbit model surgical procedure: management and preliminary results.

A rabbit model for long-term total parenteral nutrition (TPN), specially provided with cholecystostomy tube, was designed to investigate further aspects of TPN-associated cholestasis (TPN-AC). Modified surgical procedures concerning vascular access, cholecystostomy tube implantation and authors' original modalities for prolonged infusion management in the rabbit were used. Continuous TPN was performed in 30 young rabbits. Five animals died during the experiment (16.6%) and were excluded from final evaluation. Twenty-five rabbits were successfully maintained on continuous TPN for 28 days without restraint, having a cholecystostomy tube implanted 1 week after initiation of TPN. The collection of blood samples and daily parenteral administration of drugs were simply accomplished via a central venous catheter. At the same time the cholecystostomy tube enabled us to perform daily bile sampling. Saline irrigation of the biliary tree could be carried out in conscious animals maintained on TPN. A 4-week duration of TPN in this rabbit model made it possible for the first time to accomplish serial liver biopsies in order to verify the evolution of histologic changes in TPN-related hepatic dysfunction and possible effects of surgical and medical treatment. A preliminary analysis of operative findings and histology was carried out. An enlarged gallbladder containing hyperviscous bile was found in 80% of the animals 1 week after initiation of TPN. At this time it was possible to observe the first histologic changes consistent with TPN-associated hepatic disease, such as moderate to severe hepatocyte degeneration and portal inflammation. Biliary sludge was seen after 3 weeks of TPN in 70% of the rabbits, as well as a subsequent progression of TPN-associated histologic findings. Portal fibrosis and fatty liver degeneration occurred in 50% of the rabbits and bile duct proliferation in all animals. After 4 weeks of TPN (at autopsy) gallstones were found in 20% of TPN animals, as well as further progression of bile duct proliferation and fibrosis. Our first experiences with this model and preliminary results suggest that this concept offers new possibilities for further elucidation of TPN-associated hepatic dysfunction.

Hemarthrosis after trauma to the pediatric knee joint: what is the value of magnetic resonance imaging in the diagnostic algorithm?

In children, compulsory arthroscopy for hemarthrosis after knee trauma is not justified because ligamentous and meniscal damage is rare. In a prospective study, we analyzed the diagnostic value of radiography, magnetic resonance imaging (MRI), and arthroscopy in 51 patients up to 14 years of age with acute knee trauma. Plain radiography revealed 16 osseous lesions (5 metaphyseal, 3 patellar, 4 physeal fractures, 3 avulsions of the tibial spine, and 1 osseous ligamentous tear). In 29 patients, the cause of hemarthrosis remained unclear. All patients were evaluated by MRI. A diagnosis could be assigned to all 29 patients. MRI demonstrated lesions in 38 patients. In addition, the following lesions were discovered: 8 patellar dislocations, 13 bruises, 1 rupture of the anterior cruciate ligament, 1 osteochondritis dissecans, and 13 joint effusions. In 13 patients, MRI was followed by arthroscopy to confirm the diagnosis. Both, MRI and arthroscopy missed two osteochondral fractures. In addition, three chondral lesions were not picked up by MRI. MRI is a reliable tool for assessing the extent of knee lesions in children.