Steven H. Erdman

Café-au-lait spots and early onset colorectal neoplasia: a variant of HNPCC?

Background: Café-au-lait spots (CALS) are classically found in neurocutaneous syndromes such as neurofibromatosis, but have not been associated with hereditary colorectal cancer. However, review of hereditary colorectal cancer case reports reveals occasional description of CALS on physical exam. Methods: We describe the colonic and extracolonic phenotype in a family with CALS and early onset colorectal neoplasia (adenomas and/or cancer) and review 23 additional families reported in the literature. Results: Among the 24 families, 32/59 (54.2%) individuals had colorectal adenomas diagnosed at a mean age of 15.7 ± 1.1 (SE) years (range 5–38 years). The majority (24/32, 75.0%) of persons at first colorectal examination had oligopolyposis (< 100 polyps) versus polyposis (≥ 100 polyps). Forty-two of 59 (71.2%) individuals were affected with colorectal cancer, diagnosed at a mean age of 31.9 ± 2.7 years (range 5–70 years). A brain tumor was found in 28/59 (47.5%) affected individuals (4 families with 2 or more cases) with an overall mean age of diagnosis of 16.5 ± 1.2. Lymphoma and/or leukemia was found in 8/24 (33.3%) families (one family with 3 cases). Two families had mutation of the mismatch repair gene, hPMS2 (1 with homozygous germline mutation), while two carried homozygous germline mutations of another mismatch repair gene, hMLH1. Conclusions: Café-au-lait spots with early onset colorectal neoplasia may identify families with a variant of HNPCC characterized by oligopolyposis, glioblastoma at young age, and lymphoma. This variant may be caused by homozygous mutation of the mismatch repair genes, such as hPMS2 or hMLH1.

Essential fatty acid deficiency and postresection mucosal adaptation in the rat

The effect of short-term (biochemical) and long-term (clinical) essential fatty acid (EFA) deficiency on mucosal adaptation was studied in a surgical model of short bowel syndrome. Rats fed an EFA-deficient diet for 4 wk had biochemical evidence of EFA deficiency (hepatic and red blood cell triene to tetraene ratios greater than 0.4). Resected animals (70% proximal jejunoileal resection) receiving an EFA-deficient diet had a significantly impaired intestinal mucosal hyperplasia response in all remaining small bowel segments compared with resected controls. The effect of refeeding a control diet to clinically EFA-deficient resected rats was also evaluated. Short-term refeeding (2 wk) of a control diet resulted in a significant return toward normal tissue triene to tetraene ratios. Concomitantly, refed animals had significantly greater mucosal adaptation in the remaining duodenal/jejunal segment compared with resected animals maintained on an EFA-deficient diet postoperatively. These experiments underscore the dynamic nature of tissue EFA status and the importance of fatty acids in the normal compensatory mechanisms of mucosal adaptation after resection.

Impact of Personalized Feeding Program in 100 NICU Infants: Pathophysiology-based Approach for Better Outcomes

Objectives: In neonatal intensive care unit infants referred for home-tube feeding methods, we evaluated the effect of an innovative diagnostic and management approach on feeding outcomes at discharge and 1 year, by comparing data from historical controls; we hypothesized that clinical and aerodigestive motility characteristics at evaluation were predictive of feeding outcomes at discharge; we assessed the economic impact of feeding outcomes. Patients and Methods: Patients (N = 100) who were referred for development of long-term feeding management strategy at 46.4 ± 13.1 weeks’ postmenstrual age were compared with 50 historical controls that received routine care. The focused approach included swallow-integrated pharyngoesophageal manometry, individualized feeding strategy, and prospective follow-up. Feeding success was defined as ability to achieve oral feedings at discharge and 1 year. Motility characteristics were evaluated in relation to feeding success or failure at discharge. Results: Higher feeding success was achieved in the innovative feeding program (vs historical controls) at discharge (51% vs 10%, P < 0.0001) and at 1 year (84.3% vs 42.9%, P < 0.0001), at a reduced economic burden (P < 0.05). Contributing factors to the innovative programs feeding success (vs feeding failure) were earlier evaluation and discharge (both P < 0.05), greater peristaltic reflex-frequency to provocation (P < 0.05), normal pharyngeal manometry (P < 0.05), oral feeding challenge success (P < 0.05), and suck-swallow-breath-esophageal swallow sequence (P < 0.05). Probability of feeding success demonstrated a prediction rate of 79.6%. Conclusions: Short-term and long-term feeding outcomes in complex neonates can be significantly improved with innovative feeding strategies at a reduced cost. Clinical and aerodigestive motility characteristics were predictive of outcomes.

Suppression of diamine oxidase activity enhances postresection ileal proliferation in the rat

To assess the influence of diamine oxidase activity on the adaptive process of the small bowel after resection, we administered aminoguanidine, a potent diamine oxidase inhibitor, to rats for 10 days after either small bowel transection (n = 5) or 80% jejunoileal resection (n = 7). Five or more additional animals from each group received saline as controls. Ileal mucosal homogenates from the resection group receiving aminoguanidine, when compared with those from resection controls, showed no diamine oxidase activity with increased putrescine content and ornithine decarboxylase activity. Mucosal proliferation, as measured by mucosal mass, protein content, and deoxyribonucleic acid content, was greater in the resected animals receiving aminoguanidine when compared with that of resection controls. Sucrase activity per gram of mucosa was almost identical in both resection groups. These results show that the suppression of diamine oxidase during the postresection adaptive period results in enhanced mucosal proliferation with no effect on mucosal functional differentiation. Diamine oxidase may play a regulatory role in adaptive intestinal proliferation.

Augmentation of postresection mucosal hyperplasia by plerocercoid growth factor (PGF)

Postresection villus hyperplasia is a major compensatory mechanism in the short-bowel patient. Substances capable of augmenting postresection mucosal hyperplasia could have therapeutic implications. Human growth hormone (hGH) and human growth hormone releasing factor (hGHRF) stimulate growth of the gastrointestinal tract; however, the diabetogenic actions of growth hormone limit its usefulness in clinical practice. Plerocercoid larvae of the tapewormSpirometra mansonoides produce an analog of hGH void of diabetogenic side effects. We assessed effects of plerocercoid growth factor (PGF) on mucosal adaptation following 70% proximal jejunoileal resection in young rats. Mucosal weight, DNA, protein, and total sucrase activity per centimeter of bowel were increased in resected PGF-treated animals compared to resected controls. We conclude PGF augments intrinsic postresection mucosal hyperplasia following extensive intestinal resection.

Double-balloon Enteroscopy: Pediatric Experience

Objectives: Double-balloon enteroscopy (DBE) is a newly developed endoscopic modality for diagnosis and treatment of small bowel disorders. Most publications on DBE are from adult medical centers. Publication related to the use and application of DBE in children and adolescents is limited. We present our experience with the use of DBE in the pediatric age group. Patients and Methods: We reviewed patient information on all of the DBE procedures performed in 2006 through 2008 at a single tertiary pediatric referral center in Columbus, Ohio. Compiled information included patient demographics, procedure indications, diagnostic and therapeutic results, and procedure-associated complications or adverse events. Results: Thirteen DBE procedures were performed on eleven 8- to 20-year-old patients. Procedure indications were based on suspicion for organic small bowel pathology after an exhaustive diagnostic evaluation including upper and lower endoscopy failed to uncover an etiology. Clinically significant lesions were identified in 46% (6/13) of the procedures performed. No serious procedure-related complications occurred. Self-limited postprocedure abdominal pain and discomfort from gaseous distension was observed in several patients. Conclusions: DBE appears to be a safe endoscopic modality for the diagnosis and treatment of children and adolescents with suspected small bowel disease. However, performance should be selectively reserved for patients with a high suspicion for small bowel pathology, in which other less invasive techniques have failed to adequately diagnose and treat a patients disease.

Lynch syndrome: a pediatric perspective.

ABSTRACT Colorectal cancer is a rare disease in the pediatric age group and, when present, suggests an underlying genetic predisposition. The most common hereditary colon cancer susceptibility condition, Lynch syndrome (LS), previously known as hereditary nonpolyposis colorectal cancer, is an autosomal dominant condition caused by a germline mutation in 1 of 4 DNA mismatch repair (MMR) genes: MLH1, MSH2, MSH6, or PMS2. The mutation-prone phenotype of this disorder is associated with gastrointestinal, endometrial, and other cancers and is now being identified in both symptomatic adolescents with malignancy as well in asymptomatic mutation carriers who are at risk for a spectrum of gastrointestinal and other cancers later in life. We review the DNA MMR system, our present understanding of LS in the pediatric population, and discuss the newly identified biallelic form of the disease known as constitutional mismatch repair deficiency syndrome. Both family history and tumor characteristics can help to identify patients who should undergo genetic testing for these cancer predisposition syndromes. Patients who carry either single allele (LS) or double allele (constitutional mismatch repair deficiency syndrome) mutations in the MMR genes benefit from cancer surveillance programs that target both the digestive and extraintestinal cancer risk of these diseases. Because spontaneous mutation in any one of the MMR genes is extremely rare, genetic counseling and testing are suggested for all at-risk family members.

A retrospective chart review of the features of PTEN hamartoma tumour syndrome in children

Objective It is recognised that 5% – 10 % of children with macrocephaly and autism spectrum disorder (ASD) and/or intellectual disability (ID) have a heterozygous pathogenic mutation in the PTEN tumour suppressor gene that is associated with PTEN hamartoma tumour syndrome. However, the clinical features and course in children with a pathogenic PTEN mutation are unclear and have not been well documented. Study objectives We undertook a retrospective chart review of children (< 18  years) with pathogenic PTEN mutations to ascertain clinical findings, clinical course and possible outcomes. Results Clinical and molecular data were collected and analysed for 47 patients with PTEN mutation from 38 eligible families. Macrocephaly (average head circumference of + 5.7  SD) with developmental delay, ID and/or ASD were the most common presenting signs/symptoms (66 %). Clinical features included dermatological findings (66 %), gastrointestinal (GI) symptoms (34 %), ASD diagnosis (50 %), abnormal brain imaging (53 % of those examined) and abnormal thyroid imaging (26 %). Conclusions This is the largest survey of clinical features in children with PTEN pathogenic mutations to date. It confirms earlier reports of increased rates of neurodevelopmental disorders. Dermatological, GI and thyroid abnormalities are age dependent and may not be present at the time of diagnosis, requiring regular monitoring and medical surveillance. Early paediatric diagnosis is important for institution of medical and developmental surveillance as well as for testing other at- risk family members.

The intestinal absorption of 3-O-methyl-D-glucose in methotrexate-treated rats: an in vivo study of small bowel function.

The in vivo absorption of 3–0-methyl-D-glucose (3MG) as a marker of intestinal function has not been studied in an animal model. We evaluated the use of 3MG as a marker of intestinal absorption when given en-terally to rats recovering from small bowel mucosal injury induced by methotrexate (MTX). Radiolabeled 3MG was administered into the duodenum of control (CON) and MTX-treated rats and blood samples were obtained at specified intervals. Mucosal permeability was also assessed using radiolabeled mannitol and polyethylene glycol 900 (PEG). Concentration time points were plotted, and area under the curve was calculated as an approximation of absorbed dose. Mucosal weight, maltase activity, and protein content were determined on mucosal scrapings. During the acute phase (day 5), 3MG absorption and maltase-specific activity were significantly decreased in the MTX group when compared to the CON group (p < 0.001). The MTX group showed a trend toward greater permeability to mannitol when compared to the CON group; however, this was not statistically significant. Mucosal permeability to PEG was similar in both groups. During a later stage in the recovery process (day 12), the area under the curve calculations for 3MG absorption were the same for both CON and MTX animals, with maltase activity in the MTX group recovering to control values. Changes in 3MG absorption paralleled total maltase activities following severe injury. These results suggest that the combined active and passive transport of 3MG in vivo could be of use as a marker of intestinal absorption in states where the small intestine has sustained major damage resulting in compromised absorption as well as brush border digestion.

Sedated Percutaneous Endoscopic Gastrostomy (PEG) Placement in the Neonate

Background: The prevalence of cholecystectomies in children is on the rise. The impact of obesity on gallbladder disease and surgical outcomes in adults is well documented; however, there is minimal data in the pediatric population. Obesity appears to be a risk factor in pediatric gallbladder disease leading to a parallel increase in cholecystectomies. Methods: A retrospective chart review was performed on patients who underwent cholecystectomies between the years 2005-2010. Data collected included age, sex, height, weight, Body Mass Index (BMI) percentiles, past medical history, indications, prior imaging, length of stay, complications, comorbidities and type of surgery. Results: Preliminary results of 58 records were reviewed. The mean age of patients was 17.8 years (range 8-21) and 82.8% were female. There were 26 in the normal weight (NW) group and 32 in the overweight (OW) (BMI >85%) group. 55% of the surgeries were performed on the OW group. The mean number of cholecystectomies was 11 per year and there was no increased incidence of cholecystectomy across 5 years. The indication for cholecystectomy did not differ between the groups. The length of stay for acute surgery was longer amongst the NW group with 3.2 days (range 1-13) compared to 2.5 days (range 1-9) for the OW group. More patients in NW group had associated comorbidities that contributed to hospital stay such as sickle cell disease, renal disease and congenital heart defects. The mean operative time was 132.9 minutes (range 79-213) in the NW group and 154.8 minutes (range 96-249) in the OW group. Conclusion: Although many pediatric patients undergoing cholecystectomy are obese, obesity may not necessarily be directly linked with an increased prevalence of surgery. Obesity did impact the mean operative time and further studies are needed to examine this data for causal relationship.