Can a familial gastrointestinal tumour syndrome be allelic with Waardenburg syndrome?

Familial gastrointestinal stromal tumours (GISTs) are rare but otherwise well-characterized tumour syndromes, most commonly occurring on a background of germline-activating mutations in the tyrosine kinase receptor c-KIT. The associated clinical spectrum reflects the constitutive activation of this gene product across a number of cell lines, generating gain-of-function phenotypes in interstitial cells of Cajal (GIST and dysphagia), mast cells (mastocytosis) and melanocytes (hyperpigmentation). We report a three-generation kindred harbouring a c-KIT germline-activating mutation resulting in multifocal GISTs, dysphagia and a complex melanocyte hyperpigmentation and hypopigmentation disorder, the latter with features typical of those observed in Waardenburg type 2 syndrome (WS2F). Sequencing of genes known to be causative for WS [microphthalmia transcription factor (MITF), Pax3, Sox10, SNAI2 ] failed to show any candidate mutations to explain this complex cutaneous depigmentation phenotype. Our case report conclusively expands the clinical spectrum of familial GISTs and shows a hitherto unrecognized link to WS. Possible mechanisms responsible for this novel cause of WS2F will be discussed.

Low-level parental mosaicism in an apparent de novo case of Peutz-Jeghers syndrome.

We report the case of a female found to have mosaicism for mutation in the STK11 gene, with the mutant allele expressed in her gametes, evident by her affected offspring, and in her gastrointestinal tract demonstrated on an excised polyp analysed for diagnosis. Mosaicism for Peutz-Jeghers syndrome (PJS) has been reported in a small number of cases previously but a clinical presentation such as this has not previously been described. This finding of mosaicism was several years after initial investigations failed to identify the same STK11 mutation in this woman whose son was diagnosed with PJS at a young age. This case highlights the importance of considering mosaicism as an explanation for apparent de novo cases of PJS syndrome. It also has implications for genetic counselling, predictive testing and cancer screening.

STK11 status and intussusception risk in Peutz-Jeghers syndrome.

BACKGROUND: Peutz-Jeghers syndrome (PJS) is caused by germline STK11 mutations and characterised by gastrointestinal polyposis. Although small bowel intussusception is a recognised complication of PJS, risk varies between patients. OBJECTIVE: To analyse the time to onset of intussusception in a large series of PJS probands. METHODS: STK11 mutation status was evaluated in 225 PJS probands and medical histories of the patients reviewed. RESULTS: 135 (60%) of the probands possessed a germline STK11 mutation; 109 (48%) probands had a history of intussusception at a median age of 15.0 years but with wide variability (range 3.7 to 45.4 years). Median time to onset of intussusception was not significantly different between those with identified mutations and those with no mutation detected, at 14.7 years and 16.4 years, respectively (log-rank test of difference, chi(2) = 0.58, with 1df; p = 0.45). Similarly no differences were observed between patient groups on the basis of the type or site of STK11 mutation. CONCLUSIONS: The risk of intussusception in PJS is not influenced by STK11 mutation status.

Upper intestinal surveillance in familial adenomatous polyposis.

Our understanding of the natural history of upper gastrointestinal (GI) involvement in familial adenomatous polyposis (FAP) is still evolving, although we know that the main cause of death after colectomy in FAP is upper GI malignancy, affecting 5% of patients. The aim of duodenal surveillance is to target high risk individuals and identify cancers early. We have screened 200 patients prospectively and have observed that duodenal polyposis progresses slowly, but there are some young people who have severe disease who merit close observation. We pay particular attention to endoscopic technique and histological detail, and use a duodenal staging system. Patients are offered randomisation to studies of chemopreventive agents, and those with advanced disease are considered for surgery. Successful management is inhibited by our deficient knowledge of the natural history of upper gastrointestinal polyposis, and by our inability to identify high risk individuals with histological markers rather than because of any technological deficiencies in endoscopic equipment.

Preventive measures in Peutz-Jeghers syndrome.

Peutz-Jeghers syndrome is a rare genetic disorder characterized by mucocutaneous melanin deposition, intestinal polyposis and an increased risk of cancer, both intestinal and extra-intestinal. We describe the current status of diagnosis and the methods by which the consequences of this condition can be minimized. A surveillance program for those diagnosed is also included.

Upper gastrointestinal pathology in familial adenomatous polyposis: results from a prospective study of 102 patients.

Multiple gastric and duodenal biopsy specimens from 102 asymptomatic patients with familial adenomatous polyposis, taken during a prospective endoscopic screening programme were examined. One hundred patients had microscopic gastroduodenal pathology, often in the absence of macroscopic lesions. Adenomas were found in 94 patients in the duodenum, in the second and third parts. Hyperplasia of villous and crypt epithelium was also seen, sometimes in the absence of adenomas: this may be a precursor of neoplastic change. In the stomach fundic gland polyps were the commonest abnormality, seen microscopically in 44 patients. Chronic antral gastritis was common in patients without fundic polyps. Gastric adenomas were present in six patients, all of whom also had duodenal adenomas. If duodenal adenomas in familial adenomatous polyposis have a similar malignant potential to those in the colorectum sequential endoscopy and biopsy are necessary to detect cancer in these patients.

Evidence for adenoma-carcinoma sequence in the duodenum of patients with familial adenomatous polyposis. The Leeds Castle Polyposis Group (Upper Gastrointestinal Committee).

AIMS: To explore the association between duodenal adenoma and carcinoma in patients with familial adenomatous polyposis (FAP). METHODS: A multicentre survey of 1262 patients with FAP yielded 47 cases of duodenal cancer. The association between adenoma and cancer was assessed in these cases. RESULTS: Adenomatous tissue was found within duodenal cancer in 29 of 44 (66%) patients with FAP and in mucosa adjacent to duodenal cancer in 31 of 42 (73%) such patients. Adenomas were found as a component of, or adjacent to, duodenal cancer in 38 of 45 (84%) patients. CONCLUSIONS: These observations support the existence of the adenomacarcinoma sequence in the duodenum of patients with FAP. Factors associated with malignant change included villous histology, moderate or severe dysplasia, and the presence of stage IV duodenal polyposis.

Development of duodenal cancer in a patient with familial adenomatous polyposis.

A Japanese woman with familial adenomatous polyposis in whom a duodenal ampullary adenoma underwent malignant change during a 10-year follow-up period is reported. After restorative proctocolectomy in 1989, and extensive small bowel resection for desmoid disease in 1991, regular surveillance duodenoscopies, including three to nine biopsies (mean, 4.8) were performed annually or biannually. Until 1995, the endoscopic findings of duodenal polyposis (including an ampullary polyp) did not progress and the histopathology did not worsen. In 1996, there was an increase in the number and size of the duodenal polyps, and the ampulla of Vater looked enlarged. Open surgery was discussed but not proceeded with because of the risk for short bowel syndrome. In January 1998, she was admitted with a diagnosis of acute pancreatitis. Duodenoscopy and radiological examination revealed that an advanced ampullary cancer had developed, and histopathology revealed a well-differentiated adenocarcinoma. Multiple hepatic metastases and ascites led to her death, in June, 1998. This in-vivo demonstration of the adenoma-carcinoma sequence highlights current limitations in the surveillance and treatment of duodenal lesions.

Screening modalities in familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer.

The syndromes known as familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC) represent paradigms of the arguments for and against screening surveillance. This article details the protean manifestations of these conditions. It is not a how-to-do-it article with a suitably selected tranche of endoscopic pictures, but rather, it is an attempt to see what should be done.

Inhibition of proliferation of a colon cancer cell line by indole-3-carbinol.

OBJECTIVE: To observe the effect of Indole-3-carbinol (I3C), a naturally occurring component of cruciferous vegetables, on cell proliferation of a colon cancer cell line. METHODS: Cell proliferation was measured using three different methods; 3H-thymidine incorporation, cell count and colourimetric assay. RESULTS: Each method of measurement revealed that I3C significantly reduced cell proliferation at concentrations of > 0.1 mM. CONCLUSION: The present study demonstrates for the first time the capacity of indole-3-carbinol to inhibit cell proliferation of a colon cancer cell line.

The use of 32P-postlabelling in studies of the nature and origin of DNA adducts formed by bile from patients with familial adenomatous polyposis and from normal patients.

32P-postlabelling is a highly sensitive technique for the detection of DNA adducts. It is unique in that it requires no prior knowledge of the nature of adducts or adduct-forming species under investigation. In the past, we have used this technique to investigate the role of bile in the production of foregut adenomas in patients with familial adenomatous polyposis (FAP). We have found that bile contains constituents that form DNA adducts directly, and after metabolic activation, and that the bile of FAP patients has an increased capacity for adduct formation with DNA in vitro, in human cell lines in culture, and in the gastrointestinal tract of rats given bile by gavage. The sensitivity of 32P-postlabelling is such that it is difficult to obtain sufficient quantities of DNA adducts for chemical analysis. The nature of the adducts produced by bile, or of the bile constituents that produce them is as yet undetermined. In the present studies, we have combined 32P-postlabelling with indirect methods to gain some insight into the nature of DNA adducts produced by bile and the properties of the reactive species that form them. Firstly, bile was incubated with synthetic monodeoxynucleotides or polydeoxynucleotides. Bile did not produce adducts when incubated with monodeoxynucleotides or single-stranded polydeoxynucleotides. However, it did produce adducts when incubated with double-stranded polydeoxynucleotides. The pattern of adduct formation suggested that human bile forms a mixture of adenine and guanine adducts. Secondly, bile was fractionated by extraction with blue cotton or with neutral, acid or alkaline organic solvent. Blue cotton, which efficiently and selectively absorbs mutagens having 3 or more fused aromatic rings, did not absorb biliary constituents that could form adducts with DNA in vitro or with DNA of MCL-5 cells, a metabolically competent human cell line. This suggests that biliary DNA adduct precursors are polar compounds that contain fewer than 3 aromatic rings or are non-aromatic. Acidic organic extracts of human bile produced much higher levels of DNA adducts in vitro or with DNA of MCL-5 cells than did neutral or alkaline organic extracts, suggesting that constituents of bile that form DNA adducts are acidic in nature.

Duodeno-gastric reflux and gastric adenomas: a scintigraphic study in patients with familial adenomatous polyposis.

To test whether the presence of gastric adenomas (dysplasia) was associated with gastric reflux of duodenal contents, six patients with familial adenomatous polyposis (FAP) who had gastric adenomas and nine matched FAP patients without gastric adenomas underwent scintigraphic duodeno-gastric reflux scanning. Reflux was graded 0-6, where 0 = no reflux, 1 = intermittent reflux into antrum only, 2 = prolonged reflux into antrum only, 3 = intermittent reflux into body, 4 = prolonged reflux into body, 5 = intermittent reflux into body and fundus, and 6 = prolonged reflux into body and fundus. FAP patients with gastric adenomas had more severe reflux (median 6, range 4-6) than did controls (median 3, range 0-6; P = 0.009, Mann-Whitney U test). These results are consistent with a role for bile in the development of gastric adenomatous polyps and suggest that bile is involved in the dysplasia-carcinoma sequence.

Rectal polyposis as a guide to duodenal polyposis in familial adenomatous polyposis.

Almost all patients with familial adenomatous polyposis (FAP) develop duodenal polyps, the severity of which is graded stage 1 (minor) to stage V (cancer). Regular endoscopy is recommended for all patients with FAP. To test whether the development of severe duodenal polyposis could be predicted in another way, rectal and duodenal polyp severity were compared in 91 patients with FAP. The fulguration ratio (number of rectal fulgurations divided by number of years since colectomy) supplied the rectal polyp severity index. Patients with stage V duodenal polyposis had significantly higher fulguration ratios (median 0.38) than did patients with stage 1 disease (median 0; P = 0.009). However, the wide scatter of results means that rectal polyp severity cannot be used as a guide to duodenal polyp severity in individual patients. The coexistence of populations with severe duodenal and rectal polyposis suggests that environmental factors are important in phenotypic expression in FAP.

Surveillance of duodenal polyps in familial adenomatous polyposis: progress report.

Familial adenomatous polyposis (FAP) is characterized by the presence of premalignant adenomas of the large and small bowel. Prophylactic colectomy deals with the risk for colon cancer, leaving duodenal cancer as the leading cause of death. Although most FAP patients have duodenal adenomas, only approximately 5% develop duodenal cancer. This study looks at progression of duodenal polyps with time. The outcome of endoscopic surveillance in the duodenum of 70 patients with familial adenomatous polyposis was determined. A mean of 40 months elapsed between endoscopies. Outcome was measured using video comparison and a staging system that includes histological assessment. Duodenal cancer developed in one patient, and was suspected in two others. The stage of duodenal polyposis worsened in another seven patients. When histology was ignored, comparison of video recordings in 52 patients showed a worsening in 21 (40%). In conclusion, further surveillance appears warranted so that patients at high risk for duodenal cancer might receive early treatment. Should slow progression of duodenal polyposis be shown to be associated with low risk, then most patients can be safely offered less frequent endoscopies than hitherto.

Case report: metachronous central nervous system desmoid tumours and thyroid carcinoma in a young familial adenomatous polyposis patient.

We report a familial adenomatous polyposis patient with a known truncating mutation on exon 15 of the APC gene who developed an invasive follicular thyroid cancer in addition to multiple intra-cranial and spinal desmoids. This combination of manifestations has not previously been recorded in the literature.