Biomedical subjects
Publications and source records attributed to G Möslein.
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Familial adenomatous polyposis (FAP) is a genetic disorder leading to the early development of numerous polyps of the entire colorectum. First polyps usually emerge in puberty and cause symptoms in the third and fourth decade of life when a malignant transformation of the adenomas via an adenoma-carcinoma-sequence has often already occurred. Extracolonic manifestations and age of onset of the disease show a wide range of variability rendering the establishment of unequivocal standards for the timing of diagnostic, prophylactic and therapeutic modalities difficult. We report the cases of two unrelated children who presented with severe symptomatic, pancolonic polyposis already at the age of 3. Molecular diagnostics revealed a 'new mutation' in one case, the other child had a family history for FAP. Rapid progression of the disease with anemia and slight growth retardation were the indications for prophylactic surgery at the age of 7. The operative procedure performed was restorative proctocolectomy followed by an ileal pouch-anal anastomosis. Both children developed small bowel adhesions that forced us to perform an early closure of the protective ileostomy 3 weeks postoperatively. The subsequent course was uneventful. The children are now thriving and lead a normal social life. After only 3 months their stool frequency ranged between 2 and 5 times daily.
The life-threatening event of early colorectal cancer in FAP patients may effectively be prevented by prophylactic colectomy. Desmoid tumors and periampullary carcinoma are now becoming the most frequent causes of death in FAP patients. Since the establishment of the Heidelberg polyposis registry in January 1991 we evaluated the frequency of desmoid tumors in 171 prospectively reexamined FAP patients. 29 patients (17%) with desmoid tumors were identified. In our series R0-resection with a wide security margin was performed in 12 cases, 3 of which developed a desmoid recurrence, 8 are free of desmoids and one treated for an intraabdominal desmoid states being well but refuses a radiological reevaluation. Tumor debulking was performed in 6 patients and led to an aggressive desmoid progression in 4 patients despite additional postoperative administration of tamoxifen and sulindac. Nonsurgical treatment with tamoxifen and sulindac seemed beneficial in 5 of 7 patients, 4 showed a stagnation of tumor growth, a reduction of an abdominal wall desmoid was documented in one female with a further intraabdominal desmoid. In life-threatening cases chemotherapy and radiation therapy may be considered. In two females radiation therapy resulted in a remarkable tumor reduction. The operative trauma of previous colectomy is considered the most relevant predisposing external factor inducing desmoid growth in FAP patients. 50% (11/22) of the desmoid tumors in our series were diagnosed within the first two years postoperatively, and 72% (18/22) of the desmoids developed within the first four years after colectomy.(ABSTRACT TRUNCATED AT 250 WORDS)
The clinical course of familial adenomatous polyposis (FAP) varies considerably between patients. Prediction of the severity of the disease is important in the interest of effective cancer prevention. We examined whether age at diagnosis of FAP due to gastrointestinal symptoms and age at death due to colorectal cancer are related to the site of mutation in the responsible gene. 225 families with FAP were screened for mutations. The deletion of 5 base pairs at codon 1309 within exon 15 (known to be the most common mutation) was identified in 20 families; other mutations within exons 7-15 were found in 49 families. In patients with the 5 base-pair deletion at codon 1309, gastrointestinal symptoms and death from colorectal cancer occurred about 10 years earlier than in patients with other mutations. The 1309 mutation leads to development of colonic polyps at a younger age, thus giving rise to an earlier malignant transformation. This relationship should be taken into account in strategies for preventing cancer in patients with FAP.
In a retrospective study we evaluated the data of 92 patients (41 women, 51 men, age median: 63 years) with diverticulitis of the sigma who were treated surgically in our clinic from January 1986 till December 1992. Twelve patients (13%) suffered from suppression of the immune system due to a corticoid therapy (n = 3), chemotherapy (n = 1), combination of corticoid therapy and chemotherapy (n = 1), combination of chemotherapy and azathioprine, leucopenia due to carbimazole therapy as a side effect (n = 1) and immunosuppression with prednisone, azathioprine and cyclosporine after renal and heart transplantations (n = 5). The therapy was Hartmann's procedure in 5 patients, drainage and loop colostomy in one patient, sigma resection with primary anastomosis without a protective enterostomy in 5 patients and with a loop ileostomy in one patient. One patient died in the early postoperative course. Sigma diverticulitis in immunosuppressed patients is a well-known problem especially in large clinics with organ transplantation units. In contrast to reports from up to the eighties we found no significant difference in the postoperative morbidity and mortality after surgical treatment of acute sigma diverticulitis in immunosuppressed patients compared to non immunosuppressed patients.
In order to enable consequent screening in at risk persons and life-long follow-up in patients, a computer-based polyposis registry was initiated in 1991. It now includes data of 130 FAP patients and 179 risk persons from 87 families, that were seen in our clinic since 1982. 20.5% of the "probands" (symptomatic patients) had a colorectal carcinoma at the time of diagnosis in contrast to none in the "call-up" group. The most reliable screening method as yet has proven to be the flexible sigmoidoscopy with histological verification of the adenomatous nature of the polyps. Congenital hypertrophy of the retinal pigment epithelium was only seen in 50% of our patients. The exact localisation of the FAP gene in August 1991 will soon significantly improve the prognostic value of molecular genetic screening procedures. The improved prognostic value of the method will enable early and even prenatal diagnosis. It will not any more be necessary to wait for the phenotypic manifestation (colorectal polyps) in order to be sure of the diagnosis FAP.
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