Hereditary desmoid disease in a family with a germline Alu I repeat mutation of the APC gene.

Two families with autosomal dominantly inherited desmoid tumors have recently been shown to have germline mutations at the 3' end of the APC gene. We subsequently identified an Amish family with autosomal dominantly inherited desmoid tumors. Genetic analysis performed on one family member, a 47-year-old man with multiple desmoid tumors and no colon polyps, revealed a protein truncating mutation in the middle of the APC gene. The truncating mutation is the result of a 337-bp insertion of an Alu I sequence into codon 1526 of the APC gene. The presence of a poly(A) tail at the 3' end of the insertion suggests that the Alu I sequence was inserted by a retrotranspositional event. Germline insertions of Alu I sequences have occasionally been reported to cause other genetic diseases including type I neurofibromatosis, hereditary site-specific breast cancer (BRCA2), and hemophilia B. However, this is the first report of a germline mutation of the APC gene resulting from an Alu I insertion.

Phenotypic expression of disease in families that have mutations in the 5' region of the adenomatous polyposis coli gene.

BACKGROUND: Germline mutation in a gene on chromosome 5 (the adenomatous polyposis coli gene) causes familial adenomatous polyposis of the colorectum. Phenotypic manifestations of this condition vary, but the exact relation of the phenotype to the mutation site along the gene has not been fully described. OBJECTIVE: To determine how the location of mutations along a gene that is associated with multiple colorectal polyps (the adenomatous polyposis coli gene) is related to the phenotypic expression of the syndrome in families. DESIGN: Prospective cohort study. SETTING: Polyposis registry. PATIENTS: 20 patients from 7 families that had mutations in the adenomatous polyposis coli gene that were located toward the 5' end of codon 158 (proximal 5' families), were compared with 52 patients from 7 families that had mutations downstream from codon 158, in codons 179 to 625 (distal 5' families). MEASUREMENTS: Sex, age at diagnosis of familial adenomatous polyposis, number of polyps at first examination of the colon, distribution of polyps, age at diagnosis of colorectal cancer, and location of colorectal cancer. RESULTS: Mutations that were proximal to codon 158 were found in 7 of 112 families (6%). At the first examination of the colon, 8 of 17 (47%) patients in proximal 5' families and 9 of 48 (19%) patients of similar ages in distal 5' families were found to have fewer than 100 adenomas (P = 0.029). The distribution of polyps was frequently right-sided in patients in proximal 5' families (P = 0.001). The cumulative probability of survival without colorectal cancer was greater for patients in proximal 5' families (P = 0.041). CONCLUSIONS: Families with adenomatous polyposis that have proximal 5' mutations of the adenomatous polyposis coli gene are more likely to have a heterogeneous phenotype with delayed development of colonic polyposis and colorectal cancer than are families with distal 5' mutations of the gene. Management should include genotyping of patients who are at risk, colonoscopic surveillance of genotypically positive persons, and prophylactic colectomy if several adenomas are found.

Intra-arterial chemotherapy for palliation of fungating breast cancer. A case report and review of the literature.

The infusion of chemotherapy into arteries that feed locally advanced tumors has theoretical appeal, since the tumor mass may be exposed to high drug concentrations with administration of reduced or conventional doses of chemotherapy. Experience in applying this technique to patients with breast cancer in the United States is limited. Locally advanced, fungating breast cancers pose particularly difficult management problems for which intra-arterial drug delivery may be appropriate in carefully, selected cases. Disseminated cancer, physical deformity, foul odor, bleeding, and infection, as well as associated psychosocial factors, contribute to the complexity of caring for these patients. We report the case of a patient with a massive fungating breast cancer who was effectively palliated with intra-arterial administration of mitomycin, fluorouracil, cisplatin, and mitozantrone. The rapidity of our patient's response using this approach supports the observations of other investigators. We offer a review of the literature reporting the application of this technique for patients with locally advanced breast cancer. Further study of intra-arterial chemotherapy in carefully selected patients with locally advanced and fungating breast cancers is warranted.

Colorectal cancer: evidence for distinct genetic categories based on proximal or distal tumor location.

PURPOSE: To examine studies of normal colon and colorectal cancer for evidence that the location of the primary tumor proximal or distal to the splenic flexure of the colon may determine distinct genetic categories of this disease. DATA IDENTIFICATION: Studies were identified through a manual search of journals, through MEDLINE, and through review of bibliographies in identified articles. STUDY SELECTION: Approximately 300 articles were examined. About 150 articles were excluded because tumor location was not reported or was reported in a way that did not permit correlation with results or conclusions. DATA EXTRACTION: Articles were selected either because the presentation of data permitted correlation of results with anatomic regions of the colon or because they were relevant to inherited colorectal cancer. RESULTS OF THE ANALYSIS: Differences were noted in biologic properties of proximal and distal segments of normal fetal and adult colonic epithelium and in the epidemiologic, pathologic, cytogenetic, and molecular features of proximal and distal colorectal cancer. Some differences correlated with the features of inherited colorectal cancer (proximal, nonpolyposis or distal, and polyposis forms). CONCLUSIONS: Developmental and biologic differences in proximal and distal colon may reflect differing susceptibilities to neoplastic transformation. Differences in proximal and distal colorectal cancer suggest that each may arise through different pathogenetic mechanisms. Proximal tumors appear to represent a genetically more stable form of the disease and may arise through the same mechanisms that underlie inherited nonpolyposis colon cancer. Distal tumors show evidence of greater genetic instability and may develop through the same mechanisms that underlie polyposis-associated colorectal cancer syndromes.

Pityrosporum folliculitis after bone marrow transplantation. Clinical observations in five patients.

A skin rash in marrow graft recipients often poses difficult diagnostic problems because multiple causes may be implicated, and clinical and histopathologic findings may be nonspecific. Five recipients of allogeneic bone marrow transplants had pityrosporum folliculitis diagnosed by skin biopsy in the early weeks (less than 18 days) after transplantation. In all cases, patients were febrile and leukopenic (granulocyte count, less than 500 cells/mm3), and were receiving broad-spectrum antibiotics at onset of the skin rash. Erythematous macules and papules were distributed primarily over the chest, shoulders, and upper back, and pustules and crusts developed in some cases. Granulocyte counts of more than 500 cells/mm3 were associated with resolution of the rash. Pityrosporum infection should be considered in the differential diagnosis of skin rashes in marrow graft recipients.