Family history characteristics, tumor microsatellite instability and germline MSH2 and MLH1 mutations in hereditary colorectal cancer.

Recent characterization of the molecular genetic basis of hereditary nonpolyposis colorectal cancer provides an important opportunity for identification of individuals and their families with germline mutations in mismatch repair genes. Cancer family history criteria that accurately define hereditary colorectal cancer are necessary for cost-effective testing for germline mutations in mismatch repair genes. The present report describes the results of analysis of 33 colorectal cancer cases/families that satisfy our modified family history criteria (Mount Sinai criteria) for colorectal cancer. Fourteen of these families met the more stringent Amsterdam criteria. Germline MSH2 and MLH1 mutations were identified by the reverse transcription-polymerase chain reaction and the protein truncation test, and confirmed by sequencing. Microsatellite instability analysis was performed on available tumors from affected patients. MSH2 or MLH1 mutations were detected in 8 of 14 Amsterdam criteria families and in 5 of the remaining 19 cases/families that only satisfied the Mount Sinai criteria. Three of the latter families had features of the Muir-Torre syndrome. A high level of microsatellite instability (MSI-H) was detected in almost all (16/18) colorectal cancers from individuals with MSH2 and MLH1 mutations, and infrequently (1/21) in colorectal cancer specimens from cases without detectable mutations. Families with germline MSH2 and MLH1 mutations tended to have individuals affected at younger ages and with multiple tumors. The Amsterdam criteria are useful, but not sufficient, for detecting hereditary colorectal cancer families with germline MSH2 and MLH1 mutations, since a proportion of cases and families with mutations in mismatch repair genes will be missed. Further development of cancer family history criteria are needed, using unbiased prospectively collected cases, to define more accurately those who will benefit from MSH2 and MLH1 mutation analysis.

Acalculous cholecystitis associated with cytomegalovirus and sclerosing cholangitis in a patient with acquired immunodeficiency syndrome.

Intra- and extrahepatic bile-duct strictures, papillary stenosis and acalculous cholecystitis have all been described in ill patients with acquired immunodeficiency syndrome (AIDS). Acalculous cholecystitis associated with cytomegalovirus (CMV), Cryptosporidium or Campylobacter organisms has typically been described in critically ill or moribund patients. The authors report a case of acute acalculous CMV cholecystitis in a 28-year-old man who presented with abdominal pain. The patient was infected with the human immunodeficiency virus (HIV) but was ambulatory and had had no AIDS-defining illness. The patient did not have any well-recognized risk factors for acalculous cholecystitis, showing that this entity can occur in relatively healthy HIV-infected patients as well as in the terminal stages of AIDS. The diagnosis should be considered when such a patient presents with abdominal pain. Furthermore, this patient had sclerosing cholangitis of the intra- and extrahepatic bile ducts as well as papillary stenosis. The cause of the acalculous cholecystitis was presumed to be CMV, but the disease progressed despite therapy with foscarnet.