Gloria M. Petersen

Screening guidelines and premorbid diagnosis of familial adenomatous polyposis using linkage

Restriction fragment-length polymorphisms in the chromosome 5q21-22 region can now be used clinically for premorbid diagnosis and counseling in familial adenomatous polyposis. Two families are presented in which DNA diagnosis for familial adenomatous polyposis was performed using linked restriction fragment-length polymorphisms. Screening guidelines are improved using data from the polyposis registers at St. Marks Hospital (London) and Western Australia (Perth) on at-risk family members who subsequently developed familial adenomatous polyposis. In these registers, 103 of 137 relatives tested positive on initial screening; of the remaining 34, the average interval between initial negative screening and development of familial adenomatous polyposis was 7.5 years. All those who had inherited the familial adenomatous polyposis gene manifested the polyps by age 34 years. Combined with linkage marker data, the a priori 50% risk for relatives can now be reduced to less than 0.5% by age 30 years if there is an initial negative result on sigmoidoscopy and a negative diagnosis by linkage analysis. The screening management for those found by linkage to have inherited familial adenomatous polyposis remains unchanged from established recommendations; however, for individuals who most likely have not inherited familial adenomatous polyposis, the clinician can emphasize the positive aspects of screening management, including longer screening intervals.

Risk factors for gallstone formation during rapid loss of weight

Risk factors for the development of gallstones during rapid weight loss were assessed in 457 subjects who entered a weight control program (520 kcal/day). Absence of gallstones in these subjects was documented by ultrasonography prior to entry into the study. Ultrasonography was performed again at 16 weeks on the subjects who remained in the study (N=248). The incidence of gallstones by 16 weeks of rapid weight loss was 10.9% (27/248). Most factors associated with gallstones in the general population, eg, older age, female gender, parity, positive family history, etc, were not associated with gallstones in this population. The risk factors for developing gallstones included increased initial body mass index [weight (kg)/height (m)2], amount of body mass index loss, and serum triglyceride levels. The positive predictive value of these risk factors was 75%, but the sensitivity was only 12%. These observations indicate that risk factors for the development of gallstones during rapid weight loss are probably different from those in the general population. The factors identified by this study are useful in predicting patients at high risk for gallstones. However, since only a minority of gallstones that form can be predicted, further study is needed to identify additional factors that will improve our ability to predict gallstone formation.

Genetic marker family studies in familial Mediterranean fever (FMF) in Armenians

Familial Mediterranean fever is an autosomal recessive disease manifested by recurrent short episodes of fever associated with polyserositis. It is common in a variety of Mediterranean and near Eastern populations. The biochemical defect is unknown, and there have been few studies of genetic marker associations or linkage with the disease. We have screened blood samples from members of 14 nuclear Armenian families, the population with the highest known gene frequency, for 19 different polymorphic phenotypic genetic markers. These 14 families included 31 affected and 43 unaffected family members. No association was found with any of the markers studied. Linkage could be excluded at the distance of 0–15% recombination with 14 markers. Linkage could not be excluded with 5 other markers. These results exclude the FMF gene from those portions of the human gene map that are at least 0.5% recombination distance from these 14 genetic markers, and represent the first comprehensive step in the eventual localization and isolation of the FMF gene.

Genetic Counseling for Familial Adenomatous Polyposis with Chromosome 5q Linkage Information

Molecular genetic markers linked to familial adenomatous polyposis (FAP) in the chromosome 5q21-22 region now permit the clinical application of linkage information for premorbid diagnosis in at-risk individuals. While screening management for those found by linkage to have inherited FAP remains unchanged from established recommendations, we have developed new screening guidelines for individuals who most likely have not inherited FAP. we propose baseline flexible sigmoidoscopies at ages 11 and 12, with repeated screening every 3 years thereafter until age 35. For such relatives, the clinician can emphasize the positive aspects of screening management (i.e., longer screening intervals).