Preliminary evidence of genetic anticipation in Graves' disease

Despite strong epidemiologic evidence in favor of a genetic component in the etiology of Graves' disease, few hereditary risk factors have been consistently identified. The term genetic anticipation denotes a decrease in the age of onset as disease is passed through generations. In the past 5 years, genetic anticipation has been described in immune-mediated diseases such as rheumatoid arthritis and chronic inflammatory bowel disease, and recently this phenomenon has been linked to unstable expanded trinucleotide repeat sequences in several diseases. If present in Graves' disease, anticipation could provide clues to its genetic etiology. The aim of the present study was to investigate whether genetic anticipation may occur in Graves' disease. Age at diagnosis and age at ascertainment were registered and compared in 33 same-gender parent-offspring pairs with Graves' disease from multiply affected families primarily ascertained for a genetic linkage study. The mean age at diagnosis was 46.6 years (range, 16-77) in the parents and 34.1 years (range, 16-44) in the children. The difference in the mean age at diagnosis between parents and their children was 12.5 years (95% confidence interval 3.0-21.9), p = 0.010. Children were younger than their parents at diagnosis in 25 of 33 pairs (76%). In 7 pairs (21%), the parent was diagnosed after the child according to the calender years. Essentially similar results were obtained after controlling for gender and smoking habits. In conclusion, our data suggest that patients in the second affected generation seem to acquire their disease at an earlier time in life in familial cases of Graves' disease, indicating that genetic anticipation might occur.