Peutz-Jeghers syndrome: 78-year follow-up of the original family

Background The association between heredity, gastrointestinal polyposis, an d mucocutaneous pigmentation in Peutz-Jeghers syndrome (PJS) was first reco gnised in 1921 by Peutz in a Dutch family. This original family has now bee n followed-up for more than 78 years. We did mutation analysis in this fami ly to test whether the recently identified LKB1 gene is indeed the PJS gene in this family. Methods The original family was retraced and the natural history of PJS was studied in six generations of this kindred by interview, physical examinat ion, chart view, and histological review of tissue specimens. DNA-mutation analysis was done in all available descendants. Findings Clinical features in this family included gastrointestinal polypos is, mucocutaneous pigmentation, nasal polyposis, and rectal extrusion of po lyps. Survival of affected family members was reduced by intestinal obstruc tion and by the development of malignant disease. A novel germline mutation in the LKB1 gene was found to cosegregate with the disease phenotype in th e original family. The mutant LKB1 allele carried a T insertion at codon 66 in exon 1 resulting in frameshift and stop at codon 162 in exon 4. Interpretation The morbidity and mortality in this family suggest that PJS is not a benign disease. An inactivating germline mutation in the LKB1 gene is involved in the PJS phenotype in the original and oldest kindred known to be affected by PJS.