Elsevier

The Lancet

Volume 353, Issue 9160, 10 April 1999, Pages 1211-1215
The Lancet

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

https://doi.org/10.1016/S0140-6736(98)08018-0Get rights and content

Summary

Background

The association between heredity, gastrointestinal polyposis, and mucocutaneous pigmentation in Peutz-Jeghers syndrome (PJS) was first recognised in 1921 by Peutz in a Dutch family. This original family has now been followed-up for more than 78 years. We did mutation analysis in this family 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 examination, 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 polyposis, mucocutaneous pigmentation, nasal polyposis, and rectal extrusion of polyps. Survival of affected family members was reduced by intestinal obstruction and by the development of malignant disease. A novel germline mutation in the LKB1 gene was found to cosegregate with the disease phenotype in the 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.

Introduction

In 1921, the Dutch physician Peutz described the combination of gastrointestinal polyps and mucocutaneous melanin spots in three young siblings.1 Of the seven children in this family, five had numerous dark pigmented spots on the face, on the lips, and in the mouth; three of them, one girl and two boys, suffered from attacks of colicky abdominal pain and rectal blood loss. Intussusception of the small bowel leading to ileus developed in two patients, who were both found to have multiple polyps throughout the small and large intestine. The resected jejunal polyps in one patient showed malignant degeneration. Both patients reported severe nasal polyposis. Their father, who had no complaints, was found to have some pigmented spots on the mucous membranes of his mouth. He recalled having facial pigmented spots which apparently had disappeared. Two of his sisters with similar pigmentations had died, at the age of 11 years and 20 years, of intestinal obstruction.

The observations made by Peutz led to the definition of autosomal dominant syndrome characterised by gastrointestinal polyposis and mucocutaneous pigmentation, now known as Peutz-Jeghers syndrome (PJS). Jeghers published ten additional cases in 1942.2 The Dutch family originally described by Peutz was followedup by van Wijk, who published his findings in a thesis in 1950 and included a new generation.3 We retraced the family 78 years after the initial description by Peutz and present further follow-up over six generations.

The PJS gene has now been identified and found to encode the serine threonine kinase LKB1 or STK11.4, 5 We therefore did mutation analysis to determine whether a defect in the LKB1 gene is responsible for the PJS phenotype in the original Peutz kindred.

Section snippets

Family study

We requested physicians in the Netherlands with an interest in gastroenterology to ask patients with PJS to participate in a clinical genetic study. Patients who agreed were visited by one of us. Two of these patients were found to be members of the original family described by Peutz. With their help, all other living descendants in this family were contacted, interviewed, and examined. Charts and tissue specimens were collected with their consent. Medical histories of deceased family members

Pedigree

Figure 1 shows the updated pedigree of the original family. In total, 22 people (nine female, 13 male) were diagnosed as being affected and 31 as unaffected. The phenotypic status of 25 individuals is unknown because of lack of information, or (in three cases) because the symptom-free individual has not yet reached the age of 25 years. Members of the second and third generation were described by Peutz1 in 1921, whereas van Wijk3 added clinical findings in the third and fourth generation in 1950.

Discussion

This report is of the longest follow-up of PJS in the largest family known to be affected by this syndrome. In addition, a novel germline mutation in the LKB1 gene was found to be responsible for conferring the PJS phenotype in the original Peutz kindred.

The original description of the syndrome by Peutz1 was remarkably complete, because he recognised both the key features of the disease as well as less obvious features, including anaemia due to intestinal blood loss and the potentially

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