Elsevier

The Lancet

Volume 363, Issue 9412, 13 March 2004, Pages 852-859
The Lancet

Mechanisms of Disease
A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4)

https://doi.org/10.1016/S0140-6736(04)15732-2Get rights and content

Summary

Background

Juvenile polyposis and hereditary haemorrhagic telangiectasia are autosomal dominant disorders with distinct and non-overlapping clinical features. The former, an inherited gastrointestinal malignancy predisposition, is caused by mutations in MADH4 (encoding SMAD4) or BMPR1A, and the latter is a vascular malformation disorder caused by mutations in ENG (endoglin) or ACVRL1 (ALK1). All four genes encode proteins involved in the transforming-growth-factor-β signalling pathway. Although there are reports of patients and families with phenotypes of both disorders combined, the genetic aetiology of this association is unknown.

Methods

Blood samples were collected from seven unrelated families segregating both phenotypes. DNA from the proband of each family was sequenced for the ACVRL1, ENG, and MADH4 genes. Mutations were examined for familial cosegregation with phenotype and presence or absence in population controls.

Findings

No patient had mutations in the ENG or ACVRL1 genes; all had MADH4 mutations. Three cases of de-novo MADH4 mutations were found. In one, the mutation was passed on to a similarly affected child. Each mutation cosegregated with the syndromic phenotype in other affected family members.

Interpretation

Mutations in MADH4 can cause a syndrome consisting of both juvenile polyposis and hereditary haemorrhagic telangiectasia phenotypes. Since patients with these disorders are generally ascertained through distinct medical specialties, genetic testing is recommended for patients presenting with either phenotype to identify those at risk of this syndrome. Patients with juvenile polyposis who have an MADH4 mutation should be screened for the vascular lesions associated with hereditary haemorrhagic telangiectasia, especially occult arteriovenous malformations in visceral organs that may otherwise present suddenly with serious medical consequences.

Introduction

Juvenile polyposis is an autosomal dominant malignancy predisposition affecting the gastrointestinal epithelium. Classic juvenile polyps consist of stromal elements with a normal epithelial layer and are distinct from both adenomatous polyps and those of the Peutz-Jegher type.1 Although solitary juvenile polyps are common in children, juvenile polyposis is marked by the presence of many polyps either in the colon or throughout the gastrointestinal tract. Patients with juvenile polyposis typically present with rectal bleeding in the first decade of life and have an increased risk of colon carcinomas later in life. Although juvenile polyps are also a feature of other genetic syndromes, juvenile polyposis is a distinct disorder that is caused by mutations in either MADH4 or BMPR1A.2, 3

Hereditary haemorrhagic telangiectasia (Osler-Weber-Rendu disease) is an autosomal dominant disorder of vascular dysplasia that affects many organs. Characteristic symptoms include skin and mucosal telangiectases, pulmonary, cerebral, and hepatic arteriovenous malformations, and haemorrhage associated with these vascular lesions. Mutations in either ENG (endoglin) or ACVRL1 (ALK1), encoding two endothelial-specific receptors for transforming growth factor β (TGFβ), cause this disorder.4, 5

Although both of these inherited disorders are uncommon, there are many reports of patients and families with both disorders, or of patients with juvenile polyposis who show some symptoms of hereditary haemorrhagic telangiectasia.6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 These associations have led some researchers to propose that juvenile polyposis with pulmonary arteriovenous malformations be judged a distinct syndrome.6, 7 The two disorders overlap genetically as well as clinically. The four genes involved in their pathologies encode members of the tgf-β signalling pathway. Endoglin and ACVRL1 (activin A receptor, type II like 1) are endothelial-specific type III and type I receptors for TGF-β, and BMPR1A is a type I receptor for bone morphogenetic protein, another of the TGF-β superfamily of ligands. SMAD4, encoded by MADH4, is the only identified Co-SMAD in human beings. This protein is an integral downstream effector of the TGF-β signal transduction pathway binding to R-SMADs and transporting them to the cell nucleus to induce specific transcriptional events.

We investigated the underlying genetic aetiology of this syndrome. Seven unrelated families or individuals displaying both juvenile polyposis and hereditary haemorrhagic telangiectasia phenotypes were ascertained and characterised clinically and molecularly.

Section snippets

Patients and families

Patients were enrolled in the study with approval from the relevant institutional review boards and after giving informed consent. Diagnosis of juvenile polyposis was based on the accepted diagnostic criteria of the presence of any one of the following: five or more colorectal juvenile polyps; juvenile polyps throughout the gastrointestinal tract; or any juvenile polyps in a patient with a family history of juvenile polyposis.17 Diagnosis of hereditary haemorrhagic telangiectasia was based on

Results

The coding exons and at least 50 bp of the flanking intronic regions of the ENG and ACVRL1 genes were sequenced from genomic DNA from representative affected members from each family with the combined juvenile polyposis and hereditary haemorrhagic telangiectasia phenotype. Three exonic sequence changes were identified but none altered the aminoacid sequence of the respective protein (207G→A, L69L, and 1029C→T, T343T in ENG, both previously reported as population polymorphisms, and 1131A→G,

Discussion

Is this dual-disorder state in fact a distinct genetic syndrome? All affected patients in this study showed clinical features of both juvenile polyposis and hereditary haemorrhagic telangiectasia (table 1) involving both the gastrointestinal epithelium and the vascular endothelium. This pattern of distinct primary malformations affecting various tissues is caused by a single genetic defect, so it meets the definition of a genetic syndrome. The phenotypes of hereditary haemorrhagic

Glossary

consensus splice sequence motifs
Conserved nucleotide sequences that flank the 5′ and 3′ ends of exons to direct the splicing of mRNA transcripts.
de-novo mutation
A spontaneous mutation occurring during gametogenesis that results in a new mutation in the offspring, which was not present in either parent.
mkk4/jnk pathway
The mitogen-activated protein-kinase kinase (MKK) 4/c-Jun N-terminal kinase (JNK) pathway is involved in differentiation-related cellular processes.
mkk3/p38 pathway
The

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