A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4).
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-beta 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.


CONCLUSIONS
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.
Gallione
Carol J
CJ
Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA.
Repetto
Gabriela M
GM
Legius
Eric
E
Rustgi
Anil K
AK
Schelley
Susan L
SL
Tejpar
Sabine
S
Mitchell
Grant
G
Drouin
Eric
E
Westermann
Cornelius J J
CJ
Marchuk
Douglas A
DA
D011125:Adenomatous Polyposis Coli / Q000453:epidemiology / Q000235:genetics*; D015897:Comorbidity; D004268:DNA-Binding Proteins / Q000235:genetics*; D015870:Gene Expression / Q000235:genetics / Q000502:physiology; D006801:Humans; D009154:Mutation; D010641:Phenotype; D015398:Signal Transduction / Q000235:genetics* / Q000502:physiology; D051901:Smad4 Protein; D013577:Syndrome; D013683:Telangiectasia, Hereditary Hemorrhagic / Q000453:epidemiology / Q000235:genetics*; D015534:Trans-Activators / Q000235:genetics*
D004268:DNA-Binding Proteins; C497796:SMAD4 protein, human; D051901:Smad4 Protein; D015534:Trans-Activators