title: Overlapping spectra of SMAD4 mutations in juvenile polyposis (JP) and JP-HHT syndrome.
abstract: Juvenile polyposis (JP) and hereditary hemorrhagic telangiectasia (HHT) are clinically distinct diseases caused by mutations in SMAD4 and BMPR1A (for JP) and endoglin and ALK1 (for HHT). Recently, a combined syndrome of JP-HHT was described that is also caused by mutations in SMAD4. Although both JP and JP-HHT are caused by SMAD4 mutations, a possible genotype:phenotype correlation was noted as all of the SMAD4 mutations in the JP-HHT patients were clustered in the COOH-terminal MH2 domain of the protein. If valid, this correlation would provide a molecular explanation for the phenotypic differences, as well as a pre-symptomatic diagnostic test to distinguish patients at risk for the overlapping but different clinical features of the disorders. In this study, we collected 19 new JP-HHT patients from which we identified 15 additional SMAD4 mutations. We also reviewed the literature for other reports of JP patients with HHT symptoms with confirmed SMAD4 mutations. Our combined results show that although the SMAD4 mutations in JP-HHT patients do show a tendency to cluster in the MH2 domain, mutations in other parts of the gene also cause the combined syndrome. Thus, any mutation in SMAD4 can cause JP-HHT. Any JP patient with a SMAD4 mutation is, therefore, at risk for the visceral manifestations of HHT and any HHT patient with SMAD4 mutation is at risk for early onset gastrointestinal cancer. In conclusion, a patient who tests positive for any SMAD4 mutation must be considered at risk for the combined syndrome of JP-HHT and monitored accordingly.
authors.affiliation: Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Carol
authors.initials: C
authors.lastname: Gallione
authors.forename: Arthur S
authors.initials: AS
authors.lastname: Aylsworth
authors.forename: Jill
authors.initials: J
authors.lastname: Beis
authors.forename: Terri
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authors.lastname: Berk
authors.forename: Barbara
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authors.lastname: Bernhardt
authors.forename: Robin D
authors.initials: RD
authors.lastname: Clark
authors.forename: Carol
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authors.lastname: Clericuzio
authors.forename: Cesare
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authors.lastname: Danesino
authors.forename: Joanne
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authors.lastname: Drautz
authors.forename: Jeffrey
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authors.lastname: Fahl
authors.forename: Zheng
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authors.lastname: Fan
authors.forename: Marie E
authors.initials: ME
authors.lastname: Faughnan
authors.forename: Arupa
authors.initials: A
authors.lastname: Ganguly
authors.forename: John
authors.initials: J
authors.lastname: Garvie
authors.forename: Katharine
authors.initials: K
authors.lastname: Henderson
authors.forename: Usha
authors.initials: U
authors.lastname: Kini
authors.forename: Tracey
authors.initials: T
authors.lastname: Leedom
authors.forename: Mark
authors.initials: M
authors.lastname: Ludman
authors.forename: Andreas
authors.initials: A
authors.lastname: Lux
authors.forename: Melissa
authors.initials: M
authors.lastname: Maisenbacher
authors.forename: Sara
authors.initials: S
authors.lastname: Mazzucco
authors.forename: Carla
authors.initials: C
authors.lastname: Olivieri
authors.forename: Johannes K
authors.initials: JK
authors.lastname: Ploos van Amstel
authors.forename: Nadia
authors.initials: N
authors.lastname: Prigoda-Lee
authors.forename: Reed E
authors.initials: RE
authors.lastname: Pyeritz
authors.forename: Willie
authors.initials: W
authors.lastname: Reardon
authors.forename: Kirk
authors.initials: K
authors.lastname: Vandezande
authors.forename: J Deane
authors.initials: JD
authors.lastname: Waldman
authors.forename: Robert I
authors.initials: RI
authors.lastname: White
authors.forename: Charles A
authors.initials: CA
authors.lastname: Williams
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Marchuk
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D005770:Gastrointestinal Neoplasms / Q000175:diagnosis / Q000235:genetics; D006801:Humans; D007223:Infant; D008875:Middle Aged; D009154:Mutation; D017434:Protein Structure, Tertiary; D051901:Smad4 Protein / Q000235:genetics*; D013577:Syndrome; D013683:Telangiectasia, Hereditary Hemorrhagic / Q000235:genetics*
chemical_list: C497796:SMAD4 protein, human; D051901:Smad4 Protein