Overlapping spectra of SMAD4 mutations in juvenile polyposis (JP) and JP-HHT syndrome.
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.
Gallione
Carol
C
Duke University Medical Center, Durham, North Carolina 27710, USA.
Aylsworth
Arthur S
AS
Beis
Jill
J
Berk
Terri
T
Bernhardt
Barbara
B
Clark
Robin D
RD
Clericuzio
Carol
C
Danesino
Cesare
C
Drautz
Joanne
J
Fahl
Jeffrey
J
Fan
Zheng
Z
Faughnan
Marie E
ME
Ganguly
Arupa
A
Garvie
John
J
Henderson
Katharine
K
Kini
Usha
U
Leedom
Tracey
T
Ludman
Mark
M
Lux
Andreas
A
Maisenbacher
Melissa
M
Mazzucco
Sara
S
Olivieri
Carla
C
Ploos van Amstel
Johannes K
JK
Prigoda-Lee
Nadia
N
Pyeritz
Reed E
RE
Reardon
Willie
W
Vandezande
Kirk
K
Waldman
J Deane
JD
White
Robert I
RI
Williams
Charles A
CA
Marchuk
Douglas A
DA
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*
C497796:SMAD4 protein, human; D051901:Smad4 Protein