title: Appreciating the broad clinical features of SMAD4 mutation carriers: a multicenter chart review.
abstract: Heterozygous loss-of-function SMAD4 mutations are associated with juvenile polyposis syndrome and hereditary hemorrhagic telangiectasia. Some carriers exhibit symptoms of both conditions, leading to juvenile polyposis-hereditary hemorrhagic telangiectasia syndrome. Three families have been reported with connective tissue abnormalities. To better understand the spectrum and extent of clinical findings in SMAD4 carriers, medical records of 34 patients (20 families) from five clinical practices were reviewed. Twenty-one percent of the patients (7/34) had features suggesting a connective tissue defect: enlarged aortic root (n = 3), aortic and mitral insufficiency (n = 2), aortic dissection (n = 1), retinal detachment (n = 1), brain aneurysms (n = 1), and lax skin and joints (n = 1). Juvenile polyposis-specific findings were almost uniformly present but variable. Ninety-seven percent of the patients had colon polyps that were generally pan-colonic and of variable histology and number. Forty-eight percent of the patients (15/31) had extensive gastric polyposis. Hereditary hemorrhagic telangiectasia features, including epistaxis (19/31, 61%), mucocutaneous telangiectases (15/31, 48%), liver arteriovenous malformation (6/16, 38%), brain arteriovenous malformation (1/26, 4%), pulmonary arteriovenous malformation (9/17, 53%), and intrapulmonary shunting (14/23, 61%), were documented in 76% of the patients. SMAD4 carriers should be managed for juvenile polyposis and hereditary hemorrhagic telangiectasia because symptoms of both conditions are likely yet unpredictable. Connective tissue abnormalities are an emerging component of juvenile polyposis-hereditary hemorrhagic telangiectasia syndrome, and larger studies are needed to understand these manifestations.
authors: Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.
authors: Karen E
authors: KE
authors: Wain
authors: Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, USA.
authors: Marissa S
authors: MS
authors: Ellingson
authors: Department of Pathology, University of Utah, Salt Lake City, Utah, USA.
authors: Jamie
authors: J
authors: McDonald
authors: High Risk Cancer Clinics, Huntsman Cancer Institute, Salt Lake City, Utah, USA.
authors: Amanda
authors: A
authors: Gammon
authors: GeneDx, Gaithersburg, Maryland, USA.
authors: Maegan
authors: M
authors: Roberts
authors: Medical Genetics, Mayo Clinic, Rochester, Minnesota, USA.
authors: Pavel
authors: P
authors: Pichurin
authors: 1] Department of Medicine, University of Melbourne, Melbourne, Australia [2] Genetic Medicine, Royal Melbourne Hospital, Melbourne, Australia.
authors: Ingrid
authors: I
authors: Winship
authors: Medical Genetics and Gastroenterology, Mayo Clinic, Jacksonville, Florida, USA.
authors: Douglas L
authors: DL
authors: Riegert-Johnson
authors: Clinical Cancer Genetics, City of Hope, Duarte, California, USA.
authors: Jeffrey N
authors: JN
authors: Weitzel
authors: Health Science Research, Mayo Clinic, Scottsdale, Arizona, USA.
authors: Noralane M
authors: NM
authors: Lindor
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D003238:Connective Tissue / Q000473:pathology*; D006801:Humans; D007223:Infant; D044483:Intestinal Polyposis / Q000151:congenital* / Q000235:genetics / Q000473:pathology; D008875:Middle Aged; D009154:Mutation; D009386:Neoplastic Syndromes, Hereditary / Q000235:genetics* / Q000473:pathology*; D012189:Retrospective Studies; D015398:Signal Transduction; D051901:Smad4 Protein / Q000235:genetics*; D013683:Telangiectasia, Hereditary Hemorrhagic / Q000235:genetics* / Q000473:pathology*; D016212:Transforming Growth Factor beta / Q000235:genetics; D055815:Young Adult
chemical_list: C497796:SMAD4 protein, human; D051901:Smad4 Protein; D016212:Transforming Growth Factor beta