Appreciating the broad clinical features of SMAD4 mutation carriers: A multicenter chart review

Karen E. Wain, Marissa S. Ellingson, Jamie McDonald, Amanda Gammon, Maegan Roberts, Pavel Pichurin, Ingrid Winship, Douglas L. Riegert-Johnson, Jeffrey N. Weitzel, Noralane M. Lindor

Research output: Contribution to journalArticlepeer-review

35 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)588-593
Number of pages6
JournalGenetics in Medicine
Issue number8
StatePublished - Aug 2014


  • HHT
  • JP
  • SMAD4
  • connective tissue

ASJC Scopus subject areas

  • Genetics(clinical)


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