BACKGROUND: Juvenile polyposis syndrome is a dominant GI polyposis syndrome 
defined by ≥ 5 GI juvenile polyps or ≥ 1 juvenile polyps with a family history 
of juvenile polyposis. Mutations in BMPR1A or SMAD4 are found in 50% of 
individuals. Hereditary hemorrhagic telangiectasia is a dominant disorder 
characterized by epistaxis, visceral arteriovenous malformations, and 
telangiectasias. Hereditary hemorrhagic telangiectasia is diagnosed when ≥ 3 
criteria including clinical manifestations or a family history, are present. A 
juvenile polyposis-hereditary hemorrhagic telangiectasia overlap syndrome has 
previously been reported in 22% of patients with juvenile polyposis due to a 
SMAD4 mutation.
OBJECTIVE: Our objective was to determine the prevalence and clinical 
manifestations of hereditary hemorrhagic telangiectasia by Curacao criteria in 
our juvenile polyposis SMAD4 patients.
DESIGN, PATIENTS, AND SETTING: This was a cohort study of juvenile polyposis 
patients in our inherited colon cancer registries. Hereditary hemorrhagic 
telangiectasia manifestations were obtained from medical records, patient 
contact, and/or prospective hereditary hemorrhagic telangiectasia screening. The 
Curacao criteria was used for diagnosis of hereditary hemorrhagic telangiectasia 
(≥ 3 criteria diagnostic; 2 criteria suspect of).
MAIN OUTCOME MEASURES: Prevalence and clinical manifestations of hereditary 
hemorrhagic telangiectasia in juvenile polyposis SMAD4 patients.
RESULTS: Forty-one juvenile polyposis families were identified. Genetic testing 
was available for individuals within 18 families. SMAD4 mutations were found in 
21 relatives in 9 families. Eighty-one percent of SMAD4 patients had hereditary 
hemorrhagic telangiectasia and 14% were suspected of having hereditary 
hemorrhagic telangiectasia. Epistaxis and asthma are the most common symptoms in 
our overlap patients. Symptomatic and subclinical arteriovenous malformations 
were noted near universally.
LIMITATIONS: There was a single, tertiary referral center.
CONCLUSIONS: Nearly all juvenile polyposis SMAD4 patients have the overlap 
syndrome. The clinical implications and need for hereditary hemorrhagic 
telangiectasia screening are important factors for genetic testing in juvenile 
polyposis. Health care providers must be cognizant of the juvenile 
polyposis-hereditary hemorrhagic telangiectasia overlap syndrome and the 
implications for management of these patients.