The prevalence of hereditary hemorrhagic telangiectasia in juvenile polyposis syndrome
Margaret O'Malley1, Lisa LaGuardia, Matthew F Kalady
1Sanford R. Weiss MD Center for Hereditary Colorectal Neoplasia in the Digestive Disease Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Insights
Nearly all patients with juvenile polyposis SMAD4 mutations have an overlap syndrome with hereditary hemorrhagic telangiectasia. This highlights the importance of screening for hereditary hemorrhagic telangiectasia in these individuals.
Area of Science:
- Genetics
- Gastroenterology
- Vascular Medicine
Background:
- Juvenile polyposis syndrome (JPS) is an autosomal dominant disorder characterized by numerous gastrointestinal juvenile polyps.
- SMAD4 mutations are identified in approximately 50% of JPS patients.
- Hereditary hemorrhagic telangiectasia (HHT) is a vascular disorder presenting with epistaxis and arteriovenous malformations.
Purpose of the Study:
- To determine the prevalence and clinical features of HHT in patients with JPS and SMAD4 mutations.
- To assess the diagnostic utility of the Curacao criteria for HHT in this cohort.
Main Methods:
- A cohort study was conducted using inherited colon cancer registries.
- HHT manifestations were gathered from medical records, patient interviews, and prospective screening.
- The Curacao criteria were applied for HHT diagnosis (≥3 criteria) and suspicion (2 criteria).
Main Results:
- Of 41 JPS families, 9 had individuals with SMAD4 mutations (21 relatives).
- Eighty-one percent of SMAD4 mutation carriers met the diagnostic criteria for HHT, and 14% were suspected of having HHT.
- Epistaxis and asthma were the most frequent symptoms; arteriovenous malformations were nearly universal.
Conclusions:
- The juvenile polyposis-hereditary hemorrhagic telangiectasia overlap syndrome is highly prevalent in SMAD4 mutation carriers.
- Genetic testing for JPS necessitates awareness of potential HHT co-occurrence and the need for screening.
- Healthcare providers should recognize this overlap syndrome for appropriate patient management.
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.
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