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Juvenile Polyposis Syndrome, SMAD4 Mutations, and Hereditary Hemorrhagic Telangiectasia

Schwenter, Frank*; Ratjen, Felix; Berk, Terri*; Gallinger, Steve*; Gryfe, Rob*; Gradinger, Abigail B.*; Faughnan, Marie E.§; Durno, Carol A.

Journal of Pediatric Gastroenterology & Nutrition: January 2012 - Volume 54 - Issue 1 - p 120–122
doi: 10.1097/MPG.0b013e3182238514
Case Reports

*Zane Cohen Familial Gastrointestinal Cancer Registry and Department of Surgery, the Mount Sinai Hospital

Division of Gastroenterology, Hepatology, and Nutrition

Division of Respiratory Medicine, the Department of Pediatrics, Hospital for Sick Children, Toronto HHT Centre

§Division of Respirology, Department of Medicine, St Michael's Hospital, Keenan Research Centre of the Li Ka Shing Knowledge Institute and St Michael's Hospital, Division of Respirology, Department of Medicine, University of Toronto, Toronto, Canada.

Address correspondence and reprint requests to Dr Carol Durno, The Hospital for Sick Children, Division of Gastroenterology, Hepatology, and Nutrition, 555 University Ave, Toronto, ON M5G 1X8, Canada (e-mail:

Received 6 April, 2011

Accepted 2 May, 2011

This study was supported by Zane Cohen Digestive Disease Center, Nelson Arthur Hyland Foundation, Keenan Research Centre of the Li Ka Shing Knowledge Institute, and St Michael's Hospital.

The authors report no conflicts of interest.

Solitary juvenile hamartomatous polyps in the colorectum are common in young children and typically present with rectal bleeding. Juvenile polyposis syndrome (JPS) is an autosomal dominant condition characterized by multiple juvenile polyps most commonly found in the colorectum, but can occur throughout the gastrointestinal tract (1). In contrast to patients with solitary polyps, patients with JPS have a markedly increased risk of developing early-onset gastrointestinal cancer. The relative risk for colorectal cancer is 34%, with a lifetime cancer risk of 39% reported as early as 15 years (2). Extracolonic gastrointestinal cancers have been reported in JPS, including stomach and small bowel with a lower frequency than colorectal cancer. Approximately 30% to 40% of patients with JPS have germ-line mutations identified in either the BMPR1A or SMAD4 gene with half to two-thirds of identified mutations being detected in the SMAD4 gene (3,4). A combined syndrome of hereditary hemorrhagic telangiectasia (HHT) and JPS associated with SMAD4 gene mutations was described (5). Initial clinical signs of HHT may be subtle or absent, because disease expression is age related; however, early interventional treatment can prevent life-threatening complications of arteriovenous malformations (AVMs). We present a kindred to highlight the JPS-HHT phenotype and describe the challenges encountered when evaluating patients for JPS-HHT.

Recognizing the JPS-HHT association has clinically significant implications for patients with either JPS or HHT, and so it is critical to make a molecular diagnosis in patients with JPS and HHT to determine whether they are at risk of the combined syndrome.

The patient, a 14-year-old girl, presented with a 6-month history of fatigue and severe iron-deficiency anemia. She denied rectal bleeding, but did have a history of epistaxis. Family history included polyps and colorectal cancer affecting both the father and the paternal grandfather. She had a normal physical examination. Colonoscopy showed 15 polyps in the transverse and right colon (largest 3 × 1 cm), which were on long stalks with a lobulated appearance. The upper endoscopy did not show any polyps. Five polyps were removed by snare polypectomy. Pathologic examination was consistent with juvenile polyps, without evidence of dysplasia. The patient met the diagnostic criteria for JPS (1).

The patient's paternal grandfather was diagnosed with colorectal cancer at 76 years of age. The grandfather presented with rectal bleeding and had 7 inflammatory polyps. At the time of the cancer diagnosis, 8 adenomatous polyps were reported in the colectomy specimen. No other family members have been confirmed with polyps or other malignancies.

The patient's 47-year-old father had a history of epistaxis and in situ carcinoma diagnosed at 28 years of age. He had presented with rectal bleeding and was found to have a 2 × 2 cm polypoid mass in the sigmoid colon. Pathology consisted of a mixed villoadenomatous polyp with focal adenocarcinoma. When he was 32 years of age, a tubular adenoma with low-grade dysplasia was identified in the transverse colon. Three more juvenile polyps in the cecum, rectum, and stomach showed no dysplasia or evidence of neoplastic changes. In view of the early colorectal in situ carcinoma diagnosis, the multiple juvenile and neoplastic polyps, and the history of epistaxis, the combined syndrome of JPS-HHT was suspected. Genetic mutation testing confirmed a SMAD4 mutation (intron 12, c.1447 + 1G>A). Brain magnetic resonance imaging (MRI) did not reveal any cerebral AVMs, and computerized tomography (CT) of the chest did not reveal any pulmonary AVMs.

The patient also carried the SMAD4 mutation and was referred to the HHT clinic. The patient's subsequent workup for HHT included a normal MRI of the brain, but a chest CT revealed a pulmonary AVM (feeding artery diameter <3 mm) in the left lower lobe.

The patient's 13-year-old brother was found to carry the same SMAD4 mutation. He had blood in the stool on 2 occasions and epistaxis but no other symptoms. No telangiectasias were seen on examination. At colonoscopy, 9 polyps were identified in the transverse colon including 3 large polyps (3 × 1 cm), whereas the upper endoscopy was normal. The pathology consisted of juvenile polyps without evidence of dysplasia. Brain MRI screening was negative for cerebral AVMs, but a chest CT revealed a pulmonary AVM (feeding artery >3 mm) in the left lower lobe.

At colonoscopy, 18 months later, the patient (then 15 years of age) had more than 15 large lobulated polyps, which could not be removed endoscopically and was referred for subtotal colectomy. The pathology showed multiple juvenile polyps of variable size and shape (Fig. 1). One juvenile polyp showed adenomatous transformation with low-grade dysplasia (Fig. 2).

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JPS and HHT are most frequently present as distinct diseases; however, a small number of families have an overlap syndrome, JPS-HHT, with SMAD4 mutation. We report a kindred with JPS-HHT presenting with JPS- and HHT-related symptoms and organ involvement. HHT is an autosomal dominant disorder, characterized by the presence of vascular malformations (telangiectasia, AVMs). Chronic gastrointestinal (GI) bleeding develops in approximately 20% of patients with HHT (6), typically in the fifth decade of life and often presenting with anemia. The GI bleeding in HHT occurs secondary to gastrointestinal telangiectasias, which can occur throughout the GI tract, though primarily in the stomach and small bowel. Although the most common symptom of HHT is recurrent epistaxis, patients with HHT are also at risk of organ AVMs in the brain, lungs, liver, and pancreas.

Reports of patients with JPS and pulmonary AVMs in multiple family members have been reported even before the JPS-HHT association has been described (7,8). Clubbing has also been reported in some patients with JPS, a physical finding reported in approximately 10% of patients with pulmonary AVM. HHT is often not diagnosed until later in adult life, and therefore it is likely that many of these JPS cases with pulmonary AVMs and/or clubbing may have in fact had unrecognized HHT.

The majority of patients with HHT (>80%) have mutations in either the endoglin or ACVRL1 genes. Approximately 2% of patients with HHT carry SMAD4 mutations (9), with most SMAD4 families reported to date having the combined JPS-HHT syndrome. Patients with JPS or colorectal cancer can be asymptomatic and may not experience rectal bleeding, but it is important for clinicians to realize that this subset of (SMAD4 mutation positive) patients with HHT is at increased risk of juvenile polyps and colorectal cancer (5,10,11).

As such, patients with either HHT or JPS found to harbor SMAD4 mutations and their at-risk family members should be counseled and referred for screening related to both disorders. Current gastrointestinal management recommendations for JPS include colonoscopy every 2 to 3 years and upper endoscopy every 1 to 3 years beginning with symptoms or in the teens if no symptoms occur (2,12). In patients with HHT, screening and preventive treatment are recommended for pulmonary AVMs and cerebral AVMs (13). The feeding vessel size in pulmonary AVMs is relevant because vessels >3 mm have been associated with an increased risk of complications such as brain abscesses. Endovascular embolization is recommended for feeding vessels >3 mm. Pulmonary AVMs are frequently asymptomatic, but patients are at risk for secondary neurologic (stroke, cerebral abscess) or hemorrhagic (hemoptyisis, hemothorax) complications, which can be prevented with transcatheter embolotherapy. Routine screening of all of the patients with HHT with contrast echocardiography is recommended, followed in positive cases with diagnostic CT of chest (13) and preventive treatment of all significant pulmonary AVMs (13). Similarly, routine screening for cerebral AVMs is recommended, with MR head, with consideration for preventive treatment on a case-by-case basis. Children with HHT often lack the typical clinical features of HHT such as telangiectasia or epistaxis, but are also at risk of pulmonary and cerebral AVMs (14), which can lead to life-threatening complications (15,16).

The prevalence of the combined syndrome of JPS and HHT is not known. As clinicians become more aware of the combined syndrome and more patients with JPS and HHT undergo SMAD4 gene mutation screening and are clinically screened for JPS or HHT, we will hopefully develop a more accurate estimate of the prevalence of JPS-HHT among SMAD4 mutation–positive patients with JPS. There does not appear to be a specific mutation in SMAD4 that predisposes to JPS-HHT (17) and so the combined syndrome should be considered with any SMAD4 mutation. Even if germ-line mutations can be identified in 30% to 40% of patients with JPS, genotyping has not always been recommended, provided that this information has not been considered relevant for management of the disease. The discovery of the combined syndrome of JPS-HHT raises the importance of making a molecular diagnosis in patients with JPS and our reported kindred highlights this. Our kindred highlights the variation in the JPS-HHT phenotype in patients carrying the same SMAD4 mutation, underlining the importance of incorporating the comprehensive family history and assessment in the diagnostic process. Clinical heterogeneity within and among families has also been described with other HHT genotypes.

Prospective studies will aid in understanding the spectrum of the JPS-HHT gastrointestinal phenotype and will allow the development of evidence-based guidelines for screening protocols for gastrointestinal cancer, HHT, and AVMs. Larger studies will also provide a better understanding of the phenotype of the combined syndrome.

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The authors wish to thank Dr Robert Riddell for reviewing the pathology and assisting with the figures; and Heather Miller for assisting with manuscript preparation.

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