What is Juvenile Polyposis (JP)-Hereditary Hemorrhagic Telangiectasia (HHT) overlap syndrome?

Juvenile Polyposis-HHT Overlap Syndrome

Juvenile polyposis-HHT overlap syndrome is a combined genetic disorder caused by SMAD4 mutations that manifests with both gastrointestinal juvenile polyps (carrying significant cancer risk) and life-threatening arteriovenous malformations in multiple organs, occurring in 1-2% of HHT cases and requiring comprehensive screening for both polyposis-related malignancies and vascular complications. 1, 2

Genetic Basis

• The syndrome results exclusively from mutations in the SMAD4 gene (also called MADH4), located on chromosome 18q 1, 3
• SMAD4 encodes a protein in the TGF-β signaling pathway, and mutations cause both phenotypes to manifest simultaneously 1, 3
• This represents an autosomal dominant inheritance pattern with 50% transmission risk to offspring 2
• Up to 76% of SMAD4 mutation carriers develop features of HHT, including potentially asymptomatic but life-threatening arteriovenous malformations 2

Clinical Manifestations

Gastrointestinal Features (Juvenile Polyposis Component)

• Patients develop few to hundreds of juvenile polyps throughout the gastrointestinal tract, particularly in the colon, stomach, and small intestine 1
• Polyps are hamartomatous with dense stroma, cystic architecture with mucus-filled glands, prominent lamina propria, and inflammatory infiltration 1
• Typical presenting symptoms include rectal bleeding, anemia from gastrointestinal blood loss, abdominal pain, or intussusception 1, 4
• SMAD4 carriers have significantly higher risk of severe gastric polyposis, and all gastric cancers in one cohort occurred exclusively in SMAD4 carriers 2
• Cumulative lifetime colorectal cancer risk is 39-68%, with relative risk of 34 compared to general population 1, 4
• Gastric cancer risk is 21% in those with gastric polyps 1, 4

Vascular Features (HHT Component)

• Spontaneous and recurrent epistaxis (nosebleeds) occurs in over 90% of adults, typically starting at mean age 11 years 2, 5
• Multiple mucocutaneous telangiectasias develop at characteristic sites including lips, oral cavity, fingers, and nasal mucosa 1, 2
• Arteriovenous malformations develop in brain, lungs, gastrointestinal tract, liver, and retina, creating risk of stroke, cerebral abscess, or hemorrhage 2, 6
• Pulmonary AVMs create right-to-left shunts causing hypoxemia and paradoxical emboli leading to stroke or brain abscess 2
• Hepatic vascular malformations are more common and symptomatic in females 2
• Cardiovascular anomalies including cardiac and CNS vascular abnormalities occur in up to 30% of patients 1, 4

Diagnostic Approach

Clinical Diagnosis

• Diagnosis requires meeting criteria for BOTH conditions: JPS criteria (≥5 juvenile polyps in colorectum, juvenile polyps throughout GI tract, or any number with positive family history) AND HHT Curaçao criteria (≥3 of: epistaxis, telangiectasias, visceral lesions, affected first-degree relative) 2, 4, 3
• Patients may initially present with only one phenotype, making genetic testing critical for identifying the overlap syndrome 3, 7

Genetic Testing

• SMAD4 genetic testing should be performed in all patients with either juvenile polyposis OR HHT, as failure to identify the overlap leads to missed screening for life-threatening complications 2, 3
• Testing should include both sequencing and deletion/duplication analysis 2
• Three cases of de novo SMAD4 mutations have been documented, so absence of family history does not exclude diagnosis 3

Mandatory Screening Protocol

Vascular Screening (Critical for Preventing Mortality)

• All SMAD4 mutation carriers must undergo screening for pulmonary AVMs using contrast echocardiography or chest CT, as these can be treated presymptomatically to prevent stroke and cerebral abscess 2, 5
• MRI of brain is required to detect cerebral vascular malformations 2, 5
• Doppler ultrasonography as first-line imaging for hepatic involvement in all patients 2, 5
• Liver biopsy must be strictly avoided due to high hemorrhage risk 2, 5
• Thoracoabdominal contrast CT to identify additional arteriovenous malformations 6

Gastrointestinal Screening

• SMAD4 mutation carriers require upper GI tract surveillance every 1-3 years starting at age 18 years (earlier than the age 25 recommended for BMPR1A mutations) 2
• Colonoscopy with polypectomy at 2-year intervals for colorectal surveillance 1, 4
• Upper endoscopy to evaluate for gastric and duodenal polyps and telangiectasias 2, 4

Management Strategy

Gastrointestinal Management

• Primary treatment consists of repeated endoscopic polypectomy at 2-year intervals for both colorectal and upper GI polyps 1, 4
• Colectomy with ileorectal anastomosis is appropriate for patients with high polyp burden that cannot be managed endoscopically 1, 4
• Treatment aims to reduce cancer risk and prevent symptoms including bleeding, anemia, and diarrhea 1, 4

Vascular Management

• Percutaneous transcatheter embolization for pulmonary AVMs regardless of feeding artery size due to paradoxical embolism risk 2
• Stepwise approach for bleeding: nasal moisturization first, escalate to oral tranexamic acid, then local ablative therapies, and reserve systemic bevacizumab for refractory cases 2
• Iron replacement therapy for anemia from chronic bleeding 2

Multidisciplinary Care

• All patients with SMAD4 mutations should be managed in conjunction with a specialist HHT center with experience in evaluating and managing both HHT and juvenile polyposis complications 2
• Genetic counseling is essential given 50% inheritance risk 2

Critical Clinical Pitfalls

• Patients with SMAD4 mutations may lack overt clinical symptoms of HHT but remain at risk of asymptomatic AVMs that can present suddenly with catastrophic complications 2, 3
• Failure to screen for juvenile polyposis in SMAD4-positive HHT patients leads to missed gastrointestinal cancers 2
• Conversely, failure to screen for vascular malformations in patients presenting with juvenile polyposis can result in preventable stroke or hemorrhage 3, 7
• The syndrome exhibits phenotypic diversity with some patients showing predominantly upper GI involvement and others predominantly lower GI involvement 8
• Pregnancy poses particular risk as hormonal and hemodynamic changes cause rapid PAVM growth with higher complication risk 5