Clinical Phenotype of Patients with Both ENG and SMAD4 Mutations
A patient with both ENG and SMAD4 mutations would present with a combined syndrome manifesting features of HHT type 1 (from ENG), juvenile polyposis syndrome, and the HHT-JPS overlap syndrome (from SMAD4), creating a severe multi-system phenotype requiring comprehensive screening and specialized management. 1
Primary Clinical Manifestations
Hereditary Hemorrhagic Telangiectasia Features (from both mutations)
Epistaxis presents as spontaneous and recurrent nosebleeds, typically debuting earlier and potentially more severe due to the ENG mutation, occurring in over 90% of patients 2, 3
Mucocutaneous telangiectasias develop at characteristic sites including lips, oral cavity, fingers, and nasal mucosa, representing one of the four Curaçao diagnostic criteria 2, 4
Pulmonary arteriovenous malformations (PAVMs) occur with significantly higher frequency and larger size in patients with ENG mutations (HHT1), creating right-to-left shunts that cause hypoxemia and risk of paradoxical emboli leading to stroke or cerebral abscess 2, 3
Cerebral arteriovenous malformations are more common with ENG mutations, with nearly one in five HHT patients developing stroke or cerebral abscess 2, 3
Juvenile Polyposis Features (from SMAD4)
Gastrointestinal polyposis demonstrates 100% penetrance in patients with SMAD4 mutations, with two distinct phenotypes: predominantly upper gastrointestinal involvement (9/14 patients) or predominantly lower gastrointestinal involvement (5/14 patients) 5, 6
Severe gastric polyposis occurs with significantly higher risk in SMAD4 carriers (73% versus 8%; p<0.001), with all cases of gastric cancer in one cohort occurring exclusively in SMAD4 pathogenic variant carriers 1
Early onset colorectal cancer develops at a mean age of 28 years in JP-HHT patients with SMAD4 mutations, representing a critical mortality risk 6
Colonic polyps require surveillance starting at age 15 years or earlier if symptomatic, with 1-3 year intervals based on polyp burden 1, 6
Combined Syndrome-Specific Features (from SMAD4)
Severe anemia occurs at significantly higher rates than in HHT patients without SMAD4 mutations, resulting from combined epistaxis and gastrointestinal bleeding from both telangiectasias and polyps 6
Hepatic arteriovenous malformations may be present, though hepatic involvement is generally more common in HHT2 (ACVRL1 mutations) 3
Cardiovascular anomalies including thoracic aortic disease (38% of SMAD4 carriers) and mitral valve dysfunction have been reported 1
Musculoskeletal anomalies are frequently identified in the HHT-JPS overlap syndrome, emphasizing the systemic nature of this combined condition 5
Critical Life-Threatening Risks
Asymptomatic Arteriovenous Malformations
Patients may lack overt clinical symptoms of HHT but remain at risk of asymptomatic AVMs that can result in life-threatening complications including stroke, cerebral abscess, or catastrophic hemorrhage 1, 2
Pulmonary AVMs must be treated presymptomatically to prevent stroke and cerebral abscess, as these create direct artery-to-vein connections bypassing capillaries 2
Gastrointestinal Malignancy Risk
All gastric cancers in one cohort occurred exclusively in SMAD4 pathogenic variant carriers, making intensive gastrointestinal surveillance mandatory 1
Colorectal cancer develops at early ages (mean 28 years) in JP-HHT patients, requiring aggressive screening protocols 6
Mandatory Screening Protocol
Immediate Upon Diagnosis
Screen for pulmonary AVMs using contrast echocardiography or chest CT immediately, as PAVMs are more frequent and larger in HHT1 (ENG mutations) and can be treated presymptomatically 2
Perform brain MRI to detect cerebral vascular malformations, as cerebral AVMs occur more commonly in HHT1 and carry high stroke risk 2
Conduct Doppler ultrasonography as first-line imaging for liver involvement, but never perform liver biopsy due to catastrophic hemorrhage risk 2, 4
Gastrointestinal Surveillance
Initiate colonoscopic surveillance at age 15 years or earlier if symptomatic, with 1-3 yearly intervals personalized according to colorectal phenotype 1, 6
Begin upper GI tract surveillance every 1-3 years starting at age 18 years (earlier than the age 25 recommended for BMPR1A mutations alone), due to the 73% prevalence of gastric polyposis in SMAD4 carriers 1
Ongoing Monitoring
Assess complete blood count and iron studies regularly to monitor for severe anemia from combined bleeding sources 6
Screen for cardiovascular anomalies including aortopathy and valvular dysfunction, which occur in 38% of SMAD4 carriers 1
Management Coordination
All patients with both ENG and SMAD4 mutations must be managed in conjunction with a specialist HHT center with experience in evaluating and managing both HHT and juvenile polyposis complications, as these patients face life-threatening risks from multiple organ systems 1, 2
Coordinate care between gastroenterology (for polyposis surveillance and cancer screening), interventional radiology (for AVM treatment), hematology (for anemia management), and genetics services 1, 2
Prioritize quality of life in treatment decisions, as chronic bleeding causes significant psychosocial morbidity, social isolation, and difficulties with employment and daily activities 2
Critical Pitfalls to Avoid
Never rely on absence of symptoms to defer screening for AVMs, as asymptomatic pulmonary and cerebral AVMs can present suddenly with stroke, cerebral abscess, or catastrophic hemorrhage 1, 2
Never perform liver biopsy in any patient with proven or suspected HHT due to high hemorrhage risk from vascular malformations 2, 4
Never delay gastrointestinal surveillance based on absence of polyps in childhood, as SMAD4 mutations demonstrate 100% penetrance of polyposis phenotype and all gastric cancers occurred in SMAD4 carriers 1, 6
Do not focus solely on hemoglobin levels when assessing anemia severity—ferritin and transferrin saturation must also be normalized, as iron deficiency without anemia still causes significant fatigue and morbidity 2