YES NO UNKNOWN. Stage I: Rule-Out Dashboard ACTIONABILITY PENETRANCE SIGNIFICANCE/BURDEN OF DISEASE NEXT STEPS. YES ( 1 of above)

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1 Stage I: Rule-Out Dashboard GENE/GENE PANEL: ENG, ACVRL1, SMAD4, GDF2 DISORDER: Hereditary Hemorrhagic Telangiectasia HGNC ID: 3349, 175, 6770, 4217 OMIM ID: , , , ACTIONABILITY PENETRANCE 1. Is there a qualifying resource, such as a practice guideline or systematic review, for the genetic condition? YES NO 2. Does the practice guideline or systematic review indicate that the result is actionable in one or more of the following ways? 4. Is there at least one known pathogenic variant with at least moderate penetrance ( 40%) or moderate relative risk ( 2) in any population? YES NO UNKNOWN SIGNIFICANCE/BURDEN OF DISEASE Yes No Patient Management Surveillance or Screening 5. Is this condition an important health problem? YES NO Family Management NEXT STEPS Circumstances to Avoid YES ( 1 of above) NO 3. Is the result actionable in an undiagnosed adult with the genetic condition? YES NO 6. Are Actionability (Q2-3), Penetrance (Q4), and Significance (Q5) all YES? YES (Proceed to Stage II) NO (Consult Actionability Working Group) Exception granted, proceed to Stage II Exception not granted, STOP 1

2 GENE/GENE PANEL: ENG, ACVRL1, SMAD4, GDF2 DISORDER: Hereditary Hemorrhagic Telangiectasia Topic Narrative Description of Evidence Ref Signif/Burden of Condition 1. What is the nature of the threat to health for an individual carrying a deleterious allele? Prevalence of the genetic disorder Clinical Features (Signs/symptoms) Natural History (Important subgroups & survival/recovery) The estimated prevalence of hereditary hemorrhagic telangiectasia (HHT) ranges from 1/10,000 to 1/5000. HHT is characterized by the presence of multiple arteriovenous malformations (AVMs) that lack intervening capillaries and result in direct connections between arteries and veins. Small telangiectases close to the surface of the skin and mucous membranes often rupture and bleed after slight trauma and are most evident on the lips, tongue, buccal mucosa, face, chest and fingers. They are common in adulthood throughout the gastrointestinal mucosa. Recurrent and spontaneous epistaxis (nosebleed) is the most common symptom of HHT and is the most common feature to bring young individuals with HHT to medical attention. It is caused by minor insults from drying air and repeated minor abrasions to the fragile nasal mucosa. Epistasis and/or GI bleeding can cause mild to severe anemia, often requiring iron replacement therapy or blood transfusion. HHT is often complicated by the presence of AVMs in the brain, lung, gastrointestinal tract, and liver. In contrast to complications of smaller telangiectases, the complications of AVMs often result from the shunting of blood, leading to increased cardiac output and, in the lung, desaturation of arterial blood. Patients with mutations in the SMAD4 genes may also be affected by a rare syndrome that combines HHT and juvenile polyposis. Although HHT is a developmental disorder and infants are occasionally severely affected, in most people the features are age-dependent and the diagnosis is not suspected until adolescence or later. The average age of onset for epistaxis is 12 years, with 50-80% of patients affected before the age of 20 and 78-96% developing it eventually. Most patients report the appearance of telangiectasia of the mouth, face, or hands 5-30 years after the onset of nose bleeds, most commonly during the third decade. GI bleeding, when present, usually presents in the 5 th or 6 th decades of life. Patients rarely develop significant GI bleeding before 40 years of age. Women are affected with GI bleeding in a ratio of 2-3:1. AVMs of the brain are typically present at birth, whereas those in the lung and liver typically develop over time. Hemorrhage is often the presenting symptom of cerebral AVMs, while visceral AVMs may cause transient ischemic attacks, embolic stroke, and cerebral or other abscesses. Hepatic AVMs can present as high-output heart failure, portal hypertension, or biliary disease. 2. How effective are interventions for preventing the harm? Information on the effectiveness of the recommendations below was not provided unless otherwise stated. To establish the extent of disease and needs in an individual diagnosed with HHT the following evaluations are recommended: Medical history and physical exam Complete blood count Measurement of oxygen saturation via pulse oximetry Contrast echocardiography for detection of pulmonary shunting/avm and measurement of the pulmonary artery systolic pressure as a screen for pulmonary Patient artery hypertension (Tier 3) Management Patients with HHT-related epistaxis should use agents that humidify the nasal mucosa to prevent endonasal crusting that can damage endonasal telangiectasia and cause bleeding. There are small case series of various topical medications, including lubricants (e.g., saline, antibiotic ointments), as well as topical estrogen cream/ointment and antifibrinolytics, with variable success in decreasing HHT-related epistaxis. There are insufficient published data to recommend one topical therapy over another; however, expert experience is that there is (1, 2) (1, 2) (1, 2) 2

3 mild benefit from humidification and that the risk of topical lubricants and saline is very low. (Tier 2) Surveillance When considering nasal surgery for reasons other than epistaxis the patients and the clinician should obtain consultation from an otorhinolaryngologists with expertise in HHTrelated epistaxis who can guide procedural interventions to minimize risk of worsening epistaxis. (Tier 2) Patients should undergo annual evaluation by a health care provider familiar with HHT, including interval history for epistaxis or other bleeding, shortness of breath or decreased exercise tolerance, and headache or other neurologic symptoms. (Tier 3) Patients with HHT should be screened for cerebral vascular malformations (CVMs). Screening is recommended in the first 6 months of life (or at time of diagnosis), with unenhanced MRI and in an adult patient at age 18 using MRI with and without contrast. Those screening positive should be referred to a center with neurovascular expertise to be considered for invasive testing and individualized management. There is no evidence for any role of repeat MRI screening in adults after an initial negative study. While the rationale for screening for CVMs in HHT is that screening will detect a treatable CAVM before the development of a life-threating or debilitating complications, there no published studies of the efficacy or safety of any form of treatment of CVMs in HHT patients. (Tier 2) No published studies of the efficacy or safety of any form of treatment of CAVMs in HHT patients were identified. This recommendation was based on the effectiveness presented in several large case studies of embolization, microsurgery and stereotactic radiation in patients with non-hht CAVMs. However, more recently in 2014, the results of A Randomised trial of Unruptured Brain Arteriovenous malformations (ARUBA) indicated that individuals who were randomized to medical management alone (pharmacologic therapy for neurologic symptoms as needed) compared to medical management with interventional therapy (surgery, embolization, radiotherapy, alone or in combination) had a significantly decreased risk of death or stroke (hazard ratio 0.27, 95% CI ). This trial included 223 randomized patients with a mean follow-up of 33.3 months. No harms were identified, other than a higher number of strokes (45 vs 12, p<0 0001) and neurological deficits unrelated to stroke (14 vs 1, p=0 0008) in patients allocated to interventional therapy. (Tier 5) Studies of the natural history of cerebral AVMS in patients with HHT are limited. A study of 29 HHT patients with CAVMs found a bleeding risk of 0.4% to 0.7%. A more recent study of 153 HHT patients followed over three years found an overall bleeding rate of 1% per year, with a rupture rate of 0.4% per year for unruptured AVMs and 10% per year for ruptured AVMs. While not specific to HHT patients, the ARUBA study and a recent meta-analysis both found rupture rates of around 2.2% per year for unruptured AVMs. (Tier 5) Patients with HHT should be screened for pulmonary arteriovenous malformations (PAVMs) using transthoracic contrast echocardiography (TTCE). The rationale for screening HHT patients for PAVMs is that screening will detect a treatable PAVM before the development of a life-threatening or debilitating complication. Screening should be performed at the time of initial clinical evaluation to identify patients appropriate for treatment. In patients with negative initial screening, repeat screening should be considered every 5-10 years, within 5 years preceding a planned pregnancy, or after pregnancy. Embolization has been shown in several non-controlled series to be efficacious and have shown high rates of immediate technical success. Longer term, reperfusion did occur in up to 15% of patients and growth of small PAVMs in up to 18%.(Tier 2) (3, 4) (5) 3

4 Family Management Circumstances to Avoid Stage II: Summary Report Patients over 35 should have annual measurements of hemoglobin or hematocrit levels due to the increased risk of GI bleeding with age. Oral and/or intravenous iron supplementation is recommended as first-line therapy for mild anemia and chronic bleeding secondary to HHT-related telangiectasia. There are no studies of iron replacement in HHT. Directed endoscopic evaluation should be undertaken in patients with anemia disproportionate to epistaxis. (Tier 2) Women should be screened and treated as indicated for pulmonary and cerebral AVMs before pregnancy to avoid serious complications. (Tier 3) Individuals with SMAD4 mutations, which are also associated with juvenile polyposis, should undergo gastrointestinal screening for polyposis and gastrointestinal malignancy as per national juvenile polyposis screening recommendations. (Tier 2) [This topic is addressed in a separate report on Juvenile Polyposis Syndrome] If an HHT causing mutation is identified in the index case, diagnostic genetic testing for HHT can be offered to all at risk relatives. (Tier 2) Family members at risk for HHT or in whom HHT has not been ruled out should undergo annual evaluation by a health care provider familiar with HHT, including interval history for epistaxis or other bleeding, shortness of breath or decreased exercise tolerance, and headache or other neurologic symptoms. (Tier 3) Asymptomatic children of a parent with HHT should be considered to have possible HHT unless excluded by genetic testing. If genetic testing is not possible, the clinician should proceed as if the child has HHT and consider appropriate screening for visceral AVMs. (Tier 2) Patients with possible HHT should be screened for CVMs. Screening is recommended in the first 6 months of life (or at time of diagnosis) with an unenhanced MRI and in an adult patient at age 18 using MRI with and without contrast. All patients with a positive MRI should be referred to a center with neurovascular expertise for consideration of invasive testing and further management. (Tier 2) Family members with SMAD4 mutations should undergo gastrointestinal screening for polyposis and gastrointestinal malignancy as per national screening recommendations. (Tier 2) [This topic is addressed in a separate report on Juvenile Polyposis Syndrome] While HHT-related epistaxis is not an absolute contraindication to anticoagulation/antiplatelet therapy, these agents can increase the risk of epistaxis and the decision to use these agents should be based on the individual patient risks and benefits. (Tier 2) Individuals with significant epistaxis are advised to avoid vigorous nose blowing, lifting of heavy objects, straining during bowel movements, and finger manipulation in the nose. (Tier 4) Scuba diving should be avoided unless contrast echocardiography performed within the last five years was negative for evidence of a right to left shunt. (Tier 4) Description of sources of evidence: Tier 1: Evidence from a systematic review, or a meta-analysis or clinical practice guideline clearly based on a systematic review Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources 4

5 Tier 5: Evidence from a non-systematically identified source 5

6 GENE/GENE PANEL: ENG, ACVRL1, SMAD4, GDF2 DISORDER: Hereditary Hemorrhagic Telangiectasia Topic Narrative Description of Evidence Ref 3. What is the chance that this threat will materialize? Mode of Inheritance Prevalence of Genetic Mutations Penetrance OR Relative Risk (include high risk racial or ethnic subgroups) Autosomal dominant Information on the prevalence of HHT-related mutations was unavailable. No evidence was identified on the penetrance of HHT mutations among screen-identified mutation carriers. A French-Italian HHT network examined the frequency of manifestations among 343 patients including 135 probands and 208 relatives with ENG or ACVRL1 mutations (mean age of 50.) Among those with an ENG mutation the frequency of manifestations were: Epistaxis: 97% Telangiectases: 98% Pulmonary AVM: 54% Cerebral AVM: 9% Hepatic AVM: 44% GI bleeding: 7% Among those with an ACVRL1 mutation the frequency of manifestations were: Epistaxis: 89% Telangiectases: 93% Pulmonary AVM: 13% Cerebral AVM: 4% Hepatic AVM: 57.6% GI bleeding: 16.4% (Tier 5) SMAD4: A retrospective review from 5 clinical centers identified 34 SMAD4 mutation carriers from 20 families with a mean age of 35.1 years. Features associated with HHT were documented in 76% of individuals. Epistaxis: 61% Telangiectases: 48% Pulmonary AVM: 53% Cerebral AVM: 4% Hepatic AVM: 38% Colon polyps: 97% (Tier 5) (6) (7) Expressivity Only three HHT patients have been identified with GDF2 mutations. All three individuals had epistaxis and telangiectases. One patient was found to have abnormal liver enyzmes and portal hypertension. The other two patients were not screened for solid organ involvement. (Tier 3) No information on relative risk was identified. Intrafamilial variability is considerable among HHT with signs and symptoms presenting with various severities and at varying ages of onset. (Tier 4) 4. What is the nature of the intervention? Nature of Intervention Identified interventions include various forms of imaging. 5. Would the underlying risk or condition escape detection prior to harm in the (8) 6

7 setting of recommended care? Chance to Escape Clinical Detection Although HHT is a development disorder and infants are occasionally severely affected, in most people the features are age-dependent and the diagnosis is not suspected until adolescence or later. In addition, HHT is often not diagnosed, and entire families therefore remain unaware of available screening and treatment, and children and adults unnecessarily develop stroke or life-threatening hemorrhage. (1, 2) Final Consensus Scores Gene(s) Outcome/intervention pair Severity Likelihood Effectiveness Nature of the Intervention Total Score Anticipatory treatment to avoid CAVM 2 2E 2B 3 9EB ENG morbidity/cerebral MRI Anticipatory treatment to avoid PAVM 2 3E 3B 3 11EB morbidity/ttce Anticipatory treatment to avoid CAVM 2 1E 2B 3 8EB ACVRL1 morbidity/cerebral MRI Anticipatory treatment to avoid PAVM 2 2E 3B 3 10EB morbidity/ttce Anticipatory treatment to avoid CAVM 2 1E 2B 3 8EB SMAD4 morbidity/cerebral MRI Anticipatory treatment to avoid PAVM 2 3E 3B 3 11EB morbidity/ttce Anticipatory treatment to avoid CAVM 2 0D 2B 3 7DB GDF2 morbidity/cerebral MRI Anticipatory treatment to avoid PAVM 2 0D 3B 3 8DB morbidity/ttce To see the scoring key, please go to: Date of Search (MM.DD.YYYY): References 7

8 1. Faughnan ME, Palda VA, Garcia-Tsao G, Geisthoff UW, McDonald J, Proctor DD, et al. International guidelines for the diagnosis and management of hereditary haemorrhagic telangiectasia. Journal of medical genetics. 2011;48: McDonald J, Pyeritz RE. Hereditary Hemorrhagic Telangiectasia. GeneReviews(R) Gupta S, Faughnan ME, Bayoumi AM. Embolization for pulmonary arteriovenous malformation in hereditary hemorrhagic telangiectasia: a decision analysis. Chest. 2009;136(3): Mohr JP, Parides MK, Stapf C, Moquete E, Moy CS, Overbey JR, et al. Medical management with or without interventional therapy for unruptured brain arteriovenous malformations (ARUBA): a multicentre, non-blinded, randomised trial. Lancet. 2014;383(9917): Brinjikji W, Iyer VN, Sorenson T, Lanzino G. Cerebrovascular Manifestations of Hereditary Hemorrhagic Telangiectasia. Stroke; a journal of cerebral circulation. 2015;46(11): Lesca G, Olivieri C, Burnichon N, Pagella F, Carette MF, Gilbert-Dussardier B, et al. Genotype-phenotype correlations in hereditary hemorrhagic telangiectasia: data from the French-Italian HHT network. Genetics in medicine : official journal of the American College of Medical Genetics. 2007;9: Wain KE, Ellingson MS, McDonald J, Gammon A, Roberts M, Pichurin P, et al. Appreciating the broad clinical features of SMAD4 mutation carriers: a multicenter chart review. Genetics in medicine : official journal of the American College of Medical Genetics. 2014;16(8): O'Neill M. TELANGIECTASIA, HEREDITARY HEMORRHAGIC, TYPE 5; HHT5 OMIM2013. Available from: 8