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Hereditary Hemorrhagic Telangiectasia

Synonyms: HHT, Osler-Weber-Rendu Disease

, MS, CGC and , MD, PhD, FACMG.

Author Information
, MS, CGC
Co-Director, HHT Clinic
Departments of Radiology and Pathology
University of Utah Medical Center
Salt Lake City, Utah
, MD, PhD, FACMG
Departments of Medicine and Genetics
Perelman School of Medicine at the University of Pennsylvania
Director, HHT Center
Hospital of the University of Pennsylvania
Philadelphia, Pennsylvania

Initial Posting: ; Last Update: July 24, 2014.

Summary

Disease characteristics. Hereditary hemorrhagic telangiectasia (HHT) is characterized by the presence of multiple arteriovenous malformations (AVMs) that lack intervening capillaries and result in direct connections between arteries and veins. Although HHT is a developmental disorder and infants are occasionally severely affected, in most people the features are age-dependent and the diagnosis not suspected until adolescence or later. Small AVMs (or telangiectases) close to the surface of the skin and mucous membranes often rupture and bleed after slight trauma. The most common clinical manifestation is spontaneous and recurrent nosebleeds (epistaxis) beginning on average at age 12 years. Approximately 25% of individuals with HHT have GI bleeding, which most commonly begins after age 50 years. Large AVMs often cause symptoms when they occur in the brain, liver, or lungs; complications from bleeding or shunting may be sudden and catastrophic.

Diagnosis/testing. The diagnosis of HHT is based on the presence of epistaxis, cutaneous or mucosal telangiectases, visceral AVMs, family history, and presence of a pathogenic variant. HHT is caused by pathogenic variants in a number of genes involved in the TGF-β/BMP signaling cascade: ENG, the gene encoding the cell surface co-receptor endoglin; ACVRL1 (previously ALK1), also a gene encoding a cell surface receptor; SMAD4, a gene encoding an intracellular signaling molecule; GDF2, a gene encoding a growth/differentiation factor; and at least two other as-yet unidentified genes. Molecular genetic testing of ENG, ACVRL1, SMAD4, and GDF2 detects pathogenic variants in approximately 80%-87% of individuals who meet unequivocal clinical diagnostic criteria for HHT.

Management. Treatment of manifestations: Nosebleeds are treated with humidification, nasal lubricants, topical agents, systemic hormones, oral drug therapy, laser ablation, septal dermoplasty, and nasal closure. GI bleeding is treated with iron replacement therapy and (if needed) endoscopic ablation, surgical resection of bleeding sites, and/or medical therapy. Pulmonary AVMs with feeding vessels 2-3 mm or greater in diameter require catheter-based occlusion with coils. Cerebral AVMs are treated, when indicated by location or symptoms, by surgery, embolotherapy, and/or stereotactic radiosurgery. Hepatic AVMs are usually asymptomatic, but can lead to high-output cardiac failure, liver fibrosis, and rarely liver failure. Most individuals with symptomatic hepatic AVM are managed medically; liver transplantation is recommended for the small number of symptomatic persons who cannot be managed medically. Women with HHT considering pregnancy are screened and treated for pulmonary and cerebral AVMs; pulmonary AVMs discovered during pregnancy are treated during the second trimester. Iron replacement is preferred for anemia, but transfusion of packed red blood cells may be necessary for symptomatic anemia.

Prevention of secondary complications: When pulmonary AVMs are present or suspected, antibiotic prophylaxis for dental and invasive procedures and a filter on intravenous lines to prevent air bubbles from being inadvertently infused is recommended.

Surveillance: Annual evaluations for anemia; evaluation for pulmonary AVMs by pulse oximetry every one to two years during the first decade of life and every five years by contrast echocardiogram thereafter. Appearance of contrast on the left side of the heart after four to eight cardiac cycles, or in the presence of an intracardiac shunt, is evaluated further with high-resolution CT angiography of the chest. While most cerebral AVMs are congenital lesions, reports of the development or evolution of cerebral AVMs in the first two decades of life exist; therefore, rescreening for cerebral AVMs through brain MRI is recommended after puberty if the initial brain MRI was done in childhood. Periodic screening for gastrointestinal polyps and malignant change in persons with juvenile polyps is recommended.

Agents/circumstances to avoid: Vigorous nose blowing; electric or chemical cautery for nosebleeds; anticoagulant and anti-inflammatory agents (including aspirin) in individuals with significant nose or GI bleeding.

Genetic counseling. HHT is inherited in an autosomal dominant manner with considerable intrafamilial variability. Most individuals have an affected parent. Each child of a proband and the sibs of most probands are at a 50% risk of inheriting the pathogenic variant. Prenatal testing is possible for pregnancies at increased risk if the pathogenic variant in the family is known.

Diagnosis

Clinical Diagnosis

The diagnosis of hereditary hemorrhagic telangiectasia (HHT) is based on the presence of multiple arteriovenous malformations (AVMs), which may be evident as telangiectases on the skin, mucus membranes, or both, and as larger visceral AVMs [Marchuk et al 1998, Faughnan et al 2011, McDonald et al 2011a, Guttmacher et al 2012].

Findings

  • Nosebleeds (epistaxis). Spontaneous and recurrent (Night-time nosebleeds heighten the concern for HHT.)
  • Mucocutaneous telangiectases (small blanchable red spots that are focal dilatations of post-capillary venules or delicate, lacy red vessels composed of markedly dilated and convoluted venules). Multiple, at characteristic sites, including lips, oral cavity, fingers, and nose. Transillumination of the digits is helpful for detecting vascular lesions not evident on the skin [Mohler et al 2009].
  • Visceral arteriovenous malformation (AVM). An arteriovenous malformation lacks capillaries and consists of direct connections between arteries and veins. AVMs may be:
  • Family history. A first-degree relative in whom HHT has been diagnosed

The clinical diagnosis of HHT [Shovlin et al 2000] is considered:

  • Definite when three or more findings are present;
  • Possible or suspected when two findings are present;
  • Unlikely when one or no findings are present.

Note: The application to children of these clinical diagnostic criteria, established mostly for adults, can be misleading. Symptoms and signs of HHT generally develop during childhood and adolescence, such that the absence of epistaxis, telangiectases, or symptoms of solid organ AVM is common in affected children [Morgan et al 2002, Mei-Zahav et al 2006]. Children at risk for HHT by virtue of having an affected parent should undergo molecular genetic testing to confirm or refute the diagnosis if a familial pathogenic variant has been identified. In families in which a pathogenic variant has not been identified, at-risk children should have repeat clinical evaluation for manifestations of the disorder as they age.

Molecular Genetic Testing

Genes. There are four genes in which pathogenic variants are known to cause hereditary hemorrhagic telangiectasia:

  • ENG. Hereditary hemorrhagic telangiectasia type 1 (HHT1)
  • ACVRL1 (previously ALK1). Hereditary hemorrhagic telangiectasia type 2 (HHT2)
  • SMAD4. Hereditary hemorrhagic telangiectasia variably associated with juvenile polyposis
  • GDF2. Hereditary hemorrhagic telangiectasia type 5 (HHT5) [Wooderchak-Donahue et al 2013]

The percentage of pathogenic variants in ENG and ACVRL1 are virtually equal (53% and 47% respectively) if founder effects are excluded [Bayrak-Toydemir et al 2004].

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in HHT

Gene 1 Proportion of HHT Attributed to Pathogenic Variants in This Gene 2Test Method
ENG39%-59% 3, 4
(~50% in N America)
Sequence analysis 5
Deletion/duplication analysis 6, 7
ACVRL125%-57% 3, 4
(~35% in N America)
Sequence analysis 5
Deletion/duplication analysis 6, 7
SMAD41%-2% 3, 4, 8Sequence analysis 5
Deletion/duplication analysis 3, 9
GDF2<1% 10Sequence analysis 5
Other or Unknown 11, 12NANA

1. See Table A. Genes and Databases for chromosome locus and protein name. See Molecular Genetics for information on allelic variants detected in this gene.

2. The proportion of ENG and ACVRL1 pathogenic variants is roughly similar, with a slight preponderance of ENG pathogenic variants in North America and in northern Europe [Brusgaard et al 2004, Letteboer et al 2005, Schulte et al 2005, Bossler et al 2006, Prigoda et al 2006, Gedge et al 2007] and a greater preponderance of ACVRL1 pathogenic variants in southern Europe [Lenato et al 2006, Lesca et al 2006, Olivieri et al 2007].

3. Sequence analysis of ENG, ACVRL1, and SMAD4 identifies pathogenic variants in approximately 75% of individuals with HHT [Bossler et al 2006, Prigoda et al 2006, Gedge et al 2007, Richards-Yutz et al 2010].

4. There are no common pathogenic variants, and sequence variants interpreted to be of uncertain significance are particularly common.

5. Sequence analysis detects variants that are benign, likely benign, of unknown significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

6. Testing that identifies exonic or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

7. The use of deletion/duplication analysis in addition to sequence analysis increases the detection rate by approximately 10% for ACVRL1- and ENG-related HHT [Bossler et al 2006, Prigoda et al 2006, McDonald et al 2011b].

8. Or approximately 10% of those who test negative for a pathogenic variant in ENG and ACVRL1 [Gallione et al 2006, Lesca et al 2006, Prigoda et al 2006]

9. No deletions or duplications involving SMAD4 have been reported to cause SMAD4-related hereditary hemorrhagic telangiectasia. (Note: By definition, deletion/duplication analysis identifies rearrangements that are not identifiable by sequence analysis of genomic DNA.)

10. Pathogenic variants in GDF2 were identified in three individuals with features of HHT [Wooderchak-Donahue et al 2013].

11. One individual with signs of HHT and prominent pulmonary hypertension had a pathogenic variant in BMPR2 [Rigelsky et al 2008].

12. Linkage analysis in one pedigree suggests a 5.4-cm disease gene interval on chromosome 5 (HHT3) [Cole et al 2005]. Linkage analysis in another pedigree suggests a disease gene in a 7-Mb region on the short arm of chromosome 7 (7p14) (HHT4) [Bayrak-Toydemir et al 2006a]. Rare pedigrees are not linked to any of these loci, suggesting additional heterogeneity.

Testing Strategy

To confirm/establish the diagnosis in a proband

Single gene testing. One strategy for molecular diagnosis of a proband suspected of having HHT is cascade single gene testing.

  • Simultaneous testing of ENG and ACVRL1 by both sequence analysis and duplication/deletion analysis is recommended given the relatively high percentage of mutation-negative results and uncertain variants by sequence analysis alone.
  • SMAD4 sequence analysis should be considered first in any person with HHT and intestinal polyps. SMAD4 sequence analysis should also be considered in symptomatic individuals in whom no pathogenic variant is identified through sequence analysis and deletion/duplication analysis of ENG and ACVRL1.
    • Note: It is important to differentiate those with SMAD4-related HHT from those with ENG- or ACVRL1-related HHT, as medical management differs significantly for affected individuals based on this distinction.
  • GDF2 sequence analysis could be considered for symptomatic individuals in whom no pathogenic variant is identified in ENG, ACVRL1, or SMAD4 particularly if dermal telangiectases appear larger than pinhead-pinpoint size and are not limited to the hands, mouth and face.

Multi-gene panel. Another strategy for molecular diagnosis of a proband suspected of having HHT is use of a multi-gene panel. Note: The genes included and the methods used in multi-gene panels vary by laboratory and over time.

Clinical Description

Natural History

Hereditary hemorrhagic telangiectasia (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 arteriovenous malformations are called telangiectases. Telangiectases are most evident on the lips, tongue, buccal mucosa, face, chest, and fingers, and are common in adulthood throughout the gastrointestinal mucosa. They may appear as pinhead-size lesions or as larger, even raised lesions with multiple draining venules. All telangiectases are distinguished from petechiae and angiomata by their ability to blanch with gentle pressure, and then immediately refill. Because of their thin walls, narrow tortuous paths, and proximity to the surface of the skin or to a mucous membrane, telangiectases can rupture and bleed after only slight trauma. Since the contractile elements in the vessel wall are lacking, given the abnormal arterial connection, bleeding from telangiectases is frequently brisk and difficult to stop.

The term AVM usually refers to the "large" telangiectases, greater than a few millimeters in diameter and sometimes up to several centimeters in diameter. AVMs occur most commonly in the brain, lung, or liver. In the brain, they are typically present at birth, whereas they typically develop over time in the lung and liver. In contrast to the 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. Lung AVMs also provide a ready right-to-left shunt for venous emboli (clots or bacteria) to reach the arterial circulation. Occasionally, a pulmonary AVM can rupture, leading to hemoptysis.

The most common features that bring young individuals with HHT to medical attention are epistaxis (nosebleeds) and telangiectases. The nasal mucosa is fragile and minor insults from drying air and repeated minor abrasions result in recurrent bleeding. Epistaxis has an average age of onset of approximately 12 years. As many as 95% of affected individuals eventually experience recurrent epistaxis, with one third having onset by age ten years, approximately 80% by age 20 years, and 90% before age 30 years [Berg et al 2003]. However, many do not have nosebleeds that are frequent or severe enough to cause anemia or to result in medical treatment or consultation. Epistaxis was a common cause of death in HHT before the development of blood transfusion.

While similar proportions of affected individuals eventually develop telangiectases of the face, oral cavity, or hands, the average age of onset is generally later, but may be during childhood. Thirty percent of affected individuals report telangiectases first appearing before age 20 years and two thirds before age 40 years [Berg et al 2003].

Telangiectases can also be found anywhere in the gastrointestinal (GI) system. Most commonly, the stomach and the proximal small intestine (duodenum) are involved. Approximately one quarter of all individuals with HHT eventually have gastrointestinal bleeding [Kjeldsen et al 2000, Longacre et al 2003, Ingrosso et al 2004, Proctor et al 2005]. Bleeding from GI telangiectases most commonly begins after age 50 years, is usually slow but persistent, and often becomes increasingly severe with age. No particular foods, activities, or medications have been identified as contributors to GI bleeding in individuals with HHT.

Epistaxis and/or GI bleeding can cause mild to severe anemia, often requiring iron replacement therapy or rarely, blood transfusion.

Pulmonary AVMs occur in approximately 30%-50% of affected individuals and cerebral AVMs in at least 10% [Kjeldsen & Kjeldsen 2000, Bayrak-Toydemir et al 2004]. Spinal AVMs appear to be significantly less common, but may present with paralysis. The frequency of hepatic vascular abnormalities was 74% in one study that systematically imaged the liver of affected individuals using CT [Ianora et al 2004] and 41% in another study using ultrasound examination [Buscarini et al 2004a]. However, only a small minority (8% in the study using CT) were symptomatic. Vascular lesions in the pancreas are common but rarely a clinical issue [Lacout et al 2010]. Although data suggest that the incidence of visceral AVMs may depend on the gene mutated, with pulmonary and possibly cerebral AVMs being more common with pathogenic variants in ENG (HHT1) than in ACVRL1 (HHT2) and hepatic AVMs more common in HHT2 [Kjeldsen et al 2005, Bayrak-Toydemir et al 2006b, Letteboer et al 2006], all of these lesions have been seen in individuals with both HHT types.

Although hemorrhage is often the presenting symptom of cerebral AVMs, most visceral AVMs present as a consequence of blood shunting through the abnormal vessel and bypassing the capillary bed. Shunting of air, thrombi, and bacteria through pulmonary AVMs, thus bypassing the filtering capabilities of the lungs, may cause transient ischemic attacks (TIAs), embolic stroke, and cerebral and other abscesses. Migraine headache, polycythemia, and hypoxemia with cyanosis and clubbing of the nails are other complications of pulmonary AVMs [Shovlin & LeTarte 1999, Kjeldsen et al 2000, Cottin et al 2007]. Hepatic AVMs can present as high-output heart failure, portal hypertension, or biliary disease [Garcia-Tsao et al 2000]. Hepatic focal nodular hyperplasia is also associated with the shunting effects of blood through these high-flow vascular lesions [Buscarini et al 2004b, Brenard et al 2010].

In one series, serious neurologic events including TIA, stroke, and brain abscess occurred in 30%-40% of individuals with pulmonary AVMs with feeding arteries 3.0 mm or greater in diameter [White 1996]. These neurologic complications may occur in individuals with isolated pulmonary AVMs and near-normal arterial oxygen tension. Pulmonary AVMs frequently enlarge with time [White 1996]. One study of 42 children with pulmonary AVMs demonstrated that children can have life-threatening complications from these lesions. More than half presented with exercise intolerance, cyanosis, or clubbing, and although the neurologic complications were less frequent than in adults, they had occurred in 19% prior to detection and treatment [Faughnan et al 2004].

Pulmonary hypertension is another pulmonary vascular manifestation of HHT. Although much less common than pulmonary AVMs, it can either result from systemic arteriovenous shunting in the liver increasing cardiac output or be clinically and histologically indistinguishable from idiopathic pulmonary arterial hypertension [Cottin et al 2007, Girerd et al 2010, Austin et al 2012] (see Pulmonary Arterial Hypertension).

Table 2. Age of Onset of Various Signs of HHT

Sign 1Age in Years
0-910-1920-2930-3940-4950-5960+
Nosebleed
n=492
37%33%12%7%4%2%
Telangiectases
n=406
10% 20%20%18%11%5%10%
GI bleed
n=114
4% 7%11%25%18%21%4%

1. n = number of individuals reporting [Guttmacher, unpublished]

Genotype-Phenotype Correlations

Data suggest that while no absolute genotype-phenotype correlations exist between clinical phenotypes and specific pathogenic variants or mutational types [Shovlin et al 1997], certain clinical manifestations may be more common in particular types – for example, pulmonary AVMs in HHT1 and hepatic AVMs in HHT2. However, both types are clearly multisystem vascular dysplasias with most manifestations described in both [Kjeldsen et al 2005, Bayrak-Toydemir et al 2006b, Letteboer et al 2006, Lesca et al 2007].

Pulmonary hypertension in the absence of severe vascular shunting, a rare HHT manifestation, has occurred mostly in individuals with pathogenic variants in ACVRL1, but has also been reported in individuals with pathogenic variants in ENG [Trembath et al 2001, Soubrier et al 2013].

Pathogenic variants in SMAD4 have been reported in families with a combined syndrome of JPS and HHT [Gallione et al 2004], as well as in families reported to have JPS or HHT only. A recent study found that the majority of families with a SMAD4 pathogenic variant who had presented as JP only were found to have features of HHT when specifically reexamined for such manifestations [O’Malley et al 2011].

Penetrance

HHT displays age-related penetrance with increased manifestations developing over a lifetime (see Table 2).

  • Approximately 50% of diagnosed individuals report having nosebleeds by age ten years and 80%-90% by age 21 years. As many as 95% eventually develop recurrent epistaxis.
  • The percentage of individuals with telangiectases of the hands, face, and oral cavity is similar to the percentage with epistaxis, but the age of onset of telangiectases is generally five to 30 years later than for epistaxis [Plauchu et al 1989, Porteous et al 1992].
  • Intracranial hemorrhage secondary to AVM has been reported as the presenting symptom of HHT in infants and children with HHT [Morgan et al 2002].

Anticipation

While intrafamilial variability is considerable, there has been no systematic generational progression to suggest anticipation.

Nomenclature

The original description of the syndrome was made by Sutton in 1864. However, Osler in the USA, Parkes Weber in the UK, and Rendu in France are typically given credit, hence the eponymous Osler-Weber-Rendu syndrome (or Rendu-Osler-Weber in articles in the French literature). The designation “hereditary hemorrhagic telangiectasia” was suggested in 1912 by one of Osler’s residents.

The gene now identified as ACVRL1 is referred to in many publications as ALK1. Note: other genes were also previously named ALK1.

Prevalence

A number of studies indicate that HHT is significantly more frequent than formerly thought, at least in the populations investigated. The overall incidence of HHT in North America is estimated at 1:10,000 [Marchuk et al 1998]; however, it is likely that this is an underestimate [Guttmacher et al 2012]. For example, when a proband is diagnosed, it is not unusual to identify multiple relatives in the family who have not been diagnosed with HHT but have experienced epistaxis, embolic stroke, or GI bleeding.

HHT occurs with wide ethnic and geographic distribution. The condition is especially prevalent in the Netherland Antilles because of a founder effect.

Differential Diagnosis

Telangiectases and epistaxis can be seen in otherwise healthy individuals. Recurrent epistaxis can be a sign of various bleeding diatheses, including von Willebrand disease.

Telangiectases occur in a number of conditions:

  • Ataxia-telangiectasia, characterized by progressive cerebellar ataxia beginning between age one and four years, oculomotor apraxia, frequent infections, choreoathetosis, telangiectases of the conjunctivae, immunodeficiency, and an increased risk for malignancy, particularly leukemia and lymphoma. Diagnosis relies on clinical findings (including slurred speech, truncal ataxia, and oculomotor apraxia), family history, and neuroimaging. Pathogenic variants in ATM are causative.
  • CRST (calcinosis, Raynaud phenomenon, sclerodactyly, telangiectasia) syndrome
  • Capillary malformation-arteriovenous malformation (CM-AVM) caused in some affected individuals by pathogenic variants in RASA1. RASA1-related disorders are characterized by the presence of multiple, small (1-2 cm in diameter) capillary malformations mostly localized on the face and limbs. About 30% of affected individuals also have associated arteriovenous malformations (AVMs) and/or arteriovenous fistulas (AFVs), fast-flow vascular anomalies that typically arise in the skin, muscle, bone, spine, and brain. In persons with RASA1-related disorders cutaneous zones of numerous pinpoint telangiectases, each surrounded by a white pale halo and typically distributed on the limbs or trunk, have also been described [Revencu et al 2013]. This distribution of telangiectases and the presence of “halos” surrounded each red spot is not typical of HHT. Several individuals with a RASA1 mutation have the clinical diagnosis of Parkes Weber syndrome (multiple micro-AVFs associated with a cutaneous capillary stain and excessive soft tissue and skeletal growth of an affected limb).
  • Hereditary benign telangiectasia, characterized by widespread telangiectases, predominantly on the face, upper limbs, and upper trunk. The telangiectases are venular and associated with upper dermal atrophy. It should be suspected in persons without the history/family history of nosebleed or other bleeding, mucosal telangiectases, AVM, or characteristic pattern of telangiectasia distribution found in HHT.
  • Pregnancy
  • Chronic liver disease (However, the telangiectases are almost always of the ‘spider’ class and occur on the face and chest and around the umbilicus.)

Most individuals with a pulmonary AVM have HHT; an unknown percentage of individuals who have an isolated pulmonary AVM do not have HHT.

Cerebral AVMs occur most frequently as an isolated finding, but may be a manifestation of HHT or another dominantly inherited vascular dysplasia such as capillary malformation-arteriovenous malformation (CM-AVM) caused by pathogenic variants in RASA1 [Eerola et al 2003, Revencu et al 2012]. Families have also been reported with autosomal dominant AVMs of the brain and no other features of HHT. However, the presence of multiple cerebral AVMs is highly suggestive of HHT [Bharatha et al 2012]. The absence of a family history of recurrent nosebleed and presence of telangiectases specifically on the lips, face, and hands best distinguish other vascular dysplasias from HHT.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with hereditary hemorrhagic telangiectasia (HHT), the following evaluations are recommended [Faughnan et al 2011, McDonald et al 2011a]:

  • Medical history, with particular attention to epistaxis and other bleeding, anemia or polycythemia, diseases of the heart, lung and liver, and neurologic symptoms
  • Physical examination including inspection for telangiectases (particularly on fingers, lips, tongue, oropharynx, cheeks, or conjunctiva) and listening for abdominal bruits
  • Complete blood count, with particular attention to anemia or polycythemia. If anemia is present, it is important to consider other causes of anemia, particularly when the anemia seems to be disproportionate to the amount of epistaxis. People with HHT may develop medical problems unrelated to HHT (e.g., ulcers or colon cancer) that can cause GI blood loss. Polycythemia raises suspicion for pulmonary arteriovenous malformations.
  • Measurement of oxygen saturation via pulse oximetry
  • Contrast echocardiography for detection of pulmonary shunting/AVM [Gossage 2010, van Gent et al 2010] and measurement of the pulmonary artery systolic pressure as a screen for pulmonary artery hypertension [Olivieri et al 2006]. When pulmonary shunting is suggested (or if dependable contrast echocardiography is not available), CT angiography with cuts of 3 mm or less to define size and location of lesions(s) is the next step [Cottin et al 2004, Nawaz et al 2008].
  • Head MRI (with and without gadolinium) to detect cerebral AVMs, performed as early as possible, preferably in the first year of life [Morgan et al 2002, Faughnan et al 2011]. Adults, including those screened with MRI in infancy, should all have a screening head MRI to detect unsuspected vascular lesions and occult cerebral abscesses.
  • Consideration of ultrasound or CT examination for evidence of hepatic AVM if the individual has symptoms such as high-output failure associated with hepatic vascular abnormalities, otherwise unexplained elevations in liver function tests, or if presence of a visceral AVM would confirm a diagnosis of HHT

    Note: Screening for hepatic AVMs in asymptomatic individuals is not common practice because:
    • Hepatic AVMs are not usually symptomatic and, when they do become symptomatic, it is not sudden and catastrophic, as is seen with pulmonary AVMs and cerebral AVMs; and
    • Treatment options for HAVM are less satisfactory than those for PAVM or CAVM.
  • Genetics consultation, including molecular genetic analysis of the proband in a family.

Treatment of Manifestations

Nosebleeds

  • It is appropriate to consider intervention for nosebleeds in the case of anemia attributable to the nosebleeds or if an individual feels that the frequency or duration interferes significantly with normal activities.
  • Humidification and the daily application of nasal lubricants may be helpful.
  • Hemostatic products (gauze, sponge or powder products) available over the counter help patients self-manage significant nosebleeds.
  • Laser ablation typically done under general anesthesia may be the most effective intervention for control of mild to moderate nosebleeds [Mahoney & Shapshay 2006]. Office-based sclerotherapy was shown to be a potentially safe and useful alternative in an uncontrolled Spanish study [Morais et al 2012] and a small retrospective US pilot study [Boyer et al 2011].
  • Severe epistaxis, which has proven unresponsive to the above methods, is treated by Young’s nasal closure [Hitchings et al 2005, Richer et al 2012], septal dermoplasty [Fiorella et al 2005], or use of a nasal obturator [Woolford et al 2002, Bruschini et al 2011]. Surgical treatment for severe epistaxis in persons with HHT should be performed by surgeons who treat people with HHT regularly.
  • Oral drug therapy. A meta-analysis of studies of hormonal and anti-hormonal treatment concluded that estrogen-progesterone at doses used for oral contraception may eliminate bleeding in symptomatic HHT and is a reasonable initial option to consider for fertile women [Jameson & Cave 2004]. An anti-estrogen, tamoxifen, was reported to decrease nosebleeds in one series [Yaniv et al 2009]. Antifibrinolytic drugs such as tranexamic acid (Cyklokapron®) have been used with some success in selected individuals; the associated risks are not well established [Fernandez-L et al 2007]. Thalidomide, an angiogenesis inhibitor, reduced the severity and frequency of nosebleeds in six of seven affected individuals in a small series [Lebrin et al 2010]. Oral propranolol has also been suggested as a potential treatment [Albiñana et al 2012].
  • Topical drug therapy. A multi-HHT center randomized, cross-over trial (NOSE Trial) to study the efficacy of several medicated nose sprays (bevacizamab, estriol, and tranexamic acid) in the treatment of epistaxis concluded its recruitment phase in early 2014. Case reports or small series suggest that these and other topically administered agents (e.g., timolol 0.5% ophthalmic solution) may help reduce the duration or frequency of nosebleeds in those with HHT [Sadick et al 2005, Flanagan et al 2012, Guldmann et al 2012, Olitsky 2012, Reh et al 2013].
  • Case reports and a small series [Bose et al 2009, Brinkerhoff et al 2011, Patrizia et al 2011, Dupuis-Girod et al 2012] suggest that IV administration of the anti-angiogenic drug bevacizumab may be efficacious in those with severe, intractable nosebleeds.

Gastrointestinal bleeding

  • Treatment is unnecessary unless aggressive iron therapy has been ineffective in maintaining hemoglobin concentration in the normal range.
  • Endoscopy, capsule endoscopy, mesenteric and celiac angiography, and radionuclide studies may be used to localize the source of bleeding and its type [Grève et al 2010].
  • Endoscopic application of a heater probe, bicap, or laser is the mainstay of local treatment.
  • Small bowel bleeding sites and larger vascular malformations can be removed surgically after they are identified by nuclear medicine studies.
  • For severe GI bleeding associated with intractable iron deficiency anemia, various pharmacologic agents have shown promise based on case reports or small uncontrolled series. Treatment with oral estrogen-progesterone or tranexamic acid has decreased transfusion needs [Proctor et al 2008]. A number of single cases have been reported of dramatic reduction in GI bleeding after IV administration of the anti-angiogenic drug bevacizumab [Flieger et al 2006, Fodstad et al 2011].

Anemia

  • Treatment of anemia with iron replacement and red blood cell transfusion, if necessary, is appropriate.
  • Persons with iron deficiency who are intolerant of or do not respond to oral iron benefit from parenteral administration of iron.

Pulmonary AVMs

  • Treatment of PAVMs is indicated for dyspnea, exercise intolerance, and hypoxemia, but is most important for prevention of lung hemorrhage and the neurologic complications of brain abscess and stroke, even in those who are asymptomatic with respect to pulmonary function and oxygen saturation [Moussouttas et al 2000]. Any PAVM with a feeding vessel that exceeds 1.0 mm in diameter requires consideration of occlusion [Lee et al 1997, Trerotola & Pyeritz 2010]. Transcatheter embolotherapy (TCE) with coils, occluder devices (Amplatzer®), or both is the treatment of choice. Occasionally, a small lesion cannot be reached because of its location or the size of the feeding vessel. Multiple coils may be needed to occlude AVMs with large or multiple feeding arteries.
  • Long-term follow up by chest CT is indicated after transcatheter occlusion of PAVMs because of reported recanalization and development or growth of untreated PAVMs [Cottin et al 2007]. Usually a follow-up CT is done six to 12 months post-occlusion, and if no recanalized or new PAVMs are noted, follow-up CT is done at five-year intervals thereafter [Trerotola & Pyeritz 2010, Faughnan et al 2011].

Cerebral AVMs greater than 1.0 cm in diameter are usually treated using neurovascular surgery, embolotherapy, and/or stereotactic radiosurgery [Fulbright et al 1998].

Hepatic AVMs

Note: Before proceeding with treatment for any visceral AVM, individuals and their doctors are encouraged to contact the nearest multidisciplinary HHT clinic, which can be located through the HHT Foundation International to assure that appropriate diagnostic and treatment plans are in place.

Intestinal polyps. Any individual diagnosed with juvenile polyposis (JP) should be screened for manifestations of HHT, and the family should be screened for polyps. Any person with HHT who has gastrointestinal polyps, especially at an early age, should be evaluated for JP and managed accordingly (see Juvenile Polyposis Syndrome).

Prevention of Primary Manifestations

See specific organs/manifestations above. Prevention is currently focused at ablating, occluding, resecting or shrinking telangiectases and AVMs to prevent associated morbidity and mortality.

Prevention of Secondary Complications

If contrast echocardiography is positive for pulmonary shunting, even if no pulmonary AVM is demonstrated by chest CT, a lifetime recommendation for prophylactic antibiotics in accordance with the American Heart Association protocol for dental cleaning and other "dirty" procedures is advised because of the risk of abscess, particularly brain abscess, associated with right to left shunting [Christensen 1998, Dupuis-Girod et al 2007]. For the same reason, an air filter or extreme caution not to introduce air bubbles is recommended with IV lines.

Note: The risk associated with these lesions is not for subacute bacterial endocarditis (SBE).

Surveillance

The following protocol is recommended for follow up of all individuals for whom the diagnosis of HHT is definite and for all individuals at risk for HHT based on family history in whom HHT has not been ruled out by molecular diagnosis [Faughnan et al 2011]:

  • 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
  • Periodic hematocrit/hemoglobin and ferritin determination with appropriate treatment for iron deficiency anemia
  • Reevaluation for pulmonary AVM at approximately five-year intervals [Nawaz et al 2008]:
    • Contrast echocardiogram is used, if available, if the previous contrast echocardiogram did not reveal evidence of a pulmonary or intracardiac right to left shunt.
    • Chest CT rather than pulmonary angiography is used if the previous contrast echocardiogram revealed evidence of a right to left shunt.
  • Cerebral AVMs are overwhelmingly congenital lesions, but reports exist of the development or evolution of cerebral AVMs in the first two decades of life [Krings et al 2005, Hetts et al 2014]. Accordingly, many HHT experts recommend rescreening the brain once more after puberty, when the initial brain MRI was done in childhood.
  • Periodic screening for gastrointestinal polyps and malignant change in persons with juvenile polyps

Childhood

  • Because serious complications of pulmonary and cerebral AVM can occur at any age [Morgan et al 2002, Mei-Zahav et al 2006, Curie et al 2007], screening for pulmonary and cerebral AVMs is recommended in children from families with HHT, especially those with ENG pathogenic variants [Al-Saleh et al 2009].
  • Head MRI with and without gadolinium is recommended as early as the first few months of life [Faughnan et al 2011].
  • Pulse oximetry in the supine and sitting positions every one to two years during childhood is recommended as a minimum to screen for pulmonary AVMs. It may be of concern if the sitting value is even a few percentage points below that of the supine value. (Since most pulmonary AVMs are in the lower lobes, many individuals with pulmonary AVMs have higher oxygen saturation when lying than when sitting because of the effect of gravity.) Oxygen saturations below 97% should be followed up with contrast echocardiography. Many, but not all, serious complications of pulmonary AVM during childhood have occurred in hypoxemic children.
  • By at least age ten years, additional evaluation should be performed by contrast echocardiography, with a follow-up CT if positive.

Pregnancy

  • Pregnant women with HHT and undetected and/or untreated AVMs (particularly lung AVMs) are at risk for serious complications (hemothorax, transient ischemic attack [TIA] / stroke, myocardial infarction/ischemia, intracranial hemorrhagic, heart failure).
  • Women should be screened and treated as indicated for pulmonary and cerebral AVMs before pregnancy. If neither is present, or if women are treated prior to pregnancy, the risk for serious complication during pregnancy does not appear to be increased [de Gussem et al 2014].
  • A pregnant woman who has not had a recent pulmonary evaluation should be evaluated as soon as pregnancy is recognized [Shovlin et al 1995, Shovlin et al 2008]. Chest CT, with abdominal shielding, should be delayed until the second trimester.
  • Women not discovered to have pulmonary AVMs until they are already pregnant should be offered occlusion during the second trimester.
  • Asymptomatic cerebral AVMs are not generally treated during pregnancy. Thus if screening for cerebral AVMs was not done prior to pregnancy, it is typically delayed until the post-partum period. However, screening by MRI in the second or third trimester to inform delivery management, such as avoidance of prolonged labor, is a consideration [de Gussem et al 2014].
  • Complications from epidural anesthesia in HHT patients have not been reported. The risk is considered low and epidural anesthesia need not be withheld on the basis of the diagnosis of HHT [de Gussem et al 2014].

Agents/Circumstances to Avoid

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. Some individuals with HHT experience increased epistaxis after drinking alcohol.

Most otolaryngologists with experience treating individuals with HHT advise against electric and chemical cautery and transcatheter embolotherapy for treatment of recurrent nosebleeds in most situations.

Anticoagulants such as aspirin and nonsteroidal anti-inflammatory agents such as ibuprofen that interfere with normal clotting should be avoided unless required for treatment of other medical conditions. In one study, lower dose agents, particularly anti-platelet agents, were not associated with hemorrhage in a high proportion of affected individuals. The findings support the use of antiplatelet or anticoagulant agents, with caution, if there is a very strong indication for their use [Devlin et al 2013].

Scuba diving should be avoided unless contrast echocardiography performed within the last five years was negative for evidence of a right to left shunt.

Evaluation of Relatives at Risk

It is appropriate to offer molecular genetic testing to at-risk relatives if the pathogenic variant in the family is known, as early diagnosis and treatment can reduce morbidity and mortality. However, relatives who are at risk often resist advice to undergo molecular screening [Bernhardt et al 2011].

If the pathogenic variant in the family is not known, it is appropriate to offer clinical diagnostic evaluations to identify those family members who will benefit from early treatment.

Individuals at risk for HHT should follow the protocol described in Surveillance.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Newer therapies designed to interfere with the development of abnormal vascular connections include thalidomide and bevacizumab; while numerous case reports and small uncontrolled series tout promise, controlled trials are needed [Flieger et al 2006, Mitchell et al 2008, Bose et al 2009, Davidson et al 2010, Lebrin et al 2010, Brinkerhoff et al 2011, Fodstad et al 2011, Patrizia et al 2011, Dupuis-Girod et al 2012].

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Hereditary hemorrhagic telangiectasia (HHT) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Most individuals diagnosed with HHT have an affected parent.
  • A proband with HHT may rarely have the disorder as the result of de novo constitutional or somatic gene mutation [Best et al 2011].
  • Recommendations for the evaluation of parents of a child who represents an apparent simplex case (i.e., a single occurrence in a family) include physical examination, documentation of medical history targeted at symptoms and manifestations of HHT, and molecular genetic testing if a pathogenic variant in ACVRL1, ENG, SMAD4, or GDF2 has been identified in the proband.

Sibs of a proband

  • The risk to the sibs depends on the genetic status of the proband's parents.
  • If a parent of the proband is affected/has a pathogenic variant, the risk to the sibs of inheriting the variant is 50%.
  • When the parents are clinically unaffected, the risk to the sibs of a proband appears to be lower. It should be noted, however, that although highly penetrant, the disease may not present until after age 40 years. Observable symptoms and manifestations can be subtle, even well into adulthood.
  • No instances of germline mosaicism have been reported, although it remains a possibility.

Offspring of a proband. Each child of an individual with HHT has a 50% chance of inheriting the pathogenic variant.

Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent is affected or has a pathogenic variant in one of the four HHT-related genes, his or her family members are at risk.

Related Genetic Counseling Issues

See Management, Surveillance for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Considerations in families with apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant or clinical evidence of the disorder, it is likely that the mutation is de novo. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

Testing of at-risk asymptomatic individuals during adulthood and childhood. Testing of at-risk asymptomatic individuals for HHT is possible using the techniques described in Molecular Genetic Testing. Such testing is not useful in predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals. When testing at-risk individuals for HHT, an affected family member should be tested first to confirm (and identify) the molecular diagnosis in the family. Testing of asymptomatic at-risk family members usually involves pre-test consultation to discuss the possible impact of positive and negative test results. Those seeking testing should be counseled regarding possible problems that they may encounter with respect to health, life, and disability insurance coverage, employment and educational discrimination, and changes in social and family interaction. Informed consent should be procured and records kept confidential. Individuals identified to have a pathogenic variant in one of the four HHT-related genes need long-term follow up and evaluations. Although identifying affected relatives when the familial mutation is known results in considerable savings of healthcare costs over the life of the at-risk relative, for a variety of reasons, individuals at 50% risk for inheriting HHT often decline molecular genetic testing when the familial mutation is known [Bernhardt et al 2012].

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the pathogenic variant in ACVRL1, ENG, SMAD4 or GDF2 has been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing for this disease/gene or custom prenatal testing.

Requests for prenatal testing for conditions which (like hereditary hemorrhagic telangiectasia) do not affect intellect and have some treatment available are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the pathogenic variant has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • HHT Foundation International, Inc.
    PO Box 329
    Monkton MD 21111
    Phone: 800-448-6389 (toll-free); 410-357-9932
    Fax: 410-357-0655
    Email: hhtinfo@hht.org
  • National Library of Medicine Genetics Home Reference

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Hereditary Hemorrhagic Telangiectasia: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Hereditary Hemorrhagic Telangiectasia (View All in OMIM)

131195ENDOGLIN; ENG
175050JUVENILE POLYPOSIS/HEREDITARY HEMORRHAGIC TELANGIECTASIA SYNDROME; JPHT
187300TELANGIECTASIA, HEREDITARY HEMORRHAGIC, OF RENDU, OSLER, AND WEBER; HHT
600376TELANGIECTASIA, HEREDITARY HEMORRHAGIC, TYPE 2; HHT2
600993MOTHERS AGAINST DECAPENTAPLEGIC, DROSOPHILA, HOMOLOG OF, 4; SMAD4
601101TELANGIECTASIA, HEREDITARY HEMORRHAGIC, TYPE 3; HHT3
601284ACTIVIN A RECEPTOR, TYPE II-LIKE 1; ACVRL1
605120GROWTH/DIFFERENTIATION FACTOR 2; GDF2
610655TELANGIECTASIA, HEREDITARY HEMORRHAGIC, TYPE 4; HHT4
615506TELANGIECTASIA, HEREDITARY HEMORRHAGIC, TYPE 5; HHT5

Currently, all known genetic defects that cause HHT are in genes that encode proteins within the transforming growth factor beta (TGF-β) signaling pathway.

ACVRL1

Gene structure. ACVRL1 contains ten exons and spans approximately 14 kb of genomic DNA. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. Current data suggest that approximately one third of pathogenic variants in ACVRL1 are functionally null alleles [Berg et al 1997, Pece et al 1997, Gallione et al 1998, Richards-Yutz et al 2010]. No common pathogenic variants have been identified. The frequency of mutations is highest in exons 8, 7, and 3, but these account for only 65% of pathogenic variants identified and variants have been identified in all exons. Missense mutations account for more than half (53%) of pathogenic variants detected; deletions, insertions, and splice site mutations have also been reported [Abdalla & Letarte 2006, Richards-Yutz et al 2010]. (For more information, see Table A.)

Normal gene product. Serine/threonine-protein kinase receptor R3 is a type I cell-surface receptor for the TGF-superfamily of ligands. It is expressed predominantly on endothelial cells [Abdalla & Letarte 2006].

Abnormal gene product. Current data suggest that most pathogenic variants in ACVRL1 result in protein non-expression. HHT is assumed to be the result of haploinsufficiency [Abdalla & Letarte 2006].

ENG

Gene structure. ENG contains 14 exons and spans approximately 40 kb of genomic DNA. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. Current data suggest that approximately two thirds of variants in ENG are functionally null alleles [Berg et al 1997, Pece et al 1997, Gallione et al 1998, Richards-Yutz et al 2010]. There are no common pathogenic variants. The total number of variants per exon is similar with the exception of exons 1, 9b, 12, and 13, which have fewer variants. Mutations of all types have been reported [Abdalla & Letarte 2006]. (For more information, see Table A.)

Normal gene product. Endoglin is a component of the transforming growth factor beta (TGF-beta) receptor complex. It is expressed predominantly on endothelial cells.

Abnormal gene product. Current data suggest that most pathogenic variants in ENG result in non-expressed proteins. HHT is assumed to be the result of haploinsufficiency [Abdalla & Letarte 2006].

SMAD4

Gene structure. SMAD4 contains 11 exons and has a cDNA of 2680 bp. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. There are no common pathogenic variants and all types of mutations have been described. More than two thirds of mutations reported are functionally null alleles (see SMAD4 Mutation Database). Although SMAD4 pathogenic variants in individuals with JP-HHT have shown a tendency to cluster in the MH2 domain, mutations in other part of the gene also cause the combined syndrome. Any individual with a SMAD4 pathogenic variant should be considered at risk for manifestations of both JP and HHT [Gallione et al 2010, O’Malley et al 2011].

Normal gene product. SMAD4 encodes a 552-amino acid protein that functions as an intracellular signaling molecule in the TGF-beta/BMP pathway.

Abnormal gene product. Most pathogenic variants in SMAD4 result in non-expressed proteins. HHT is assumed to be the result of haploinsufficiency.

GDF2

Gene structure. GDF2 (also known as BMP9) is a small gene of 2 exons and a transcript of 1955 bp (NM_016204.2). For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. Pathogenic missense variants in GDF2 were identified in three individuals with features of HHT including epistaxis [Wooderchak-Donahue et al 2013].

Normal gene product. GDF2 encodes growth/differentiation factor 2 (also known as BMP9 or bone morphogenetic protein 9), a protein of 429 amino acids (NP_057288.1). After post-translational cleavage of the signal peptide and the propeptide, the mature peptide is 110 amino acid residues. It is a member of the bone morphogenetic protein family and the TFG-beta superfamily. The members of this family are regulators of cell growth and differentiation in both embryonic and adult tissues.

Abnormal gene product. Cell culture studies and zebrafish model experiments with the variant proteins encoded by the three mutations demonstrated that GDF2 (BMP9) is involved in angiogenesis [Wooderchak-Donahue et al 2013].

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Suggested Reading

  1. Aretz S, Stienen D, Uhlhaas S, Stolte M, Entius MM, Loff S, Back W, Kaufmann A, Keller KM, Blaas SH, Siebert R, Vogt S, Spranger S, Holinski-Feder E, Sunde L, Propping P, Friedl W. High proportion of large genomic deletions and a genotype phenotype update in 80 unrelated families with juvenile polyposis syndrome. J Med Genet. 2007;44:702–9. [PMC free article: PMC2752176] [PubMed: 17873119]
  2. Marchuk DA, Lux A. Hereditary hemorrhagic telangiectasia. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill; Chap 212. Available online. 2014. Accessed 7-21-14.

Chapter Notes

Acknowledgments

Robert I White, MD
School of Medicine, Yale University

Alan Guttmacher, MD
National Human Genome Research Institute, National Institutes of Health

Author History

Alan Guttmacher, MD; National Institutes of Health (2000-2009)
Jamie McDonald, MS, CGC (2000-present)
Reed E Pyeritz, MD, PhD, FACMG (2009-present)

Revision History

  • 24 July 2014 (me) Comprehensive update posted live
  • 5 January 2012 (me) Comprehensive update posted live
  • 19 May 2009 (me) Comprehensive update posted live
  • 22 November 2005 (me) Comprehensive update posted to live Web site
  • 16 March 2004 (cd) Revision: sequence analysis
  • 26 February 2004 (cd) Revision: quantitative PCR added as a test method
  • 4 August 2003 (cd) Revisions
  • 17 June 2003 (ca) Comprehensive update posted to live Web site
  • 26 June 2000 (me) Review posted to live Web site
  • January 2000 (jm) Original submission
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Tests in GTR by Gene

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