Hereditary Hemorrhagic Telangiectasia - HHT

  • Diagnosis
  • Screening
  • Background
  • Lab Tests
  • References
  • Related Topics

Indications for Testing

  • Confirm hereditary hemorrhagic telangiectasia (HHT) in symptomatic individuals
  • Identify familial mutation in clinically affected individuals, enabling diagnostic testing of at-risk relatives

Criteria for Diagnosis

  • HHT
    • Diagnosis considered definite with ≥3 symptoms, suspected with 2 symptoms, and unlikely with a single symptom
    • Symptoms include the following
      • Recurrent epistaxis
      • Mucocutaneous telangiectasia, particularly on lips and hands
      • Internal arteriovenous malformations (AVMs)
      • First-degree relative with HHT
  • Juvenile polyposis syndrome (JPS)/HHT
    • Combination of symptoms meeting criteria for JPS and HHT
      • JPS diagnosed if any one of the following present
        • >5 juvenile polyps of colorectum
        • Multiple juvenile polyps of upper and lower GI tract
        • Any number of juvenile polyps and family history of juvenile polyps

Laboratory Testing

  • Genetic testing – may include mutations in at least one of the following genes
    • ACVRL1, ENG, and BMP9
      • Most common mutations in HHT
      • Mutation present –  predicted to cause HHT
      • For more information on ACVRL1 and ENG mutations, refer to ARUP and the HHT Foundation International's HHT mutation database
    • SMAD4
      • Mutation present – predicted to cause JPS, JPS/HHT, or HHT
    • RASA1
      • Mutation present – predicted to cause capillary malformation/arteriovenous malformation or RASA1-related disorder
    • BMP9
      • Mutation present – predicts presence of telangiectasia syndrome

Differential Diagnosis

  • Early identification and treatment of internal arteriovenous malformations (AVMs) significantly impacts outcome
  • Screening early in life for lung and brain AVMs is recommended for affected individuals

Hereditary hemorrhagic telangiectasia (HHT) is characterized by multiple arteriovenous malformations (AVMs) and telangiectasia in specific locations. The most common symptom is nosebleeds.

Epidemiology

  • Prevalence – ~1/5,000-10,000
  • Age – variable; average onset in early teens
  • Sex – M:F, equal

Inheritance

Gene Symbol Condition Inheritance Prevalence De novo mutations
ACVRL1 (ALK1) HHT type 2/HHT2 AD ~1/5,000 Rare
BMP9 (GDF2) HHT type 5/HHT5 AD 1-2% Unknown
ENG HHT type 1/HHT1 AD ~1/5,000 Rare
RASA1 CM-AVM/RASA1-related AD ~1/100,000 in northern Europeans ~25%
SMAD4 Juvenile polyposis/HHT AD Unknown ~25%

Clinical Presentation

  • HHT
    • Mucocutaneous telangiectasias – characteristic sites are lips, oral cavity, fingers, nose, and the upper gastrointestinal (GI) tract
    • Nosebleeds (epistaxis) – spontaneous and recurrent; occur in most patients by adulthood
    • GI bleeding – 20% of patients ≥50 years
    • Internal AVMs – characteristically found in the lungs, liver, brain, and occasionally the spine
      • Brain and lung AVMs
        • Source of significant morbidity and mortality
        • Complications resulting from AVMs in the lung (stroke and brain abscess) and the liver (high-output heart failure) – typically secondary to shunting associated with these lesions, not  hemorrhaging
        • Usually congenital in HHT patients
    • Nasal and dermal telangiectasias – often not present until after the first decade
    • Patients commonly have a family history of HHT or epistaxis
  • Juvenile polyposis syndrome/hereditary hemorrhagic telangiectasia (JPS/HHT) syndrome – combines JPS and HHT
    • Polyps occur primarily in upper GI tract
    • Juvenile refers to type of polyp rather than age of patient
    • Tested families with JPS/HHT have SMAD4 mutations
Tests generally appear in the order most useful for common clinical situations. Click on number for test-specific information in the ARUP Laboratory Test Directory.

Hereditary Hemorrhagic Telangiectasia (HHT) Panel, Sequencing and Deletion/Duplication, 5 Genes 2009337
Method: Massively Parallel Sequencing/Exonic Oligonucleotide-based CGH Microarray

Limitations 

Mutations in genes not tested, deep intronic or regulatory region mutations, and breakpoints of large deletions/duplications are not determined/evaluated

Some small deletions or insertions may not be detected by massively parallel sequencing

Copy number variants <1,000 base pairs may not be detected in targeted genes

Diagnostic errors may occur due to rare sequence variations

Hereditary Hemorrhagic Telangiectasia (HHT) Sequencing, 5 Genes 2009342
Method: Massively Parallel Sequencing

Limitations 

Mutations in genes not tested, deep intronic or regulatory region mutations, and breakpoints of large deletions/duplications are not determined/evaluated

Some small deletions or insertions may not be detected by massively parallel sequencing

Copy number variants <1,000 base pairs may not be detected in targeted genes

Diagnostic errors may occur due to rare sequence variations

Hereditary Hemorrhagic Telangiectasia (ACVRL1 and ENG) Sequencing and Deletion/Duplication with Reflex to Juvenile Polyposis (SMAD4) Sequencing and Deletion/Duplication 2009008
Method: Polymerase Chain Reaction/Sequencing/Multiplex Ligation-dependent Probe Amplification

Limitations 

Breakpoints of large deletions/duplications cannot be determined

Regulatory region, intronic mutations, and mutations in genes other than ENG and ACVRL1 will not be detected

Diagnostic errors may occur due to rare sequence variations

Hereditary Hemorrhagic Telangiectasia (ACVRL1 and ENG) Sequencing and Deletion/Duplication 0051382
Method: Polymerase Chain Reaction/Sequencing/Multiplex Ligation-dependent Probe Amplification

Limitations 

Diagnostic errors can occur due to rare sequence variations

The breakpoints of large deletions/duplication cannot be determined

Regulatory region, intronic mutations, and mutations in genes other than ENG and ACVRL1 will not be detected

Follow-up 

If negative, consider Juvenile Polyposis (SMAD4) Sequencing and Deletion/Duplication testing

Familial Mutation, Targeted Sequencing 2001961
Method: Polymerase Chain Reaction/Sequencing

Familial Mutation, Targeted Sequencing, Fetal 2001980
Method: Polymerase Chain Reaction/Sequencing

Limitations 

Rare diagnostic errors can occur due to primer-site mutations

Juvenile Polyposis (SMAD4) Sequencing and Deletion/Duplication 2001971
Method: Polymerase Chain Reaction/Sequencing/Multiplex Ligation-dependent Probe Amplification

Limitations 

Diagnostic errors can occur due to rare sequence variations

Not determined or evaluated

  • Regulatory region mutations
  • Deep intronic mutations
  • Breakpoints of large deletions/duplications

Large deletions/duplications of BMPR1A exons 7 and 8 may not be detected

RASA1-Related Disorders (RASA1) Sequencing and Deletion/Duplication 2007852
Method: Polymerase Chain Reaction/Sequencing/Multiplex Ligation-dependent Probe Amplification

Limitations 

Rare diagnostic errors can occur due to probe-site mutations

Breakpoints for large deletions/duplications will not be determined

Telangiectasia Syndrome (BMP9/GDF2) Sequencing 2010015
Method: Polymerase Chain Reaction/Sequencing

Limitations 

Large deletions/duplications, deep intronic mutations, and regulatory region mutations not detected

Diagnostic errors can occur due to rare sequence variations

Mutations in other genes associated with telangiectasia syndromes will not be tested

General References

Bossler AD, Richards J, George C, Godmilow L, Ganguly A. Novel mutations in ENG and ACVRL1 identified in a series of 200 individuals undergoing clinical genetic testing for hereditary hemorrhagic telangiectasia (HHT): correlation of genotype with phenotype Hum Mutat. 2006; 27(7): 667-75. PubMed

Dupuis-Girod S, Bailly S, Plauchu H. Hereditary hemorrhagic telangiectasia: from molecular biology to patient care. J Thromb Haemost. 2010; 8(7): 1447-56. PubMed

Gedge F, McDonald J, Phansalkar A, Chou L, Calderon F, Mao R, Lyon E, Bayrak-Toydemir P. Clinical and analytical sensitivities in hereditary hemorrhagic telangiectasia testing and a report of de novo mutations J Mol Diagn. 2007; 9(2): 258-65. PubMed

McDonald J, Bayrak-Toydemir P, Pyeritz RE. Hereditary hemorrhagic telangiectasia: an overview of diagnosis, management, and pathogenesis. Genet Med. 2011; 13(7): 607-16. PubMed

McDonald J, Pyeritz R. Hereditary Hemorrhagic Telangiectasia. In: Pagon RA, Adam MP, Ardinger HH, et al, editors. GeneReviews, University of Washington, 1993-2015. Seattle, WA [Last updated Jul 2014; Accessed: Nov 2015]

Prigoda NL, Savas S, Abdalla SA, Piovesan B, Rushlow D, Vandezande K, Zhang E, Ozcelik H, Gallie BL, Letarte M. Hereditary haemorrhagic telangiectasia: mutation detection, test sensitivity and novel mutations J Med Genet. 2006; 43(9): 722-8. PubMed

Richards-Yutz J, Grant K, Chao EC, Walther SE, Ganguly A. Update on molecular diagnosis of hereditary hemorrhagic telangiectasia Hum Genet. 2010; 128(1): 61-77. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

Arthur H, Geisthoff U, Gossage JR, Hughes CC W, Lacombe P, Meek ME, Oh P, Roman BL, Trerotola SO, Velthuis S, Wooderchak-Donahue W. Executive summary of the 11th HHT international scientific conference Angiogenesis. 2015; 18(4): 511-24. PubMed

ARUP Scientific Resource for Research and Education. HHT Mutation Database. ARUP Laboratories, University of Utah. Salt Lake City, UT [Accessed: Nov 2012]

Bayrak-Toydemir P, Mao R, Lewin S, McDonald J. Hereditary hemorrhagic telangiectasia: an overview of diagnosis and management in the molecular era for clinicians. Genet Med. 2004; 6(4): 175-91. PubMed

Bayrak-Toydemir P, McDonald J, Akarsu N, Toydemir RM, Calderon F, Tuncali T, Tang W, Miller F, Mao R. A fourth locus for hereditary hemorrhagic telangiectasia maps to chromosome 7. Am J Med Genet A. 2006; 140(20): 2155-62. PubMed

Bharatha A, Faughnan ME, Kim H, Pourmohamad T, Krings T, Bayrak-Toydemir P, Pawlikowska L, McCulloch CE, Lawton MT, Dowd CF, Young WL, Terbrugge KG. Brain arteriovenous malformation multiplicity predicts the diagnosis of hereditary hemorrhagic telangiectasia: quantitative assessment. Stroke. 2012; 43(1): 72-8. PubMed

Frigerio A, Wright K, Wooderchak-Donahue W, Tan OT, Margraf R, Stevenson DA, Grimmer F, Bayrak-Toydemir P. Genetic Variants Associated with Port-Wine Stains PLoS One. 2015; 10(7): e0133158. PubMed

McDonald J, Gedge F, Burdette A, Carlisle J, Bukjiok CJock, Fox M, Bayrak-Toydemir P. Multiple sequence variants in hereditary hemorrhagic telangiectasia cases: illustration of complexity in molecular diagnostic interpretation. J Mol Diagn. 2009; 11(6): 569-75. PubMed

McDonald J, Wooderchak-Donahue W, Webb CVanSant, Whitehead K, Stevenson DA, Bayrak-Toydemir P. Hereditary hemorrhagic telangiectasia: genetics and molecular diagnostics in a new era Front Genet. 2015; 6: 1. PubMed

Millson A, Lewis T, Pesaran T, Salvador D, Gillespie K, Gau C, Pont-Kingdon G, Lyon E, Bayrak-Toydemir P. Processed Pseudogene Confounding Deletion/Duplication Assays for SMAD4 J Mol Diagn. 2015; 17(5): 576-82. PubMed

Wooderchak-Donahue W, Stevenson DA, McDonald J, Grimmer F, Gedge F, Bayrak-Toydemir P. RASA1 analysis: clinical and molecular findings in a series of consecutive cases. Eur J Med Genet. 2012; 55(2): 91-5. PubMed

Wooderchak-Donahue WL, McDonald J, O'Fallon B, Upton PD, Li W, Roman BL, Young S, Plant P, Fülöp GT, Langa C, Morrell NW, Botella LM, Bernabeu C, Stevenson DA, Runo JR, Bayrak-Toydemir P. BMP9 mutations cause a vascular-anomaly syndrome with phenotypic overlap with hereditary hemorrhagic telangiectasia. Am J Hum Genet. 2013; 93(3): 530-7. PubMed

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Last Update: August 2016