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Lip telangiectases in hereditary hemorrhagic telangiectasia

Image: “Lip telangiectases in hereditary hemorrhagic telangiectasia” by by Herbert L. Fred, MD and Hendrik A. van Dijk – Images of Memorable Cases: Cases 115 & 116, Licensed under Attribution via Commons.

Definition of HHT

HHT as genetic disorder

HHT or OWRD (Osler-Weber-Rendu disease) is an autosomal dominant genetic disorder that involves abnormal blood vessel formation throughout the body. It is a rare disorder with a variable age of presentation. Its characteristic symptoms include:

  • Epistaxis
  • Mucocutaneous telangiectases
  • Arteriovenous malformations (AVMs)

“Telangiectasia” and “arteriovenous malformation” both occur from a direct connection between an artery and a vein while bypassing the capillary system. They are pathologically-distinct terms. Telangiectasias occur on mucocutaneous surfaces, such as the skin, gastrointestinal (GI) mucosa, or upper aerodigestive tract. AVMs occur in internal organs, such as the liver, lungs, and brain.

large arteriovenous malformation in the left hemisphere

Image: “A very large arteriovenous malformation in the left hemisphere (on the right in this image) of the brain.” by The Armed Forces Institute of Pathology (AFIP). License: Public Domain

Epidemiology of HHT

Frequency of HHT

HHT occurs with equal frequency in both males and females. While the geographic distribution of the disease is wide, it is more commonly seen in Caucasians. Since it is asymptomatic, its prevalence may be underestimated. However, the overall prevalence is 1–2 cases per 10,000 people in North America. It may occur in children but is more common at puberty or during adulthood.

Etiology of HHT

Causes of HHT

autosomal dominant pattern of inheritance

Image: “Autosomal dominant – genetics” by Domaina. License: CC BY-SA 3.0

As already mentioned, it is an autosomal dominant disorder. There are five genetic types and homozygous conditions that are incompatible with life. Mutations involving Transforming Growth Factor Beta (TGF-B) signaling are responsible for the following disorders:

  • Endoglin Gene (ENG) mutations (HHT type 1): account for 80–85% cases along with type 2
  • Activin receptor-like kinase-1 (ALK1) mutations (HHT type 2)
  • Chromosome 5 mutation
  • SMAD4 (also known as MADH4)

Almost all HHT cases are congenital. A child born to a parent with HHT has a 50% chance of developing it. See the figure on the right for the inheritance pattern.

Pathophysiology of HHT

A defect in the TGF-B superfamily receptor results in an abnormal architecture of vessels with consequent malformations and aneurysms. This defect, combined with abnormal repair, results in lesions. Dilated vessels manifesting as telangiectasis are most commonly a result of:

  • Endothelial cell degeneration and junction defects
  • Perivascular connective tissue weakness

The gene expression profiles of vascular endothelial cells grown from HHT patients revealed dysregulation of genes involved in:

  • Angiogenesis
  • Cytoskeletal integrity
  • Cell migration
  • Proliferation
  • NO synthesis

Signs and Symptoms of HHT

Clinical manifestations of the condition do not appear at birth; they develop with the passage of time and increasing age. The frequency of these features is as follows.

Spontaneous and recurrent epistaxis is the most common feature (> 90%). Varying in frequency and severity, it mostly develops till adolescence. In children, it is a strong indication of AVMs in the lungs or brain, requiring intervention.

Tongue telangiectases in hereditary hemorrhagic telangiectasia

Image: “Tongue telangiectases in hereditary hemorrhagic telangiectasia” by Herbert L. Fred, MD and Hendrik A. van Dijk – Images of Memorable Cases: Cases 115 & 116. Licensed under Attribution via Commons

Skin telangiectases occur in > 75% of cases. Telangiectases are dilated blood vessels on the hands, tongue, face, lips, and GI tract. The skin lesions are often referred to as red spots. It is important to differentiate this characteristic manifestation from benign red spots.

Pulmonary or hepatic involvement (AVMs) appear in > 30% of cases and may include:

GI bleeding is > 15%, and there is a chance of  CNS lesions (involving migraine headaches, strokes, and brain abscess).

Iron deficiency/iron deficiency anemia due to chronic blood loss is also common in HHT.

Diagnosis of HHT

The clinically driven diagnosis is based on the Curacao criteria:

  • Epistaxis
  • Telangiectasis
  • Visceral lesions
  • Family history (first-degree relative)

In contrast to petechiae (small spots caused by hemorrhage), the red color of telangiectasis disappears while pressing a transparent spatula onto the skin. While lab tests may not confirm the diagnosis, they are certainly helpful for identification and assessment. These include:

  • CBC: reduced hemoglobin, iron-def anemia or polycythemia
  • Coagulation profile: deranged in severe hepatic involvement
  • Urinalysis: hematuria
  • Stool: blood presence
  • LFTs: elevated enzymes
  • Oximetry < 96% requires further testing
  • ABGs (a screening test for pulmonary AVMs)

Diagnosing HHT with radiology

Test Significance
Chest radiography May reveal an enlarged mass of arteries and veins and/or peripheral non-calcified coin lesion
Transthoracic contrast echocardiography (TTCE) Pulmonary AVMs
Barium enema
Contrast-enhanced MRI
Ultrasound and contrast radiography
Endoscopy Reveal telangiectasis
Barium enema Suspected ulcers and neoplasms
Helical CT Delineating lung and brain AVMs
Abdominal CT

Axial computed tomography of the upper abdomen showing HHT

Image: “Axial computed tomography of the upper abdomen showing HHT” by Hellerhoff. License: CC BY-SA 3.0

Genetic testing has a higher sensitivity in confirmed cases. A biopsy shows:

  • Dilated capillaries
  • Focal dilatation of post-capillary venules (telangiectasis)
  • Fully developed lesions lacking intervening capillary bed
  • New vessel formation
  • Thickened dilated vessel walls in the dermis

Differential Diagnosis of HHT

Diseases similar to HHT

With the presence of three criteria, the diagnosis is definite. But the following conditions should be ruled out as well:

  • Ataxia-telangiectasis
  • CREST syndrome
  • Pediatric Syphilis
  • Rosacea
  • Rothmund-Thomson syndrome
  • Scleroderma
  • Cockayne syndrome
  • Actinic keratosis

Treatment of HHT

HHT management aims at reducing hemorrhage and sequelae of malformations. While mild cases require no treatment, the treatment options for moderate and severe cases include:

  • Epistaxis treatment:
  • Iron supplementation
  • Humidification
  • Packing
  • Transfusion
  • Electrocautery
  • Septal dermoplasty
  • Tranexamic acid
  • Pulse-dyed laser treatment for telangiectasis
  • GI bleeding management:
  • Estrogen-progesterone therapy
  • Transfusion
  • Aminocaproic acid
  • Endoscopic photoablation
  • AV malformations are managed by:
  • Surgical resection (> 1.5 cm) (Comment: Recommendations vary from site to site, so better to delete)
  • Embolization
  • Liver transplantation
  • Long-term monitoring
  • Newer Treatments/Anti-angiogenic therapies: There is an increasing trend of the use of anti-VEGF therapies in patients with HHT. Thalidomide, Bevacizumab, and Pazopanib have reported some benefit. However, thalidomide should not be used in pregnant women as it is known to cause birth defects.

Progression and Prognosis of HHT

Screening and appropriate management tend to increase overall life expectancy. HHT is associated with significant morbidity rather than mortality and the biggest factor affecting the quality of life is recurrent epistaxis in most patients. The prognosis depends on the disease severity and especially hepatic, pulmonary, and CNS involvement.

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