Neurosurgery notes/Vascular/Vascular genetic disease/Hereditary haemorrhagic telangiectasia (HHT)

Hereditary haemorrhagic telangiectasia (HHT)

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Vascular genetic disease

General

  • Aka:
    • Osler Weber Rendu syndrome
    • Hereditary haemorrhagic telangiectasia (HHT)

Diagnosis

  • Curacao criteria:
    • Spontaneous recurrent epistaxis
    • Mucocutaneous telangiectasia
    • AVMs of visceral organs
    • First degree relatives with similar condition.
  • Outcome
    • Definite HHT if ≥3 criteria
    • Possible HHT if only 2 criteria

Genetic

  • An autosomal dominant disorder
      • Gene
      Proportion of HHT Attributed to Pathogenic Variants in Gene
      ACVRLI
      52%
      ENG
      44%
      SM4D4
      1%
      Unknown
      3%

Pathophysiology

  • Defects in a TGF-β superfamily receptor
  • Defects in the endothelial cell junctions, endothelial cell degeneration, and weakness of the perivascular connective tissue are thought to cause dilation of capillaries and postcapillary venules, which manifest as telangiectasias.
  • Genes most commonly implicated in HHT are the; Both are exclusively expressed on vascular endothelial cells. Two Genotypes
      • Type I
        • Endoglin gene (ENG; HHT type 1) = Type III TGF-β receptors
          • on chromosome 9
            • its coreceptor
            • Underlying HHT1 – the most common type
          • The endothelial cells in this syndrome lack the molecule endoglin and form abnormal vessels, especially after injury.
        • is associated with
          • Mucocutaneous telangiectasia,
          • Pulmonary AVF
          • Arteriovenous shunts of the CNS.
            • Most often seen in the pediatric population and are always pial AVF (subtype C, ventral intradural AVF, or Type IV).
      • Type 2
        • ALK-1 gene (ALK1; HHT type 2) = Type I TGF-β receptors
          • Activin receptor- like kinase- 1 (Alk- 1)
            • On chromosome 12 (responsible for HHT2)
            • Found on the surface of cells, particularly on the lining of developing arteries
      • Other genes are less frequently involved
       
       
      notion image
      • The binding of TGF-β to the type II TGF-β receptor on endothelial cells, which is accelerated in the presence of endoglin, results in the phosphorylation of the type I TGF-β receptors ALK-5 and ALK-1.
          1. Phosphorylated ALK-5 activate Smad2/3
          1. Phosphorylated ALK-1 activate Smad1/5
              • Activated Smad proteins dissociate from the type I TGF-β receptor, bind to Smad4, and enter the nucleus to transmit TGF-β signals by regulating transcription from specific gene promoters involved in angiogenesis.
      • Endoglin and ALK-1 bind directly to bone morphogenetic protein (BMP)-9 and BMP-10 and mediate their defects in conjunction with the type II BMP receptor (BMPR II).
      • Therefore, a balance between the two signalling pathways involving ALK-5 and ALK-1 is important in determining the properties of endothelial cells during angiogenesis.

Location

  • Skin telangiectasias (small AVMs) and AVMs in the
    • Lungs
      • 70% of patients with pulmonary AVMs will have HHT.
    • Liver
    • CNS
    • Pretty much anywhere else in the body

Clinical presentation

  • Classical triad
    • Epistaxis (95%)
    • Multiple mucocutaneous telangiectasias (small superficial arteriovenous malformations)
    • Positive family history of HHT
  • Intracranial haemorrhage
  • Inc risk of pulmonary arterial venous fistula → paradoxical cerebral embolism → embolic stroke / cerebral abscess formation
Feature
% of Persons with Feature
Notes
Epistaxis
95%
ㅤ
Telangiectases
95%
Primarily on the lips/tongue/ buccal/nasal/GI mucosa, face & fingers
Anaemia
50%
ㅤ
Pulmonary AVMs
30-50%
ㅤ
Hepatic AVMs
40-70%
<10% symptomatic
Cerebral AVMs
10%
ㅤ
Pulmonary hypertension
1-5%
ㅤ
(A) Telangiectasias on the tongue, lip and peri-oral region (B) palmer aspects of the hands (C) post-embolization image showing contrast blush in the nasal, upper lip and hard palate areas.
(A) Telangiectasias on the tongue, lip and peri-oral region
(B) palmer aspects of the hands
(C) post-embolization image showing contrast blush in the nasal, upper lip and hard palate areas.

Screening

  • Molecular genetic testing is offered to at-risk family members if the germline pathogenic variant has been identified in the family.
  • If the pathogenic variant in the family is not known, at-risk family members should be evaluated for signs and symptoms of HHT, and screening should be offered to at-risk family members if the diagnosis cannot be ruled out.