Abstract
Aim: The aim of this retrospective single-centre study was to evaluate whether mutations in the ENG, ACVRL1, and SMAD4 genes were associated with different phenotypes in hereditary haemorrhagic telangiectasia (HHT).Methods: The case records of 21 HHT patients with verified mutations in ENG, ACVRL1, or SMAD4 genes were reviewed. The numbers of HHT diagnostic criteria fulfilled for the three genotypes were compared, as was the prevalence of complications such as iron deficiency anaemia, gastrointestinal haemorrhage, stroke, and cerebral abscess.Results: Our results indicate that mutations in the ENG (HHT1), ACVRL1 (HHT2), and SMAD4 genes result in different HHT phenotypes. Epistaxis debuts earlier and may be more severe in HHT1 than in HHT2. The prevalence of pulmonary arteriovenous malformations (AVM) is higher in HHT type 1, whereas hepatic AVMs are more common in HHT2. One patient with mutations in both ENG and ACVRL1 genes was identified, as were two SMAD4-mutated patients suffering from the overlapping juvenile polyposis-HHT syndrome. Nearly one in five patients in our HHT population has been diagnosed with stroke or cerebral abscess, indicating a high prevalence of cerebral complications.Conclusion: Our results showing that ENG and ACVRL1 gene mutations result in different HHT phenotypes confirm the results from other HHT centres worldwide. Cerebral complications of HHT are common, underscoring the importance of regular screening for pulmonary AVMs and early intervention against such AVMs. We have identified an HHT patient with simultaneous mutations in the ENG and ACVRL1 genes. Surprisingly, this patient has had a mild course of the disease.
Highlights
Hereditary haemorrhagic telangiectasia (HHT), or Osler–Weber–Rendu syndrome, is a rare autosomal dominant genetic disorder with varying degree of penetrance (1)
Two of the HHT1 patients were diagnosed with stroke, and two other patients had been treated for brain abscess. In this retrospective single-centre study, performed at the Center for Osler’s Disease at Uppsala University Hospital, the aim was to evaluate whether mutations in the ENG, ACVRL1, and SMAD4 genes were associated with different HHT phenotypes in our patient cohort
The prevalence of HHT-related complications such as iron deficiency anaemia, GI haemorrhage, stroke, and brain abscess was evaluated. Such evaluations have previously been reported from other HHT centres (8–12), but this is the first report on genotype– phenotype association in a Swedish HHT patient population
Summary
Hereditary haemorrhagic telangiectasia (HHT), or Osler–Weber–Rendu syndrome, is a rare autosomal dominant genetic disorder with varying degree of penetrance (1). The major clinical manifestations of the disorder are the result of development of abnormal vascular structures in different body organs. These include recurrent bleeding from mucosal telangiectasias together with cardiac, cerebral, and hepatic complications caused by arteriovenous fistula formations. Gastrointestinal (GI) haemorrhage is less common in HHT and usually debuts later in life than epistaxis (3). More than half of HHT patients develop iron deficiency anaemia due to chronic blood loss (4). The HHT diagnosis is based on the Curacao criteria which are: recurrent epistaxis, mucocutaneous telangiectasias, evidence of autosomal dominant inheritance, and visceral arteriovenous malformations (AVMs) (6). The HHT diagnosis is definite if three of these criteria are present, suspected if two criteria are present, and unlikely if a patient fulfils fewer than two criteria (7)
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