Morbus Osler - ENG, ACVRL1

Osler-Rendu-Weber Syndrome, Hereditary hemorrhagic Teleangiektasia (HHT)

Clinical Features

Osler-Rendu-Weber Syndrome (hereditary hemorrhagic telangiectases, HHT or Osler's disease) is characterized by the occurrence of multiple arteriovenous short-circuits (AVM, arteriovenous malformations). Small AVMs just under the epithelium or mucous membranes often break after a mild trauma and bleed.

The most common clinical manifestation of Osler's Disease is spontaneous and recurrent nose bleeding, which usually manifests itself at around the age of 12. In approximately 25% of patients with Osler's Disease, gastrointestinal bleeding has been observed, normally beginning from 40 years of age. Large AVMs occurring in the lungs, central nervous system or gastrointestinal tract can cause serious complications from excessive bleeding.

Criteria for clinical diagnosis of Osler's Disease (Curaçao criteria):

Frequent, spontaneous epistaxis (nose bleeds)
Telangiectasia (vascular malformations) on the lips, mouth, fingers and nose
Visceral manifestation of AVM (lung, liver, central nervous system and gastrointestinal tract)

Positive family history: at least a first-degree relative with one of the above criteria

Genetic Information

Germline mutations in the ENG (endoglin) gene, which is located on chromosome 9 (9q31.1) have been described for Osler Disease (type HHT1). The ENG gene comprises 14 exons and encodes an mRNA 3142 bp in length. Endoglin, which comprises 561 amino acids, is a homodimeric membrane protein which is involved in the TGF-β signaling pathway.
In addition to ENG gene mutations, mutations in the gene ACVRL1 (synonym ALK1) have also been described (type HHT2) in patients with Morbus Osler. In the literature, the incidence of mutations in ENG (53%) and ACVRL1 (47%) have been described as nearly identical.

In a small number of patients mutations in the SMAD4-gene can be identified. These patients usually present with HTT in combination with Juvenile Polyposis.