SCIENTIFIC BACKGROUND

ACVRL1, ENG, GDF2, SMAD4

Category:

SCIENTIFIC BACKGROUND

Osler disease, also known as hereditary hemorrhagic telangiectasia (HHT) or Osler-Rendu-Weber disease, is an autosomal dominant inherited disease with a prevalence of approximately 1:6,000 to 1:10,000. Symptoms result from the presence of arteriovenous malformations (AVMs), direct connections between the arterial and venous stromal beds without intervening capillaries. Due to autosomal dominant inheritance, the recurrence risk for children of affected individuals is 50%.

 

In up to 95% of cases, leading symptoms are repeated nosebleeds from easily damaged telangiectasias (small AVM), that often start in the second decade of life.  Telangiectasias are also found on the skin, especially on the fingers, face, and chest, or on the visible mucous membranes (lips, cheek mucosa, tongue), but also in the wider gastrointestinal tract. About a quarter of affected individuals have recurrent gastrointestinal bleeding, which can also lead to chronic iron deficiency anemia. Telangiectasias often occur only after the early symptom of nosebleeds. Arteriovenous malformations can occur in various organs, including the liver and lungs or even the brain. Complications arise from bleeding and/or the AV short-circuit connections. Pulmonary AVMs (present in about 30-50% of affected individuals) can lead to transient ischemic attacks, stroke, or even brain abscesses; hepatic AVMs (present in less than half to two-thirds) are less likely to become symptomatic but are more likely to have hemodynamic effects (portal hypertension, heart failure). Intracerebral AVMs are usually congenital but occur in only about 10% of affected individuals. AVMs in the pancreas appear to be common but rarely become symptomatic, whereas intraspinal localization is rare. Pulmonary hypertension, e.g., due to increased ejection of the heart from AV shunts in the liver, is rarer than pulmonary AVMs are.

 

Pathogenic variants in four genes (ENG, ACVRL1, SMAD4, rarely GDF2) have been identified in descending frequency as the cause of the disease. Pathogenic variants in SMAD4 may also lead to a clinical picture of juvenile polyposis in combination with HHT. The diagnostic sensitivity of molecular genetic analyses is up to 75-85% in HTT.

 

So far, all known causative genes encode proteins that act in the TGF-beta signaling pathway.

 

To date, there is no curative therapy option. In the case of nosebleeds, local measures such as moistening, antifibrinolytics, cauterization, or laser coagulation may be considered; in the case of AVMs in organs, embolization may be used. Smaller studies and single case reports also show success with systemic therapy with bevacizumab, a VEGF (vascular endothelial growth factor) inhibitor.

 

References

Kritharis et al. 2018, Haematologica 103:1433 / Grigg et al. 2017, Ochsner Journal 17:157 / McDonald et al. 2015, Front Genet 6:1

GENES

ACVRL1, ENG, GDF2, SMAD4

ASSOCIATED TESTS

How to order

LATEST ARTICLES

Every year on April 25th, DNA Day celebrates the discovery of DNA’s double helix and the advances we’ve made in understanding genetics. D...

Read more

Neurodevelopmental disorders (NDDs) have diverse genetic origins, making diagnosis challenging. A new study analyzing over 1,100 pediatric patients f...

Read more

Colorectal cancer (CRC) remains one of the most prevalent and deadly cancers worldwide, with a significant number of cases presenting at an advanced ...

Read more

Carrier screening is a genetic test designed to identify whether an individual carries a gene with changes (mutations) associated with inherited diso...

Read more

Trisomy 13, also known as Patau syndrome, is a genetic condition in which cells in the body have three copies of chromosome 13 instead of two. The co...

Read more

The human brain develops through a complex series of events, with genes carefully regulating the formation of neurons and glial cells. A recent study...

Read more

Rare diseases affect between 300 and 400 million people worldwide – more than cancer and AIDS combined [1, 2], but despite this, many people face a...

Read more

Rosalind Elsie Franklin was a brilliant and meticulous research scientist whose interdisciplinary work made fundamental contributions to various area...

Read more

February, designated as Cancer Awareness Month, marks a time to reflect on the remarkable progress made in cancer research and to inspire hope for th...

Read more

Introduction Cardiovascular disease (CVD) is a major health issue as it remains a leading cause of death worldwide [1]. CVD is responsible for mor...

Read more