Hereditary Hemorrhagic Telangiectasia (HHT)/Osler-Weber-Rendu Disease, and Capillary Malformation-Arteriovenous Malformation Syndrome (CM)-AVM Panel

Hereditary Hemorrhagic Telangiectasia (HHT, aka Osler-Weber-Rendu disease), and Capillary Malformation-Arteriovenous Malformation Syndrome (CM-AVM) are related disorders of vascular dysplasia. CM-AVM is marked by the presence of multifocal, rounded, reddish lesions that may have a white halo, comprising dilated capillaries in the skin (Hershkovitz et al. 2008. PubMed: 18327598). CMs are localized mainly on the face and limbs and may or may not be combined with AVMs which are direct connections between arteries and veins.

Distinguishing features of HHT include the presence of mucocutaneous telangiectasias (small AVMs appearing as red or purple spots frequently on lips, hands, or face), bleeding episodes such as frequent epistaxis (nosebleeds), and anemia. Features of HHT and CM-AVM overlap though a few distinct differences are worth noting. For example, epistaxis is primarily a hallmark of HHT, and CMs are not seen in HHT patients. Also, the co-occurrence of capillary malformations and telangiectasias helps to differentiate CM-AVM2 from HHT.

AVMs can affect all organs of the body and present a risk for hemorrhage. In addition, the shunting of blood due to AVMs can also affect cardiac output and arterial oxygenation (McDonald et al. 2011. PubMed ID: 21546842). The severity and range of symptoms can vary widely even within families and symptoms may increase in severity as patients age (McDonald et al. 2011. PubMed ID: 21546842). In patients with HHT, about 20-25% of patients develop GI bleeding later in life that may lead to severe anemia (Abdalla et al. 2003. PubMed ID: 12843319). Hepatic AVMs are found in ~ 32% of patients and are often asymptomatic, but can cause cirrhosis and affect cardiac output (Plauchu et al. 1989. PubMed ID: 2729347; Garcia-Tsao et al. 2000. PubMed ID: 11006369). Cerebral AVMs (5-20% of cases) and Pulmonary AVMs (30-50% of cases) are usually present at birth and may cause headaches, seizures, stroke, ischemia, hypoxemia, and hemothorax (Shovlin and Letarte 1999. PubMed ID: 10413726). In general, AVMs in the liver and lungs occur more frequently in patients with HHT, whereas AVMs in the central nervous system, face, neck, and extremities occur more frequently in cases of CM-AVM (Amyere et al. 2017. PubMed ID: 28687708).

The incidence of HHT is ~ 1:5-10,000 and affects men and women and is present in all ethnic groups (Govani and Shovlin. 2009. PubMed ID: 19337313; Abdalla and Letarte. 2006. PubMed ID: 15879500). The incidence of CM-AVM is thought to be about the same as HHT (Amyere et al. 2017. PubMed ID: 28687708). HHT and CM-AVM are both autosomal dominant disorders with genetic heterogeneity and some phenotypic and genotypic overlap. HHT is associated primarily with pathogenic variants in ENG, ACVRL1, SMAD4, and in a few cases with EPHB4, GDF2, and RASA1. CM-AVM is associated primarily with pathogenic variants in the RASA1 and EPHB4 genes. Pathogenic variants are observed in over 80% of HHT patients (Kritharis et al. 2018. PubMed ID: 29794143; Abdalla and Letarte. 2006. PubMed ID: 15879500) and in over 50% of CM-AVM patients (Amyere et al. 2017. PubMed ID: 28687708). Both HHT and CM-AVM are associated with high inter- and intrafamilial clinical variability. HHT is characterized by variable penetrance whereas CM-AVM is characterized by high penetrance (almost 100%) (McDonald et al. 2011. PubMed ID: 21546842; Amyere et al. 2017. PubMed ID: 28687708).

ENG – Pathogenic variants in the ENG gene are found in ~50-60% of HHT cases (HHT1) (Kritharis et al. 2018. PubMed ID: 29794143). ENG encodes the endothelial cell surface co-receptor endoglin that binds (TGF)-ß and is essential for vascular integrity (Ríus et al. 1998. PubMed ID: 9845534). HHT1 is associated with a high incidence of pulmonary and cerebral AVMs and a higher penetrance than HHT2 in which hepatic AVMs are more common (Letteboer et al. 2006. PubMed ID: 16155196). HHT1 is thought to have a more severe phenotype than other forms of HHT. Causative variants are found throughout the ENG gene and include primarily missense and loss of function variants such as large whole or multi-exon deletions and splicing variants (Prigoda et al. 2006. PubMed ID: 16690726).

ACVRL1 – Pathogenic variants in the ACVRL1/ALK1 gene account for ~ 40% of HHT cases (HHT2) (Kritharis et al. 2018. PubMed ID: 29794143). ACVRL1/ALK1 encodes activin receptor like kinase 1 (ALK1) which is a type I receptor in endothelial cells that binds (TGF)-ß when coexpressed with a type II receptor (Johnson et al. 1996. PubMed ID: 8640225). HHT2 generally has a lower penetrance, milder phenotype, later onset of disease, and a higher occurrence of hepatic AVMs, but lower occurrence of pulmonary or cerebral AVMs than HHT1 (Letteboer et al. 2006. PubMed ID: 16155196). Over 300 causative variants have been identified throughout the ACVRL1 gene and include primarily missense/nonsense mutations. Large whole or multi-exon deletions and splicing mutations are rare (Prigoda et al. 2006. PubMed ID: 16690726).

SMAD4 - Pathogenic variants in the SMAD4 gene account for ~ 2% of HHT cases (HHT3) (Kritharis et al. 2018. PubMed ID: 29794143). Variants in SMAD4 are also associated with autosomal dominant juvenile polyposis and with the combined syndrome known as juvenile polyposis and HHT (JPHT) (Gallione et al. 2004. PubMed ID: 15031030). SMAD4 encodes a transcription factor for genes in the (TGF)-ß signaling pathway required for proper cell differentiation.

GDF2 – Pathogenic variants in GDF2 (aka BMP9) are associated with a small number of HHT cases (HHT5) (Wooderchak-Donahue et al. 2013. PubMed ID: 23972370; Hernandez et al. 2015. PubMed ID: 27081547). Some patients with GDF2-related HHT had capillary malformations similar in appearance and location to patients with CM-AVM including the back, shoulders, mouth, and face. Experimental data from zebrafish studies show that knockdown of the GDF2 protein, BP9, resulted in aberrant venous remodeling suggesting that BP9 is important for angiogenesis (Wooderchak-Donahue et al. 2013. PubMed ID: 23972370)

EPHB4 - Pathogenic variants in EPHB4 have been associated with autosomal dominant CM-AVM2 which mimics CM-AVM1 and HHT (Amyere et al. 2017. PubMed ID: 28687708). CM-AVM2 is characterized by CMs found most frequently on the extremities and trunk. About 18% of patients had AVMs, and about 15% of cases had telangiactasias similar to HHT (Amyere et al. 2017. PubMed ID: 28687708; Wooderchak-Donahue et al. 2019. PubMed ID: 30760892). EPHB4 encodes a ligand receptor expressed in aterial and venous progenitors that plays a role in vascular development (Herbert et al. 2009. PubMed ID: 19815777). EPHB4 variants are also associated with the related condition Galen aneurysmal malformation (Vivanti et al. 2018. PubMed ID: 29444212).

RASA1 – Pathogenic variants in RASA1 have been associated with autosomal dominant CM-AVM1 and HHT (Revencu et al. 2013. PubMed ID: 24038909; Hernandez et al. 2015. PubMed ID: 27081547). Over 50% of patients with CM-AVM have pathogenic loss of function variants in RASA1 (Amyere et al. 2017. PubMed ID: 28687708; Revencu et al. 2013. PubMed ID: 24038909). CM-AVM1 is characterized by multifocal CMs, similar to “port-wine stains”, and cutaneous areas of small white halos with a central red dot that increase over time (Revencu et al. 2013. PubMed ID: 24038909). Patients may or may not have AVMs and Parkes Weber syndrome. RASA1 encodes the cytoplasmic GTPase-activating protein P120RASGAP involved in vascular development and cell proliferation and differentiation (Henkemeyer et al. 1995. PubMed ID: 7477259).

Causative variants are located throughout the ENG, ACVRL1, SMAD4, GDF2, EPHB4, and RASA1 genes and include primarily missense/nonsense variants and both small and large, often multi-exon, deletions. Splice site variants and insertions are also common, but no predominant variants have been identified for any of these genes.

See individual gene summaries for more information about molecular biology of gene products and spectra of pathogenic variants.

Over 80% of HHT patients have a pathogenic variant in either ACVRL1, ENG or SMAD4 (Prigoda et al. 2006. PubMed ID: 16690726). Variants in GDF2 were found in 1.6% of HHT patients in one study (Wooderchak-Donahue et al. 2013. PubMed ID: 23972370). About 50% of CM-AVM patients have a loss of function variant in RASA1 (Amyere et al. 2017. PubMed ID: 28687708). In another study, 54 out of 365 patients (~15%) with either CMs or CM-AVMs were reported to harbor possible pathogenic variants in the EPHB4 gene (Amyere et al. 2017. PubMed ID: 28687708).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel provides 100% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing.

Since this test is performed using exome capture probes, a reflex to any of our exome based tests is available (PGxome, PGxome Custom Panels).