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Gene & Protein in Disease Genetics of arteriovenous malformations

and TNF-α–238 A alleles were independent predictors of signal. Therefore, aberrations in the BMP-9 endothelial
ICH risk in a multivariate model . In addition, they also signaling pathway have been postulated to contribute to
[82]
appear to confer greater risk for post-radiosurgical and HHT pathogenesis [26] .
post-surgical hemorrhage . Clinically, both HHT-1 and HHT-2 share all the classic
[30]
Our knowledge of the genetic risk factors associated manifestations of HHT, such as epistaxis, telangiectasias,
with AVM and their rupture has continued to garner and visceral AVM; however, the occurrence of bAVM
research interest due to its clinical utility. Future studies is approximately 10 higher in HHT-1 compared to
to continue validation of these risk factors will require HHT-2 [54,85,86] . Approximately 10% of patients with HHT
large clinical datasets and continued replicative studies. have bAVM [26,87] . Over 40% of patients with HHT develop
In addition, taking into consideration a patient’s genomic multiple bAVM with 50% manifesting symptoms, and
makeup and contributory epigenetic and clinical risk occurrence of rupture occurs in 20% of patients. While
factors would altogether provide a more accurate they cannot be distinguished solely on the basis of their
estimation of risk of AVM rupture to modulate its potential angioarchitecture, each have distinctive features. For
devastating outcomes. example, compared to the sporadic form of bAVM, those
associated with HHT are smaller with an average nidus
6. Genetic conditions associated with AVM of < 3 cm (about 1.18 inch), while the average nidus in

While our discussion thus far has focused on cerebral AVM sporadic bAVM is approximately 3 cm [54,85] . Loss-of-
and their clinical outcomes, it is also imperative to note function mutations in ENG confers a 1000-fold increased
that AVM is present in several other genetic syndromes risk of developing bAVM compared to sporadic lesions,
which we have mentioned but they will be highlighted in whereas loss-of-function mutations in ACVLR1 increase
[26]
more detail in this section. the risk by 100 folds .
6.1. HHT Additional genetic risk factors for AVM have been
identified, namely, SNPs in TNF-α and APOE, which are
HHT, also known as Osler-Rendu-Weber syndrome 1, associated with downstream vascular derangements. Kim
is an autosomal dominant vascular dysplasia consisting et al. report that the A allele of the TNF-α–238G > A
of epistaxis, mucocutaneous telangiectasias, and AVM, promoter SNP was associated with new hemorrhage in the
affecting one in 5000–8000 individuals [26,54] . HHT is a natural course of a sample of 280 AVM cases.
clinical diagnosis marked by the presence of at least three
of the following features per the Curacao criteria: Multiple 6.2. CM-AVM
mucocutaneous telangiectasias, recurrent epistaxis, Capillary malformation-AVM (CM-AVM) is an
visceral organ AVM, and HHT diagnosed in a first-degree autosomal dominant vascular syndrome characterized
relative [54,83] . These features demonstrate age-related by small, multifocal vascular macules with or without
penetrance with 50% of individuals developing epistaxis fast-flow vascular lesions [54,88,89] . Typical fast-flow lesions
by age 10, and 80–90% by age 21. Moreover, telangiectasias include arteriovenous fistulas and AVM predominantly
arise in nearly all patients by late adulthood . In addition in the central nervous system, head and neck, and/
[54]
to the brain, HHT commonly presents with AVM in the or limbs [54,89-91] . These macules typically are reddish-
liver and lungs [54,84] . brown to pink with peripheral halos, although these
Loss-of-function mutations in ENG, ACRVL1 or colors change and become browner with age [53,54,90] .
ALK1, and SMAD4 have each been identified as the While it has been reported that these macules represent
cause of a particular subclass of HHT [26,54] . HHT is sub- capillary malformations, histopathologic and ultrasonic
divided into two main subtypes; HHT1 and HHT2. examinations have confirmed that they are in fact
The classification of these subtypes is dependent on cutaneous micro or incipient AVM [54,90,91] . The macules
loss-of-function mutations in two genes connected to of CM-AVM can be distinguished from other disorders
TGF signaling pathways. For instance, loss-of-function such as simple cutaneous capillary malformations by
mutation in ENG, which codes for an accessory protein the presence of the peripheral halos. This pale rim is
in the TGF-B receptor complex, is linked to HHT-1, postulated to be the result of the AVM siphoning blood
while loss-of-function mutation in ACVLR1, a gene from the tissue immediately surrounding it, which
that codes for a transmembrane kinase associated reduces blood flow to the area . Approximately one-
[91]
with TGF-B signaling, causes HHT-2 [26] . Interestingly, third of patients with CM-AVM present with fast-flow
ACVLR1 has also been associated with signaling through vascular lesions in the CNS or skin with 10% occurring
the BMP-9, and ENG was shown to potentiate that in the brain [54,88,90,92] .

Volume 2 Issue 2 (2023) 8 https://doi.org/10.36922/gpd.0312