5  Syndromic Arteriovenous Malformations

Waleed Brinjikji and Giuseppe Lanzino

Abstract

There are a number of syndromes that have a strong association with the formation of brain arteriovenous malformation (AVM). Hereditary hemorrhagic telangiectasia (HHT) is the most common brain AVM–associated genetic syndrome affecting up to 1 in 5,000 people. Patients with HHT can present with intracranial nidal AVMs, pial arteriovenous fistulas, and capillary vascular malformations (also known as micro-AVMs). Capillary malformation-AVM (CM-AVM) syndrome, caused by a mutation in the RAS/MAPK pathway, affects 1 in 100,000 people and is associated with cutaneous capillary malformations and nidal-type brain AVMs. Parkes-Weber’s syndrome, often considered a subtype of CM-AVM syndrome, is characterized by limb AVMs, which result in hypertrophy of the affected limb. Patients with these syndromes and their relatives should consider genetic testing, and AVM screening with brain magnetic resonance imaging is recommended for affected individuals and their relatives. Wyburn-Mason’s syndrome, in which AVMs can affect any part of the optic apparatus extending from the orbit to the occipital lobe, is exceedingly rare and no known genetic associations have been found. Management of AVMs in these syndromes should be done on a case-by-case basis because each AVM and each individual are unique. Given our increased understanding of the genetic and pathophysiological aspects of AVM formation in these populations, more and more research is being done to identify nonsurgical therapies aimed at stemming the formation and long-term effects of AVMs in these populations.

Keywords: arteriovenous malformation, hereditary hemorrhagic telangiectasia, RASA, arteriovenous fistula, congenital

5.1  Introduction

Most arteriovenous malformations (AVMs) are sporadic and exhibit variable sizes, angioarchitectural features, and locations. The estimated prevalence of sporadic brain AVMs is 10:100,000 to 20:100,000 adults.¹ While the underlying pathophysiologic and genetic causes of these sporadic AVMs are unclear, there is increasing evidence that genetic factors do play a role in their development.¹

Among the AVM patient population is a subset of patients who suffer from AVMs as part of a familial or genetic syndrome. The two most common syndromes associated with brain AVMs are hereditary hemorrhagic telangiectasia (HHT), which is also known as Osler–Weber–Rendu syndrome, and the capillary malformation-AVM (CM-AVM) syndrome, which is associated with the RASA mutation. Other, more rare AVM-associated syndromes include Wyburn-Mason’s syndrome and Parkes-Weber’s syndrome (PWS).²

An understanding of syndrome-associated AVMs is important for a number of reasons. First, when working with patients who have syndrome-associated AVMs, it is important for clinicians to be aware of the other systemic manifestations of these diseases to allow for appropriate coordination of care, screening, and management. Second, in many cases, secondary central nervous system (CNS) manifestations and angioarchitectural features of AVMs can provide a clue regarding whether or not the AVM is syndrome-associated. In these cases, it is possible that the neurologist, neurosurgeon, or neuroradiologist seeing the patient could be the first to suggest the possibility of an underlying syndrome as the culprit for the AVM. Lastly, findings regarding the genetics of these syndromes have provided valuable information regarding the pathophysiology of both syndrome-associated and sporadic AVMs.

The aims of this chapter are the following: (1) to introduce the clinician to some of the more common AVM-associated syndromes including their systemic manifestations and genetics, (2) to discuss the management of patients with AVM-associated syndromes, and (3) to provide an updated review of the literature regarding the role of genetics in sporadic AVMs. For the purposes of this review, we will not be covering syndromes associated with nonshunting vascular abnormalities such as those seen in Sturge–Weber syndrome and posterior fossa malformations–hemangiomas–arterial anomalies–cardiac defects–eye abnormalities–sternal cleft and supraumbilical raphe syndrome (PHACES syndrome).

5.2  Materials and Methods

In accumulating information for the purposes of this chapter, we searched the PubMed and Online Mendelian Inheritance in Man (OMIM) databases for information regarding the genetics of brain AVMs using the following search terms: brain AVM, arteriovenous malformation, hereditary hemorrhagic telangiectasia, RASA, single-nucleotide polymorphism, genetics, Wyburn-Mason’s syndrome, and Parkes-Weber’s syndrome. We retrieved all case reports, case series, review articles, and meta-analyses regarding these syndromes and the genetics of AVMs.

5.3  Results

5.3.1  AVM-Associated Syndromes

► Table 5.1 and ► Table 5.2 summarize the salient characteristics of AVM-associated syndromes found on our literature review, including estimated diseases prevalence, estimates regarding the proportion of patients with AVMs (when available), other systemic and CNS manifestations of these syndromes, associated gene mutation and gene function, and typical angioarchitectural features (when available).

► Table 5.3 summarizes the single-nucleotide polymorphisms (SNPs) and somatic mutations that have been associated with sporadic AVMs. Included in this table are data on the function of the genes that are associated with these mutations and their putative role in AVM pathogenesis.

5.4  Discussion

5.4.1  Hereditary Hemorrhagic Telangiectasia

HHT is the most common of the AVM-associated syndromes affecting anywhere from 1:5,000 to 1:10,000 people worldwide. HHT is diagnosed clinically using the Curacao criteria.³ The four Curacao criteria are (1) spontaneous and recurrent epistaxis, (2) mucocutaneous telangiectasias (lips, oral cavity, face, and fingers), (3) visceral AVMs (brain, liver, lung, etc.), and (4) diagnosis of HHT in a first-degree relative using the same criteria. Patients who meet three or more of the four criteria are labeled as “definite HHT,” whereas those with two of the four criteria are labeled as “possible” or “suspected” HHT.⁴ The most common clinical manifestations of HHT are epistaxis, gastrointestinal bleeding, and pulmonary AVMs.

There are at least five types of HHT. HHT1 is due to a mutation in the ENG gene, which codes for endoglin. Endoglin is a component of the transforming growth factor beta (TGF-β) complex and plays an essential role in the development and regulation of human vascular endothelium. HHT2 is secondary to a mutation in the ACVRL1 gene, which codes for an activin receptor–like kinase. This protein is also involved in the TGF-β system and plays a key role in regulating vasculogenesis. There is also a juvenile polyposis with HHT syndrome secondary to a mutation in the SMAD4 gene. This gene also plays a role in vasculogenesis.

Approximately 10 to 20% of patients with HHT have a brain AVM with a higher prevalence noted in HHT1 patients.⁵ HHT-associated AVMs are classified as (1) large single-hole pial arteriovenous fistulas (AVFs), (2) AVMs with a nidus, and (3) micro-AVMs or capillary vascular malformation.⁶ The large AVMs/AVFs typically manifest in young children, while small AVMs are typically discovered in older age groups.⁶ AVFs represent about 10% of cerebral vascular malformations, while nidus-type AVMs represent about 50% of cerebral vascular malformations.⁶ Approximately 60% of patients with cerebral vascular malformations have micro-AVMs/capillary vascular malformations.

The angioarchitecture of each of these lesions differs substantially. Pial AVFs lack a nidus between the feeding artery and draining vein (i.e., a single hole with a pouch). These lesions are usually superficially located with only a tiny minority located in the deep portions of the brain.⁶ These lesions have many features that portend a poorer natural history, including arterial stenoses, feeding artery aneurysms, multiple draining veins, venous ectasia, and a pseudophlebitic pattern.⁶

Nidus-type AVMs are arteriovenous connections with an intervening nidus. About 40% of these lesions are located in eloquent areas and about 15% have deep venous drainage.⁶ Over 90% of these lesions have a Spetzler–Martin score of 2 or less.^6,7,8 The angioarchitecture of these lesions is typically benign. These lesions tend to measure less than 2 cm and lack features such as arterial stenoses, associated aneurysms, multiple draining veins, venous ectasia, and venous reflux. Associated aneurysms are signs of longstanding venous hypertension.⁶

Micro-AVMs and capillary vascular malformations lack definite shunting on angiography and have no dilated feeding arteries or veins. These are characterized by a blush of abnormal vessels in the arterial phase that persists into the late arterial and capillary phase.⁶ Angiographically, these lesions are distinct from both capillary telangiectasia and AVMs given that these are characterized by the presence of a capillary bed that is abnormally dilated. These lesions typically measure less than 5 mm in diameter, and 80% are superficial.^6,7,8

There are a number of salient features of HHT-AVMs that should lead one to consider a diagnosis of HHT if one has not already been established. Micro-AVMs/capillary vascular malformations are considered an HHT-defining feature by some authors. Pial AVFs are thought to be exceedingly rare in the sporadic AVM population, but are seen in up to 10% of HHT-AVM patients; thus, the presence of these lesions should trigger an investigation for HHT.^9,10 Regarding the nidal-type AVMs, features that should trigger an investigation for HHT are lesion multiplicity, especially when seen in superficial locations. An example of a patient with multiple AVMs in the setting of HHT is provided in ► Fig. 5.1.

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