Family History and Genetic Factors of Brain Aneurysms

This is the most important risk factor. There is a 2- to 7-fold increased risk of intracranial aneurysm (IA) formation and subarachnoid aneurismal hemorrhage (SAH) in first-degree relatives (parents, children, and siblings).

Familial intracranial aneurysms account for 7-20% of patients with aneurismal subarachnoid hemorrhage (ASAH), but are generally not associated with any heritable tissue disorders. First-degree relatives of patients with ASAH have a four-fold risk of ruptured intracranial aneurysm compared to the general population (Shievink, Genetics of intracranial aneurysms. Neurosurgery 40(4): 651-663,1998). Another study found a 2 to 7-fold increased risk with familial relatives (Pfohman, 2001). However, a commonly quoted statistic in the literature is up to 10% in certain populations can be familial (Astradsson and Astrup, An intracranial aneurysm in one identical twin, but no aneurysm in the other, Br J Neurosurg. 2001 Apr;15(2):168-71).

The highest familial association is among siblings, 52% (Astradsson, 2001; Adams, 1992). Familial aneurysms tend to rupture at a younger age (avg. 39.8 yrs), smaller size and less frequently in the anterior communicating artery than sporadic aneurysms in the general population. In siblings and twins, they tend to occur in the same or opposite vessels and rupture also at similar ages. One study shows a trend of intracranial aneurysms as having a male/female ratio of 2/1 in all patients, 3/1 for occurrence of the intracranial aneurysm in patients under 20 yrs. However, this ratio reverses itself with female predominance in patients over 60 yrs (1/2) (Adams, 1992).

Investigations for genetic markers have been performed, but none have been successful in isolating a gene that appears to be mutating coincidental to aneurismal formation or even to the weakening of vessel walls. Ostergaard et al. investigated the occurrence of the C3-F gene among patients with IA suggesting that this gene which has been associated with atherosclerotic vascular diseases may be a risk factor for early aneurysm rupture (Puchner, 1994) and a Mendelian inheritance has been postulated (Astradsson, 2001). However, in spite of these genetic studies, the pattern of inheritance for familial aneurysms (if there is one) remains unproven.

Because of the morbidity (damage to brain function) and mortality rates associated with surgical intervention, screening for aneurysms remains controversial. One paper suggests that two groups of patients may benefit from early detection: those with autosomal dominant polycystic kidney disease and those with a history of aneurysmal subarachnoid hemorrhage (Vega et al., 2002). Vega et al. recommends that these patients undergo magnetic resonance angiography (MRI), followed by neurosurgical referral if an aneurysm is detected.

Screening of patients who have two or more family members with intracranial aneurysms is also controversial. Screening of patients who have one first-degree relative with an aneurysm does not appear to be beneficial, according to Vega et al., 2002.

Ehlers-Danlos Type IV

Joint hypermobility (loose joints), fragile skin, easy bruising, and scarring characterize Ehlers-Danlos Type IV. There are five types with type IV being the most common and lethal (1 in 50,000-500,000 individuals). This results from a deficiency in type III collagen, which is a building block of artery and vein walls. Although the association between Ehlers-Danlos type IV and IA’s is well established, the frequency of patients with both Ehlers-Danlos and IA’s is not known due to the difficulty in diagnosing Ehlers-Danlos (a mild case involves only fragile skin and slight joint looseness). Aneurysms associated with this condition tend to form on medium to large arteries.

Marfan’s Syndrome

This syndrome is characterized by elongation of the bones and abnormalities in the cardiovascular system (the heart and blood vessels) and the eyes. It is caused by a mutation in a gene that codes for a protein component of microfibrils, used to make blood vessel walls flexible. About 1 in 10,000 to 20,000 people have this disorder. Aneurysms associated with this disorder tend to be saccular, fusiform, or dissecting and are usually found in the proximal intracranial carotid artery.

Neurofibromatosis Type I

This condition begins at birth and gets progressively worse, effecting 1 in every 3,000-5,000 persons. The characteristics include blood vessel constriction (stenosis), vessel rupture, tumors in the nervous system (neurofibromas) and the abnormal development of the muscles, bones and internal organs. The aneurysms in this case tend to form in medium to large-sized arteries.

Autosomal Dominant Polycystic Kidney Disease (ADPKD)

This is one of the more common heritable tissue disorders (1 in 400 to 1,000 persons). The characteristics of this disease include: enlarged kidneys, cysts in the kidneys, liver, pancreas, and spleen, cobweb-like cysts in the brain, and hernias in the groin (a vessel bulging out of the skin usually painfully). The formation of the cysts, little sacs of fluid attached to an organ, results from a genetic mutation causing abnormal cell growth and fluid secretion. Hypertension is a complication found in 75% of ADPKD patients, contributing to aneurysm formation and subarachnoid aneurismal hemorrhage in those patients.

Many studies indicate a likelihood of a relationship between ADPKD and IA’s. Estimates of the frequency of aneurysms in ADPKD patients range from 10% to 41%. IA’s have been reported in 25% of ADPKD patients and are the cause of death in 20%. Family history is an increasingly recognized risk factor for IA and SAH with ADPKD patients; about 18% to 22% of ADPKD patients with an IA have a positive family history for aneurysms.