Autosomal Dominant Polycystic Kidney Disease

Autosomal dominant polycystic kidney disease (ADPKD) affects about 1 in 400 to 1000 persons and is the most common monogenetic disease in humans.⁷ It is inherited as an autosomal dominant trait with almost complete penetrance but with variable expression. The family history is negative in about 20% of patients, thus suggesting a fairly high spontaneous mutation rate.

ADPKD is a systemic disease, and cysts are present in the kidneys, liver, pancreas, spleen, ovaries, and seminal vesicles.⁷ Moreover, ADPKD should be included among the heritable connective tissue disorders.⁵ A wide variety of connective tissues may be involved,⁷ including the heart valves (mitral valve prolapse), vasculature (aneurysms and dissections), and meninges (arachnoid cysts). Patients with ADPKD are at increased risk for the development of gastrointestinal diverticula and inguinal hernias.⁷

Neurosurgical disorders that have been associated with ADPKD include intracranial aneurysms, cervicocephalic arterial dissections, intracranial dolichoectasia, intracranial arachnoid cysts, spinal meningeal diverticula/cerebrospinal fluid leaks, and chronic subdural hemorrhages.^8–13 Intracranial aneurysms have long been known to be associated with ADPKD.^14–21 Until the underlying connective tissue defect of the disease became well known, however, aneurysms were frequently attributed to the arterial hypertension that usually accompanies ADPKD. Intracranial aneurysms are detected in approximately a fourth of patients with ADPKD at autopsy; in most of these patients, aneurysmal rupture was the cause of death. Conversely, ADPKD accounts for 2% to 7% of all patients with intracranial aneurysms. Using magnetic resonance angiography or, less commonly, catheter angiography in patients with good renal function, several groups have screened adult ADPKD patients for asymptomatic intracranial aneurysms. The detection rate has ranged between 5% and 10%.^15–19 Familial clustering of intracranial aneurysms occurs in ADPKD; the yield of screening increases to 10% to 25% in such families.^15–19 The presence of polycystic liver disease in patients with ADPKD may also increase the development of intracranial aneurysms.¹⁶

Screening patients with ADPKD for asymptomatic aneurysms remains controversial but should certainly be considered for those with a family history of intracranial aneurysms. Most asymptomatic intracranial aneurysms detected with screening are less than 6 mm in diameter. In one study, none of these small aneurysms ruptured during 500 months of cumulative follow-up.¹⁷ It has been suggested that ADPKD patients are at an increased risk for the de novo development of aneurysms some time after their first intracranial aneurysm is discovered, but the exact significance of this risk remains to be determined.²² When compared with the general population, aneurysmal subarachnoid hemorrhage (SAH) in patients with ADPKD occurs at an earlier age, but the mortality rate is similar.⁸

ADPKD is a genetically heterogeneous disease. Several loci are involved, and mutations, which are responsible for at least 85% of cases, have been identified in a gene on chromosome 16 (PKD1), as well as in a gene on chromosome 4 (PDK2).^23–26 In general, patients with mutations in the PKD1 gene are more severely affected than those with mutations in the PKD2 gene, but intracranial aneurysms are a manifestation of both types of ADPKD. Polycystin-1 and polycystin-2 are the proteins encoded by the PKD1 and PKD2 genes, respectively.²³ Both proteins are integral membrane proteins with large extracellular domains, and they probably play a role in maintaining structural integrity of the connective tissue extracellular matrix.²³

Autosomal dominant polycystic liver disease (ADPLD) is a familial form of isolated polycystic liver disease that is distinct from ADPKD.²⁷ Patients with ADPLD may also be at high risk for the development of intracranial aneurysms.²⁷

Ehlers-Danlos Syndrome Type IV

Ehlers-Danlos syndrome type IV is potentially one of the most deadly heritable connective tissue disorders that neurosurgeons may encounter. It is uncommon, with a prevalence of approximately 1 in 50,000 to 500,000 persons.²⁸ It is inherited in an autosomal dominant fashion, but the family history is frequently noncontributory because of the high spontaneous mutation rate (approximately 50%).

Ehlers-Danlos syndrome type IV can be life-threatening because spontaneous rupture, dissection, or aneurysm formation on large and medium-sized arteries occurs in all areas of the body.^5,28–30 These arterial complications cause death in most patients. Other well-described life-threatening complications of Ehlers-Danlos syndrome type IV are spontaneous rupture of the bowel or gravid uterus and spontaneous pneumothorax.^28–30

An intracranial aneurysm may be the initial manifestation of Ehlers-Danlos syndrome type IV. Consequently, neurosurgeons may be the first physicians involved in these patients’ medical care. The syndrome is often difficult to recognize because its external features can be subtle.^5,28–30 The more salient features of Ehlers-Danlos syndrome type IV are summarized in Table 359-2. The characteristic facial appearance was first described by Carl Graf, a neurosurgeon³¹; many striking examples have since been published.^29,30 The facial features consist of (1) large expressive eyes with the sclera clearly visible around the iris, (2) a thin nose, (3) thin lips, and (4) lobeless ears. Many patients with Ehlers-Danlos syndrome type IV, however, do not exhibit this facial appearance. The characteristic cutaneous features include thin and fragile skin that is almost transparent and allows the subcutaneous veins to be clearly visible. Patients bruise easily, and multiple ecchymoses are common. Scars are often papyraceous and wide, or they may be complicated by keloid formation. The skin of some patients with Ehlers-Danlos syndrome type IV, however, appears normal. The joint hypermobility is often mild and limited to the fingers and toes. Identifying Ehlers-Danlos syndrome type IV in any patient with an intracranial aneurysm is important because vascular fragility can make any invasive procedure a hazardous undertaking.

TABLE 359-2 Characteristic Features of Ehlers-Danlos Syndrome Type IV

Intracranial aneurysms and spontaneous carotid cavernous fistulas are well-described vascular complications of Ehlers-Danlos syndrome type IV.^5,28–33 In some patients, the carotid cavernous fistula is due to rupture of a cavernous carotid aneurysm, although the fistula may be caused by a simple tear in the artery in other patients. The importance of intracranial aneurysmal disease in this group of patients is well described. For example, in a cohort of 202 patients with Ehlers-Danlos syndrome type IV, 4 had ruptured intracranial aneurysms, 4 suffered an intracranial hemorrhage of undetermined cause, and 6 had carotid cavernous fistulas.²⁸ The exact incidence of intracranial aneurysms in patients with Ehlers-Danlos syndrome type IV is unknown because screening for asymptomatic intracranial aneurysms is limited and systematic autopsy studies are unavailable. Screening for asymptomatic intracranial aneurysms in these patients is not recommended because safe treatment options are limited; arteriography, endovascular intervention, and surgical treatment are all associated with high complication rates.

Mutations in the gene encoding the pro-α₁-(III) chain of collagen type III (COL3A1) on chromosome 2 are the cause of Ehlers-Danlos syndrome type IV.^{29,30,33–36} This type of collagen is the major structural component of distensible tissues, including arteries, veins, hollow viscera, and the uterus. In addition, collagen type III may play an important role in the fibrillogenesis of collagen type I. Several studies have reported evidence of abnormal collagen type III metabolism in up to 50% of patients with intracranial aneurysms who do not have Ehlers-Danlos syndrome type IV.^37–43 Mutations in the COL3A1 gene, however, are rare. For example, in a study of 40 patients with intracranial aneurysms, COL3A1 mutations were found in just 2 patients, and the functional consequences of these mutations were considered insignificant.⁴⁴ The reasons for these conflicting data are unclear.

Marfan’s Syndrome

Marfan’s syndrome affects approximately 1 in 10,000 to 20,000 people and is characterized by abnormalities of the skeleton, cardiovascular system, eye, and spinal meninges.^45,46 Aortic and mitral valve insufficiency is the most frequent cause of death in children with Marfan’s syndrome, and spontaneous aortic rupture and dissection are the most frequent causes of death in adults with the syndrome.^45,46 Dissection of medium-sized arteries, however, is much less common.⁴⁷ Although Marfan’s syndrome is easily recognized in patients who display the main features of the syndrome (particularly the skeletal manifestations of tall stature, dolichostenomelia, arachnodactyly, and anterior chest deformity), the variability in phenotypic expression is great and the diagnosis is seldom straightforward.^45,46 For example, if the parents of a patient with Marfan’s syndrome are short, the affected person’s habitus may be comparatively normal.⁴⁵ Ectopia lentis, the classic ocular manifestation of Marfan’s syndrome, is observed in only about half the cases.⁴⁵ Dural ectasia, another major diagnostic criterion of the syndrome, is usually asymptomatic and requires computed tomography or magnetic resonance imaging for diagnosis.^48,49 Other manifestations of Marfan’s syndrome include spontaneous pneumothorax, striae distensae, and retinal detachment.^45,46

Intracranial aneurysms in patients with Marfan’s syndrome may be saccular or fusiform, and intracranial dissecting aneurysms have also been described.^5,50–53 Similar to Ehlers-Danlos syndrome type IV, there is a propensity for proximal intracranial carotid artery involvement, although carotid cavernous fistulas seem to be rare.⁵ Connective tissue fragility is seldom a major problem in the neurosurgical treatment of patients with Marfan’s syndrome. The frequently observed ectasia and tortuosity of the extracranial carotid and vertebral arteries, however, may render endovascular treatment of intracranial aneurysms impossible. The association of Marfan’s syndrome and intracranial aneurysms has not been firmly established. In an autopsy series of 7 patients with Marfan’s syndrome collected during a 25-year period at the Mayo Clinic, intracranial aneurysms, one ruptured and one unruptured, were observed in 2 patients.⁵¹ Combining this autopsy study with one performed at Johns Hopkins University⁵⁴ but excluding the one ruptured aneurysm, incidental aneurysms were found in 2 (6.5%) of 31 patients.⁵⁵ This frequency is higher than would be expected in the general population, particularly in view of the young age of the patients.⁵⁵ The results of screening for asymptomatic intracranial aneurysms in patients with Marfan’s syndrome have not been reported.

Mutations in the gene encoding fibrillin-1 (FBN1) cause Marfan’s syndrome.⁵⁶ Fibrillin-1 is a fairly recently detected glycoprotein that is one of the major components of microfibrils.⁵⁷ Microfibrils are important constituents of the extracellular matrix and are distributed throughout the body in elastic tissues such as the skin and aorta and in nonelastic tissues such as the ciliary zonules of the ocular lens. In elastic arteries such as the aorta, fibrillin-1 is found in all three layers of the arterial wall. It is thought that fibrillin-1 plays an important role in maintaining the structural integrity of connective tissues, in part by providing a scaffolding for the elastic fibers. Mutations in the FBN1 gene or abnormal fibrillin metabolism (“fibrillinopathy”) have also been detected in patients with isolated features of Marfan’s syndrome but without the classic syndrome.^58–61

Neurofibromatosis Type 1

Neurofibromatosis type 1 is a progressive systemic disease that affects approximately 1 in 3000 to 5000 persons.⁶² The principal clinical features of neurofibromatosis type 1 are café au lait spots, neurofibromas, and Lisch’s nodules (hamartomas) of the iris.⁶² Although these features each occur in more than 90% of adults with neurofibromatosis type 1, the number of lesions is variable. Patients with neurofibromatosis type 1 are also at increased risk for the development of optic glioma, pheochromocytoma, dural ectasia, and skeletal abnormalities such as scoliosis and sphenoid wing dysplasia.⁶² Vascular complications of neurofibromatosis type 1 have been recognized since 1945 and are characterized by stenosis, rupture, and aneurysm or fistula formation in large and medium-sized arteries.^63–65

Intracranial aneurysms in patients with neurofibromatosis type 1 may be saccular or fusiform, and some have the appearance of dissecting aneurysms.^66–73 Surgical repair of these aneurysms may be complicated by excessive vascular fragility or distortion of anatomic landmarks caused by sphenoid wing dysplasia.⁷⁰ The intracranial aneurysms associated with neurofibromatosis type 1 often coexist with intracranial arterial occlusive disease,⁷⁴ thereby increasing the risk associated with the surgical and particularly endovascular treatment of these aneurysms. An increased probability of the development of intracranial aneurysms has not been clearly established for patients with neurofibromatosis type 1, but the number of reported cases continues to increase and some have advocated screening patients with neurofibromatosis for asymptomatic intracranial aneurysms.⁶⁷ Among a group of 100 consecutive patients with intracranial aneurysms, 1 patient was revealed to have neurofibromatosis type 1.⁷⁰ Conversely, intracranial aneurysms were detected in 2 of 22 patients with neurofibromatosis type 1 who underwent magnetic resonance imaging.⁷²

Neurofibromatosis type 1 is caused by mutations in the gene (NF1) encoding neurofibromin, a protein with a centrally located domain homologous to guanosine triphosphatase–activating protein (GAP), similar to other tumor suppressor gene products.^75,76 The GAP domain of neurofibromin colocalizes with cytoplasmic microtubules, and it has been postulated that neurofibromin may have a regulatory role in the development of various connective tissues, including vascular connective tissue, through an effect on microtubular function. In a mouse model of mutations in genes for GAP and neurofibromatosis type 1, Henkemeyer and colleagues demonstrated thinning and rupture of large and medium-sized arteries during embryonic development.⁷⁷ The GAP domain of neurofibromin, however, encompasses only about 10% of the protein, and neurofibromin may have a variety of undiscovered functions.

Bicuspid Aortic Valve

A bicuspid aortic valve (BAV) is one of the most common forms of congenital heart disease in adults and is found in 1% to 2% of the population.⁷⁸ Many patients with BAV remain asymptomatic throughout life, but aortic valve insufficiency or stenosis eventually develops in most patients. Familial clustering of BAV has been described, and screening for BAV is generally recommended for first-degree relatives. Mutations in NOTCH1 have been reported in some families with BAV, but BAV is probably genetically heterogeneous. Cystic medial necrosis of the aorta is found on microscopic examination in most patients with BAV, aortic root dilation is present in at least half the patients with BAV, and aortic dissection is the cause of death in about 5% of patients with BAV. In the past, these aortic abnormalities were believed to be due to postvalvular hemodynamic changes, but it has become well established that the aortic changes are primarily related to an underlying arteriopathy, with hemodynamic factors playing a secondary role. Therefore, BAV has been included among the heritable disorders of connective tissues, along with Marfan’s syndrome and Ehlers-Danlos syndrome. The arteriopathy of BAV does not appear to be confined to the aorta, and spontaneous dissection of the cervical and intracranial arteries has been reported in patients with BAV as well. In one recent study, intracranial aneurysms were detected in 6 of 61 patients with BAV (10%) and in 3 of 291 controls (1%).⁷⁹

Epidemiology

Familial intracranial aneurysms are much more common than has generally been appreciated. Four epidemiologic studies have examined the frequency of familial intracranial aneurysms and revealed that 7% to 20% of patients with aneurysmal SAH had first- or second-degree relatives with intracranial aneurysms (Table 359-3).^81–84 However, this familial aggregation could have been fortuitous because at least 1% of adults harbor intracranial aneurysms and most of the reported families have included only two affected members. Whether relatives of patients with intracranial aneurysms have an increased risk for the development of SAH was therefore unknown.

TABLE 359-3 Frequency of Familial Intracranial Aneurysms in Patients with Aneurysmal Subarachnoid Hemorrhage