CNS Syndromes Associated with Vascular Malformations

Syndromes that involve the brain: Head

Sturge-Weber syndrome (encephalotrigeminal or encephalofacial angiomatosis): Extensive capillary-venous malformation results in unilateral cerebral cortical atrophy associated with angioma on the face which frequently include distribution of the ophthalmic branch of the trigerminal nerve. Angiomas in other tissue including the meninges, mucous membrane, and choroid can also occur. Heriditary mechanism unknown.

Von Hippel-Lindau disease: This is a combination of of retinal angiomatosis and angioma that is histologically identical to hemangioblastoma, multiple hemangioblastomas (most frequently in the cerebellum), pheochromocytoma, pancreatic cysts and islet cell tumor, renal cysts and bilateral, often multiple renal cell carcinoma of the kidney, and in males, bilateral papillary cystadenoma of the epidydimis, hepatic cyst, and endolymphatic sac tumor in the petrous bone [Kempermann G and Neumann HP, 1998 ; Kempermann G et al., 1996].

Multiple lesions: Hemangioblastomas are usually solitary. About 20% of patients with hemangioblastomas and von Hippel-Lindau disease may have multiple lesions.

Genetics: autosomal dominant. The VHL gene is located on chromosome 3p25.3. It is a tumor suppressor gene. Deletion or unbalanced translocation (3;6, 3;8, 3;11) are seen in over 98% of all clear cell carcinoma of the kidney, regardness of whether it is a familial or sparadic case. Somatic inactivation by mutation or hypermethylation of VHL gene may also be seen. Families with a germline deletion have a low risk for pheochromocytoma and that families with a full or partial deletion of the VHL gene exhibit a phenotype with a preponderance of central nervous system hemangioblastoma [Hes F et al., 2000 ]

Terminology:

Lindau's tumor (Hemangioblastoma) is single or multiple brain tumors.
Lindau's syndrome comprises the hemangioblastic brain tumor plus cysts in both pancreas and kidney.
Lindau's disease is isolated cerebellar hemangioblastomas, which must be hereditary.
Von Hippel's disease is heriditary angiomatosis of the retina.

Familial multiple cavernous angiomas (Familial cerebro-hepato-renal cavernous angiomas): A few families with heredofamilial angiomatosis of the brain and retina associated with multiple visceral tenangiectasias and small cavernous nodules in the skin of the face and neck, multiple cavernous hemangiomas in the liver. A possible genetic locus related to this syndrome may be present on chromosome 7q11.2-q21.

Familial retinal cavernous angiomatosis: Cavernous hemangiomas of the retina associated with cerebral and cutaneous lesions of similar vascular origin. This entity is different from Wyburn-Mason syndrome and von Hippel-Lindau syndrome.

Fowler's syndrome (proliferative vasculopathy and hydranencephaly- hydrocephaly): probably autosomal recessive. This condition is lethal in newborn period. Hydranencephaly as early as 13 weeks (demonstrated by ultrasonography). Abortus show massive cystic dilatation of the ventricles and pathognomonic glomeruloid vascular proliferation, composed of inclusion-bearing endothelial cells. The cerebral hemisphere is reduced to a thin mantle (1-2 mm) with marked deficiency of young neurons. The germinal eminence over the caudate is a vestige. Massive calcification, especially near the ventricular surface of the basal ganglia, is also present. The abortus may also show arthrogryposis, pterygia, and muscular dystrophy. Migration disorder may be part of the pathogenetic mechanism.

Osler-Weber-Rendau syndrome (Hereditary hemorrhagic telangiectasia): Autosomal dominant with high penetrance. Multiple dermal, mucosal, and visceral telangiectasis and arteriovenous malformations associated with recurrent bleeding. Neurologic involvement is relatively rare but telangiectases and other vascular malformation have been documented in the CNS.

Wyburn-Mason syndrome (mesencephalo-oculofacial angiomatosis or neuroretinal angiomatosis): Heriditary mechanism unknown. Association of an arteriovenous malformation of the mid-brain with a homolateral cutaneous vascular nevus in the trigeminal distribution and retinal angiomatosis.

Ataxia-telangiectasia: Ataxia-telangiectasia is an autosomal recessive disease involving mutation of ATM gene on chromosome 11q23.1. Genetically it is characterized by genetic instability with a characteristic translocation t(14;14)(q12;q32). Clinically, there are multiple facial and ocular telangiectases, progressive functional disturbance in cerebellum and brain stem nuclei, characteristic ocular findings, and increased tendency to develop hematopoietic malignancies. Diagnosis is based on clinical features and response of cultured cells to radiation. Genetic diagnosis is not practical. Pathologically, it has atrophy of the cerebellum with loss of Purkinje cells and granular cells, degeneration of dorsal column, loss of ganglion cells and dysmorphic changes in ganglion cells.

Meningocerebral angiodysplasia and renal agenesis.

Syndromes that involve the spinal cord: Head

Cobb's syndrome: spinal cord vascular malformation associated with a cutaneous vascular anomaly in the overlying dermatome.

Foix-Alajounine syndrome (Angiodysgenetic necrotizing myelomalacia): clusters of enlarged, engorged tortuous subarachnoid veins, most prominent over the posterior aspects of the cord; patchy necrosis of the spinal-cord tissue, involving the lower thoracic and lumbosacral segments in most instances; and the presence, within the affected segments of the cord, of enlarged, apparently proliferated small blood vessels with thickened collagenous walls and lack of features defining them clearly as either arteries or veins.

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