IUHS Student-2-Student USMLE Step 1 Recall

                                                Central Nervous System

                                                       Phacomatoses

Neurofibromatosis Type I

NF1, also known as vonRecklinghausen disease, is an autosomal dominant disorder with a frequency of 1 in 3000. Half of the cases result from spontaneous new mutations, while the rest are familial.

The gene is located at 17q11.2. Mutations arise in the NF1 gene which contains approximately 250,000 base pairs (thus, the high spontaneous number of mutations seen with this very large gene) and encodes a polypeptide with 2818 amino acids.

This protein, called neurofibromin, is found in many tissues and has significant similarity to the catalytic domain of GTPase activating proteins. The NF1 protein is therefore thought to affect signal transduction by stimulating the conversion of the Ras protein from a GTP-bound active form to a GDP-bound inactive form.

Ras function plays a key role in cellular growth and differentiation, and altered NF1 control of ras may explain the neurofibromatosis phenotype. The clinical phenotype does not correlate with the type or location of the mutation, and the clinical course is highly variable.

Persons with NF1 may develop the following lesions: neurofibromas (both solitary and plexiform), gliomas, pheochromocytomas, Lisch nodules (pigmented iris hamartomas), arterial dysplasia, and multiple cafe-au-lait spots on the skin.

The cafe au lait spots range from a few millimeters in size to several centimeters. Pigmented lesions from 1 to 3 mm can be seen in the axillae and intertriginous areas.

Development of multiple neurofibromas becomes more obvious after puberty, and thereafter neurofibromas increase in size and number, from a few millimeters to several centimeters. They are most numerous on the trunk.

Plexiform neurofibromas more commonly affect the facial region.

Lisch nodules generally appear after the age of six.

Optic nerve gliomas can be seen in 15% of cases. Neurofibromas are usually asymptomatic, but may cause pain or loss of function from nerve compression.

The neurofibromas may become neurofibrosarcomas. Though meningiomas, astrocytomas, and ependymomas are more frequently seen in association with NF2, they can occur with NF1.

Persons with NF1 also have an increased risk for carcinomas. Though not common, arterial dysplasia, typically involving carotid or renal arteries, can occur with NF1 and lead to arterial stenosis or occlusion.

variable expressivity...

Neurofibromatosis 2

NF2 is an autosomal dominant disorder with a frequency of 1 in 50,000 to 100,000. About 30 to 50% of cases represent spontaneous new mutations.

There is virtually 100% penetrance but variable expressivity. The NF2 gene, located at 22q12, produces a protein known as merlin which has a structural similarity to cytoskeletal proteins and is widely distributed in tissues throughout the body.

This protein is an ezrin-radixin-moesin-(ERM)-related protein that functions as a tumor suppressor that mediates contact inhibition of growth through signals from the extracellular matrix.

Persons with NF2 have a propensity to develop

acoustic schwannomas (typically bilateral) and multiple meningiomas.

Spinal cord ependymomas can also occur. Cataracts of the crystalline lens are seen in up to 50% of persons with NF2.

Tuberous Sclerosis

Tuberous sclerosis, also known as Bourneville disease, is an autosomal dominant condition with an estimated frequency of 1 in 9000 to 10,000.

Two genetic loci have been associated with this syndrome.

The locus TSC1 at 9q34 produces a protein called hamartin.

Hamartin regulates cell adhesion via its interaction with an ezrin-radixin-moesin-(ERM)-related protein and activation of a Rho-mediated signaling pathway.

The locus TSC2 at 16p13.3 produces a protein called tuberin.

Tuberin has a region with homology to GTPase-activating protein. Both proteins act as tumor suppressors.

The neoplasms seen with tuberous sclerosis include hamartomatous growths and low grade neoplasms in a variety of organs.

The most common of these are facial angiofibromas, cerebral cortical tubers, subependymal nodules, giant cell astrocytomas, retinal glial hamartomas and astrocytomas, cardiac rhabdomyomas, renal angiomyolipomas, and subungual fibromas.

In addition, simple cysts of liver, kidney, and pancreas may be present.

autosomal dominant disease characterized by the triad of epilepsy, mental retardation, and facial skin lesions (multiple angiofibromas)...

characterized by the triad of epilepsy, mental retardation, and facial skin lesions (multiple angiofibromas)...

Cerebral cortical tubers...

The classic ocular lesions appear in over 80% of cases. The classic lesion is the "mulberry" retinal astrocytoma, particularly when multiple.

However, plaque-like retinal hamartomas are more common.

The hamartomatous growths in the cerebrum are called tubers because of their firm cut surface similar to a potato.

They average 1 to 2 cm in size and may be seen radiographically with MRI scan, particularly in T2 weighted mode. The neurons are disorganized within the tubers and do not form distinctive layers.

The subependymal nodules contain clusters of large astrocytic cells and form drop-like masses that appear as "candle gutterings" on the ventricular surface. The classic radiographic hallmark is a calcified subependymal nodule on CT scan.

The renal angiomyolipomas are seen in 50 to 80% of cases and are typically multiple. Cardiac rhabdomyomas are seen in up to 2/3 of cases and are often multiple. The size and number of these rhabdomyomas tend to decrease with age.

Von Hippel Lindaue Disease

Von Hippel-Lindau disease is a rare condition with a frequency of 1 in 40,000...autosomal dominant...

The gene for VHL disease is located at 3p25-26 and encodes for a protein called pVHL that acts a a tumor suppressor gene that inhibits the elongation step during mRNA synthesis.

Loss of this functional gene product through mutation leads to development of neoplasms. The ratio of familial to sporadic cases of VHL disease is 12 to 15:1.

The inheritance of one abnormal gene is followed by mutation in the remaining gene, leading to development of neoplasms.

The most typical neoplasms developing with VHL disease are hemangioblastomas, pheochromocytomas, retinal angiomas, cystadenomas, and renal cell carcinomas (polygonal cells)....

The mean age of onset is 26 years.

hemangioblastomas should not be removed...

Patients with VHL disease tend to present with neurological symptoms and signs from hemangioblastomas at a younger age than patients who have sporadic hemangioblastomas.

They also tend to present with multiple lesions, have spinal cord lesions, and to develop new lesions over time.

hemangioblastomas of retina and brain (cerebellum and medulla oblongata), angiomas of kidney and liver, and renal cell carcinomas (polygonal cells) (multiple and bilateral) in 25-50% of cases...