Pathology of Neurocutaneous Syndromes 

Updated: Jan 13, 2016
  • Author: Patrick S Rush, DO; Chief Editor: Adekunle M Adesina, MD, PhD  more...
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Definition

Neurocutaneous syndromes or phakomatoses from the Greek phacos = lens, spot; phaos = light, literally meaning "tumor of lenses" after the retinal hamartomas that would eventually be recognized as part of constellation of findings now recognized as tuberous sclerosis complex. Neurocutaneous syndromes represent a group of central nervous system disorders with concurrent lesions in the skin, eye, and possibly other visceral organs. [1] The neurocutaneous manifestations are related to the common ectodermal origin of these organs. They include tuberous sclerosis complex, Sturge-Weber syndrome, von Hippel-Lindau disease, and neurofibromatosis. The definition can be expanded to include other entities such as ataxia telangiectasia, incontinentia pigmenti, nevoid basal cell carcinoma syndrome (Gorlin syndrome), among others.

Tuberous sclerosis complex

Originally known as Bourneville's disease after the French neurologist, Désiré-Magloire Bourneville, tuberous sclerosis complex (TSC, which is the preferred abbreviation, to distinguish this entity from Tourette syndrome [TS]) is a genetically determined neurocutaneous syndrome—one of the most common—characterized clinically by variable neuropsychiatric manifestations that range from intractable epilepsy (including infantile spasms, which occur in as many as 20-30% of TSC infants) to mental retardation and autism and are often the defining and/or presenting feature of the illness. [2]

Clinicopathologic features of tuberous sclerosis complex have been recognized since the late 1880s. This disease involves multiple organ systems throughout the body, especially the heart, lungs, skin, and kidneys in addition to the central nervous system (CNS). Visceral manifestations of tuberous sclerosis complex include cardiac rhabdomyomas, renal angiomyolipomas, and pulmonary lymphangiomyomatosis, whereas its cutaneous signs include facial angiofibromas, subungual fibromas, Shagreen patches, and hypomelanotic macules. [2]

Because of its variable manifestations, tuberous sclerosis complex is clinically diagnosed by attention (in a given patient) to a combination of major and minor diagnostic criteria. The major criteria include the above-mentioned cutaneous lesions, as well as cortical tubers (cortical growth abnormalities), subependymal nodules (SENs), subependymal giant-cell tumors (SGCTs; formerly subependymal giant cell astrocytoma [SEGA]), cardiac rhabdomyomas, renal angiomyolipomas, multiple retinal nodular hamartomas and pulmonary lymphangiomyomatosis (LAM). (Pulmonary LAM is a disorder resulting from abnormal proliferation of smooth muscle cells within the lungs.) [3]

Minor criteria include pitting of dental enamel, gingival fibromas, hamartomatous rectal polyps, radiographic evidence of bone cysts, multiple renal cysts, "confetti" skin lesions among other features. For a clinical diagnosis of definite tuberous sclerosis complex, either 2 major features or 1 major feature and 2 minor features are required, whereas, for the diagnosis of probable tuberous sclerosis complex, only 1 major and 1 minor criteria are required. [3]

Sporadic glioneuronal hamartomas

In practice, sporadic glioneuronal hamartoma is a diagnosis rarely made in cortical resections for epilepsy—at least at the authors' center. A much more common diagnosis (the most common diagnosis in infants with intractable seizures, including infantile spasm seizures [ISS]) is that of "cortical dysplasia," a malformation of cortical development (MCD) which, in its extreme form, shows features almost identical to those of a tuber of tuberous sclerosis complex. Glioneuronal hamartomas are occasionally found at autopsy in noncortical regions, where they are not associated with the "epileptic " phenotype and are often discovered in entirely asymptomatic individuals.

Sturge-Weber Syndrome (encephalotrigeminal angiomatosis)

First described in 1879, Sturge-Weber syndrome (SWS; sometimes described as Sturge-Weber-Dimitri syndrome or by the more descriptive name encephalotrigeminal angiomatosis) is a sporadic neurocutaneous syndrome, with no known genetic cause. It is the third most common neurocutaneous disorder (after NF and TSC). [4] SWS manifests with the hallmark of a cutaneous nevus flammeus (port-wine stain) in the region of the first branch of the trigeminal nerve with an associated ipsilateral leptomeningeal (venous) angioma, which may lead to seizures and/or neurologic deficits. The ipsilateral eye is also commonly involved by some pathology, glaucoma or vascular abnormality. "Classic" Sturge-Webber syndrome manifests within the cranial vault, on the skin and in the eye as a facial angioma, leptomeningeal angioma, and glaucoma. [5, 6]

Von Hippel-Lindau Syndrome

Von Hippel-Lindau (VHL) disease is an inherited syndrome which manifests with neoplasia in a variety of organs with marked variability of expression of disease. It is inherited in an autosomal dominant fashion and has variable penetrance. This constellation of findings that occur in VHL was first described in a brother and sister in 1894. VHL is named after Eugen von Hippel, a German ophthalmologist, who described patients to have what we now know to be VHL disease; and Arvind Lindau, a Swedish neuropathologist who pieced together the systemic character and hereditary nature of the disease. [7, 8] von Hippel-Lindau disease was first used as a name to designate this disorder in 1936. The disease is characterized by multiple tumors in multiple different organs. Most commonly these are hemangioblastomas, clear cell renal cell carcinoma, pheochromocytomas, endolymphatic sac tumors, neuroendocrine neoplasms of the pancreas as well pancreatic and renal cysts.

Neurofibromatosis

Neurofibromatosis consists of two separate and different inherited autosomal dominant disorders, named neurofibromatosis 1 (NF1) (also known eponymously as von Recklinghausen disease) and neurofibromatosis 2 (NF2). These disorders are characterized broadly by the development of multiple tumors of the nervous system expressing themselves in the skin and peripheral and central nervous system. These tumors are usually benign but some may harbor malignant potential. The most common tumor present in an NF1 patients are neurofibromas, while in NF2 patients schwannomas are most common. [9]

NF1 is characterized by multiple café-au-lait spots, multiple cutaneous neurofibromas, inguinal and axillary lentigines, and Lisch nodules (melanocytic hamartomas of the iris). These findings are often readily visible on the patient in childhood, leading to early recognition of the disease presence. [10, 9]

NF2 (formerly known as central NF) has the characteristic finding of bilateral vestibular schwannomas. [11]

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Clinical Features and Imaging

Tuberous sclerosis complex

The most characteristic tuberous sclerosis complex lesions of the brain include cortical tubers, subependymal nodules (SENs), and subependymal giant cell tumors (SGCTs) (or, subependymal giant cell astrocytomas [SEGAs]). The term "tumor" rather than "astrocytoma" is preferred by some authors due to the entity’s propensity to look neuronal as well as astrocytic versus astrocytic alone. [12] The descriptor SEGA is still in widespread use and the issue of terminology has not been definitively resolved.

Neurologic manifestations, as listed above, are among the major criteria for the diagnosis of tuberous sclerosis complex and are often the presenting feature(s) of the disease. Cortical tubers, associated with infantile spasms in the very young and intractable epilepsy in older patients, are found in a large percentage of patients with tuberous sclerosis complex and have been detected (in fetal autopsies) as early as 20 weeks of gestation. [13] Tubers are clearly identifiable on high resolution neuroimaging (see the following image). Their number (obtainable on appropriate scans) has been suggested as a reliable "biomarker" for neurologic disability in affected children. [14]

MRI scan of a patient with tuberous sclerosis comp MRI scan of a patient with tuberous sclerosis complex (TSC), pretuberectomy and post-tuberectomy. Panel A shows several tubers, indicated by arrows. Panel B shows PET scan at approximately the same axial plane. Arrow indicates a region of hypometabolism in the right parieto-occipital cortex. Panel C shows post-tuberectomy MRI. (Images courtesy of Dr. Noriko Salamon, UCLA).

SEGAs/SGCTs are benign tumors with characteristic neuroimaging features, which ordinarily develop in patients younger than 20 years (see the image below). [15, 16]

MRI image of subependymal giant cell astrocytoma/s MRI image of subependymal giant cell astrocytoma/subependymal giant-cell tumor (SEGA/SGCT; arrows) occupying the right lateral ventricle. Note nonhomogeneous contrast enhancement. (Image courtesy of Dr. Noriko Salamon, UCLA).

Sturge-Weber syndrome

SWS occurs in approximately 1 in every 20,000 live births, while non-syndromic port-wine stains occur in approximately 0.3% of live births. There is an overall risk of approximately 8% of a facial port-wine stain overlaying a deeper vascular abnormality leading to SWS. [6]

Clinical manifestations of Sturge-Weber syndrome are similar to those seen in tuberous sclerosis complex—seizures, mental retardation, and focal neurologic deficits—with the obvious difference that Sturge-Weber syndrome is recognizable because of the characteristic facial port-wine stain. Seizures, especially when intractable, occurring before age 2 years may be a predictor of future neurologic problems. [17, 18] The neurologic deficit may progress to hemiparesis, almost always affecting the side of the body contralateral to the port-wine stain. Glaucoma is also a common feature of Sturge-Weber syndrome. [17]

Neuroimaging of Sturge-Weber syndrome (SWS) shows a characteristic tram-track appearance on the side of the malformation. Gliosis and microcalcifications may be seen within the cortex; soft-tissue radiographs of a fixed brain slice from an afflicted individual can yield, as a result, a dramatic tram-track appearance that recapitulates the same features noted on a lateral skull radiograph (a procedure rarely carried out in this day of highly sophisticated MRI and positron emission tomography [PET] scanning; see the images below).

Postcontrast axial T1 images. These show leptomeni Postcontrast axial T1 images. These show leptomeningeal enhancement (arrows) and enlarged left-sided choroid plexus. The venous superficial drainage is obstructed and therefore drains into the deep system, including choroid plexus, resulting in ipsilateral choroid plexus enlargement. (Images courtesy of Dr. Noriko Salamon, UCLA).
A case of bilateral Sturge-Weber syndrome (SWS; mo A case of bilateral Sturge-Weber syndrome (SWS; more severe atrophy of the left cerebral hemisphere than the right). Top 4 patients and 2 right-hand panels on the bottom represent axial cuts, while 2 left-hand panels on the bottom represent coronal cuts. FLAIR images on the top, T2-weighted images on the bottom. (Images courtesy of Dr. Noriko Salamon, UCLA).

Von Hippel-Lindau Syndrome

Hemangioblastomas are slow growing tumors that often show symptoms through mass effect, symptoms are often related to intracranial pressure, back pain, and weakness.

Neurofibromatosis

NF1 is typically a clinical diagnosis which is based upon the presence of at least two "major disease features" based on a 1988 NIH consensus conference: [19, 20]

  • Six or more café-au-lait macules (>0.5cm in children; >1.5cm in adults)
  • Two or more cutaneous or subcutaneous neurofibromas or one plexiform neurofibroma
  • Axillary or groin freckling
  • Optic pathway glioma
  • Two or more Lisch nodules (iris hamartomas seen on slit lamp examination)
  • Bony dysplasia (sphenoid wing dysplasia, bowing of long bones with or without pseudoarthritis)
  • First degree relative with NF1

Café-au-lait macules are commonly the only sign of NF1 in young children, and are present in 99% of patients by the age of 5 years old. [11] Learning disabilities and visual abnormalities are some of the more debilitating effects of the tumors of NF1

NF2 does not have outward signs of disease. Often the first sign of disease is hearing difficulties.

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Gross & Dermatologic Findings

Tuberous sclerosis complex

Grossly, the tubers of tuberous sclerosis complex are well-circumscribed (although not encapsulated), firm lesions, usually confined to the cortex and underlying white matter of one gyrus but sometimes crossing gyral boundaries (see the following image).

Specimens obtained from tuber resection from a pat Specimens obtained from tuber resection from a patient with tuberous sclerosis complex (TSC). A) External view of the specimen. B) Multiple tubers (in cut specimen) showing variable effacement of the cortex-white matter junction (eg, arrows). C) Slice from another region of the specimen shows a "tuber" (lower arrows) and a large mushroom-shaped gyrus with complete effacement of the cortex-white matter junction.

The tubers are often calcified, and this feature helps to distinguish them from regions of severe sporadic, focal, cortical dysplasia, which rarely (if ever) calcify. On cut section of a surgical or autopsy specimen, they usually take on a mushroom shape with blurring or complete loss of the grey-white matter junction. As these lesions "age," they can become cystic. [2]

Subependymal nodules (SENs; see the image below) and subependymal giant cell astrocytomas/tumors (SEGAs/SGCTs) are histologically similar lesions that are differentiated by size, with SENs being less than 1 cm and SEGAs/SGCTs being greater than 1 cm in maximal dimension. SENs are present in about 80% of patients with tuberous sclerosis complex and may develop during fetal life. [13] The small size of SENs and their lack of clinical manifestations yield very few surgical resections of such lesions; as a result, they are rarely seen by the pathologist.

Subependymal nodule (arrows) that appears to origi Subependymal nodule (arrows) that appears to originate from the septum pellucidum.

Macroscopically, SENs are small, smooth, calcified nodules that project into the ventricle; the most common locations at which they are found are in the lateral ventricles along the thalamostriate sulcus. [21]

Based upon serial neuroimaging studies, SENs are thought to give rise to SEGAs/SGCTs. SEGAs/SGCTs are comparatively rare and are present in 6-14% of patients with confirmed tuberous sclerosis complex. [15] Their most common location is the lateral ventricle at the foramen of Monro. [16] This location can lead to cerebrospinal fluid (CSF) obstruction and hydrocephalus, which in turn is the most common cause for their removal.

Sturge-Weber syndrome

In Sturge-Weber syndrome, gross sections of the affected cortical region have dark, thickened, granular leptomeninges due to the increased vasculature. The underlying cortex is atrophic.

The cutaneous findings in SWS are those of a port-wine stain. A port-wine stain is almost always present at birth, they are sharply demarcated red-to-violaceous macules or patches that are often lateralized and non-blanching, and non-regressing. These lesions should not be confused with salmon patches (colloquially "stork bite" or "angel kiss"), a common cutaneous finding after birth. These lesions are often lighter in color, symmetric, completely blanchable and resolve spontaneously.

Neurofibromatosis

Neurofibromas are solitary erythematous nodules. Subcutaneous neurofibromas may be uncomfortable or even painful. Plexiform neurofibromas classically have a "bag of worms" appearance.

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Microscopic Findings

Tuberous sclerosis complex

Histologically, in tuberous sclerosis complex, the normal hexalaminar neocortical architecture is disordered in cortical tubers, usually to a drastic degree, rendering the cortex almost unrecognizable. At higher magnification, they are composed of a mixture of relatively normal-appearing cortical neurons, dysmorphic neurons (often enlarged, with abnormal dendrites emanating from their cytoplasm), and "balloon cells," which exhibit mixed astrocytic and neuronal phenotype (see the following images). [2, 21, 22]

H&E-stained section of a tuber. Noted pronounced c H&E-stained section of a tuber. Noted pronounced cortical disorganization, with a ‘chaotic' admixture of cells with neuronal, astrocytic and indeterminate phenotype. Arrow indicates a cell with a nucleolated nucleus but pale eosinophilic cytoplasm; arrowhead indicates a balloon cell. Many of the cells appear to have cytoplasmic aggregates of basophilic material.
Cytologic features of a tuber. Panels A and B show Cytologic features of a tuber. Panels A and B show typical balloon cells at low (A) and high (B) magnification. Note glassy eosinophilic cytoplasm and characteristic coarse chromatin pattern (arrow in B). Panels C and D show dysmorphic, somewhat enlarged (eg, arrow in D) neurons in a disorganized pattern—at low magnification in C, higher magnification in D.

Balloon cells are large, usually round and oval, with eosinophilic cytoplasm, a nucleus with coarse chromatin, and prominent nucleoli. Balloon cells may be multinucleated or have multilobulated nuclei, the lobes being connected by thin "bridges."

Balloon cells characteristic of a TSC tuber. Their Balloon cells characteristic of a TSC tuber. Their presence can often be suspected at low magnification (panel A, arrows). Panel C (arrow) indicates a binucleate balloon cell. Arrows in other panels highlight balloon cells.

The dysmorphic, cytomegalic neurons within tubers may show cytoskeletal disorganization and "coarsening" on routine stains; silver stains (eg, the modified Bielschowsky technique) confirm the presence of cytoskeletal abnormalities—sometimes resembling the neurofibrillary tangles seen in Alzheimer disease (see the images below).

Dysmorphic neurons (arrows), with cytoplasm showin Dysmorphic neurons (arrows), with cytoplasm showing coarse Nissl substance (A,B) or pale amphophilic cytoplasm (C).
Silver (Bielschowsky)-stained section of a cortica Silver (Bielschowsky)-stained section of a cortical tuber, showing cytoskeletal fibrillar aggregates (eg, arrow) similar to those seen in the neurofibrillary tangles of AD. Arrowheads indicate pale-staining balloon cells.

Both subependymal nodules (SENs) and subependymal giant cell tumors (SGCTs) (or, subependymal giant cell astrocytomas [SEGAs]) are made up of dysmorphic glial cells similar to those seen within tubers, and plump cells with eosinophilic cytoplasm within a fibrillar vascular stroma (see the following image). [21] SEGAs have an additional cell type (compared with SENs) that is more elongated and spindled that sometimes forms perivascular pseudorosettes. [16, 21, 22] SEGAs can be quite pleomorphic and mitoses vary, although they may be present in 50% of cases, and they are usually few. [12] Necrosis and vascular endothelial proliferation may be present, but this does not affect prognosis. [23] Neither lesion is infiltrative.

H&E-stained section of a subependymal giant-cell t H&E-stained section of a subependymal giant-cell tumor/subependymal giant cell astrocytoma (SEGA/SGCT). The arrows highlight the plump cells with eosinophilic cytoplasm that are commonly seen.

Sturge-Weber syndrome

Microscopically, Sturge-Weber syndrome (SWS) is defined by a delicate vascular proliferation within the leptomeninges. The vessels are composed of a single layer of endothelial cells with thin connective tissue; thus, the vascular lesion can be considered a venous angioma rather than a classic arteriovenous malformation (AVM; see the image below). [24]

Angiomatosis in Sturge-Weber syndrome. Angiomatosis in Sturge-Weber syndrome.

There is associated subpial gliosis. [24] The underlying cortex and white matter, but especially the cortex, show punctate microcalcifications. [25] The affected neocortex is often atrophic, possibly due to relative anoxic-ischemic change related to the overlying leptomeningeal angioma. [5, 25] (The reader is referred to an excellent monograph on Sturge-Weber syndrome/Sturge-Weber-Dimitri syndrome (SWS/SWD) that has been published by Bodensteiner & Roach [1999].) [26] )

Von Hippel-Lindau Syndrome

Hemangioblastoma: Seventy-percent of VHL patients develop hemangioblastomas, most commonly of the CNS and retina. While not exclusive to VHL, 25% of hemangioblastomas do occur in the setting of VHL. Histologically these lesions are composed of a variably sized dense capillary network with hyperplastic endothelial cells interspersed with interstitial stromal cells with variable amounts of vacuolated cytoplasm.

Variably sized vascular network of capillaries int Variably sized vascular network of capillaries interspersed with interstitial stromal cells. [H&E, 200x (left) 400x (right)]

Neurofibromatosis (NF1)

Neurofibroma: Well circumscribed nodule of loosely arranged, non-encapsulated, short spindle cells in the dermis or subcutis. Spindle cells appear a short cells with wavy nuclei in a loose fibrillar matrix, entrapped collagen fibers occasionally give the histologic appearance of "shredded carrots."

Well-circumscribed proliferation of short spindle Well-circumscribed proliferation of short spindle cells within the dermis. [H&E, 40x]
Bland wavy spindle cells in a bland fibrillary mat Bland wavy spindle cells in a bland fibrillary matrix with inconspicuously entrapped collagen. [H&E, 200x]

Plexiform Neurofibroma: These lesions are a pathognomonic lesions of NF1. Histologically these lesions are composed of a mass of nerve fibers in a complex arrangement surrounded by extensive myxoid changes and the typically appearance of neurofibroma.

Low power appearance (20x) of the plexiform nerve Low power appearance (20x) of the plexiform nerve arrangement surrounded by myxoid stroma and conventional neurofibroma histology. [H&E, 20x]
Nerve with surrounding myxoid stroma and conventio Nerve with surrounding myxoid stroma and conventional neurofibroma histology. [H&E, 100x]

Neurofibromatosis (NF2)

Bilateral vestibular schwannomas are the classic lesion of NF2. These are histologically composed of encapsulated spindle cell tumors which are often biphasic, being composed of cellular (Antoni A) areas, and less cellular, myxoid (Antoni B) areas. Nuclei often arrange themselves in a palisaded arrangement forming organized arrangements known as Verocay bodies.

Dense, cellular (Antoni A) area demonstrating area Dense, cellular (Antoni A) area demonstrating areas of palisaded arrangements of nuclei (Verocay bodies). [H&E, 100x]
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Immunohistochemistry

Tuberous sclerosis complex

The use of immunohistochemical (IHC) stains helps to highlight some unique findings within a tuber compared with surrounding parenchyma. Glial fibrillary acidic protein (GFAP) immunohistochemistry highlights astrocytes and shows variable immunoreactivity within the previously described balloon cells (see the following image). CD68 immunostain will highlight increased numbers of microglial cells, which may be a nonspecific response to activity within "epileptogenic tissue." [27] Neurofilament immunoreactivity is variable and highlights dysmorphic neurons, whereas synaptophysin usually stains neuronal membranes.

Immunostains in cortical tubers. Synaptophysin imm Immunostains in cortical tubers. Synaptophysin immunohistochemistry (panels A, B) shows either neuronal membrane (A) or cytoplasmic (B) staining. Antibodies to neurofilament (C, D) show cytoplasmic staining that often extends into neuronal processes (C).

Neurofilament antibodies may also be valuable in highlighting neuronal architectural disarray within a tuber, although this disarray is seldom a subtle phenomenon requiring immunohistochemical confirmation. There is increased expression of cell adhesion markers, [28] which include CD44, laminins, integrins, and collagens. [26] The cells express progenitor cell markers such as nestin, vimentin, and poly sialylated neural cell adhesion molecule, but they rarely express proliferation markers, such as Ki-67. [29]

Silver stains highlight neuronal cytoskeletal abnormalities similar to those seen within neurofibrillary tangles of Alzheimer disease, although ultrastructurally, the neurons do not show the typical paired helical filaments characteristic of Alzheimer disease neurons. [30] Myelin stains (eg, Kluver-Barrera) show attenuation where the tubers extend into the subcortical white matter and can highlight the junction between a tuber and more normal brain.

Immunohistochemical studies of a subependymal giant-cell tumor (SGCT) / subependymal giant cell astrocytomas (SEGA) demonstrate GFAP expression in the elongated spindled cells but, by definition, this is variable in cells with intermediate features. [23] Neuronal differentiation is demonstrated by immunoreactivity with neurofilament protein and synaptophysin (see the image below). [21] MIB-1 (Ki-67) expression within these lesions usually shows a low labeling index, around 1%, although higher proliferative rates are seen. [31]

Immunohistochemical staining of a subependymal gia Immunohistochemical staining of a subependymal giant cell astrocytoma/subependymal giant-cell tumor (SEGA/SEGT). Panels A and B show cells with positive staining for NF and synaptophysin, proving neuronal differentiation. Panels C and D show plump glial cells positive for GFAP.
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Molecular/Genetics

Tuberous sclerosis complex

Tuberous sclerosis complex (TSC) has fascinated both neuroscientists (because of its myriad of clinical neurologic manifestations) and oncologists (because many of its clinicopathologic features result from abnormal growth of various cell types, both in the brain and extra-central nervous system [CNS] tissues).

Tuberous sclerosis complex is an autosomal dominant disorder resulting from mutations in 1 of 2 genes. Penetrance is variable, such that individuals carrying a mutation may have no manifestations until adulthood, whereas most present in infancy or childhood, sometimes even in utero (eg, TSC lesions resembling tubers and subependymal nodules have been described in a 20-week gestation fetus). [13]

The genetics of tuberous sclerosis complex were substantially advanced by the discovery, in 1993 and 1997, of 2 genes, mutations in which cause the disorder. [2] First to be discovered was the TSC2 gene (on chromosome 16p13, containing 41 exons) which encodes a protein tuberin, whereas the TSC1 gene (on chromosome 9q34, 23 exons) encodes hamartin. Both deletions and point mutations in either gene can occur to cause the disorder, and these events can take place at almost any point in each gene.

Optimally, every potential patient with tuberous sclerosis complex should be genotyped to support or confirm the clinical diagnosis—but in practice, only a few laboratories in the United States do this routinely; thus, most afflicted patients remain "genetically uncharacterized." Nevertheless greater than 200 unique allelic variations of TSC1 and almost 700 of TSC2 have been reported. [2]

Mutations in TSC2 are more common than those in TSC1, accounting for about 70-80% of cases; 15-20% of those meeting clinical diagnostic criteria for tuberous sclerosis complex (see above) do not show an identifiable TSC1/TSC2 mutation. Lesion formation in tuberous sclerosis complex appears to require inactivation of both alleles of either gene (the "2-hit" tumor suppressor gene model). A milder clinical phenotype may result when somatic mosaicism occurs in an individual with a TSC1 or TSC2 mutation. [2]

Soon after the sequences of the TSC2/TSC1 genes were published, probes were developed and labeled in order to examine gene expression within tissues and tuberous sclerosis complex–associated lesions. [32] Immuno reagents including antibodies to tuberin and hamartin were developed and could be used in immunohistochemical and immunoblotting protocols to evaluate where the proteins were expressed. [33] Both in situ hybridization and immunocytochemical studies showed that TSC2 was widely expressed throughout the body (eg, in lymphocytes, epithelia, and endocrine tissues).

Within the brain, tuberin was prominent in pyramidal neurons. [32] It was hoped that a given brain tuberous sclerosis complex lesion would show either a unique pattern of expression of either tuberin or hamartin or a characteristic lack of expression of either protein, so that a simple immunohistochemical test (on a brain biopsy) could confirm, support, or refute the diagnosis of subependymal nodules (SENs), subependymal giant-cell tumors (SGCTs) (or, subependymal giant cell astrocytoma [SEGA]), or tuber.

Because cortical tubers are almost identical to severe (sporadic) cortical dysplasia (and both lesions can result in devastating intractable seizure disorders), this would then allow the lesions of cortical tubers to be distinguished from those of severe cortical dysplasia. This hope was dashed when it became apparent, by the late 1990s, that both TSC1 and TSC2 were expressed in normal brain, cortical dysplasia, and the tubers of tuberous sclerosis complex. [34]

TSC1 and TSC2 gene products may form an intracellular complex, which can have numerous interactions with molecules critical for cell function, survival, and replication, including the biogenesis of ribosomes. Either gene product has significant interactions with molecules crucial to cell cycling and replication (the cyclin dependent kinase CDK1; cyclin A, B), the insulin signaling pathway (ISP)—including important effects on target of rapamycin (mTOR)—glycogen synthase kinase (GSK3beta), rabaptin-5, estrogen receptor alpha, calmodulin, p27, AKT, RSK1, ERK2, and Rheb, to name only a few. [2]

Molecular dissection of many of these interactions has been achieved by studying Drosophila. [2] Animal models of tuberous sclerosis complex proved elusive for many years after the genes were discovered. A sporadic rat model (the Eker rat) recapitulates some CNS features of tuberous sclerosis complex. [35] Relatively recently, a mouse model of tuberous sclerosis complex was achieved by inducing Tsc1 loss in neural progenitor cells. [36] This resulted in markedly disorganized cerebral cortex (and megalencephaly) in affected mice, with striking histologic similarities to human tubers. [37] As well, human "tuberectomy" samples have been used in conjunction with tissue microarray (TMA) methodology to examine significant differences in insulin-signaling pathway regulation between tubers and focal cortical dysplasia (FCD) lesions. [38]

Surgically resected tubers are now also amenable to detailed genetic analysis, using "deep sequencing" techniques. One such study describes the use of this technique to study all coding exons of TSC1 and TSC2, as well as activating mutation "hot spots" within KRAS (an upstream component of the MAPK pathway). [39] Germline homozygous mutations were found in over 80% of tubers, whereas the same secondary mutation in TSC2 was discovered in 6 tuber samples from one individual (autopsy material), suggesting that a "second hit" TSC2 mutation may have occurred early during brain development in that one individual, contributing to tuber formation. [39] However, no other secondary mutations were found in the other 40 tubers analyzed, suggesting that they are very rare. [39]

Sturge-Weber Syndrome (SWS)

SWS has no known familial association. It is due to an activating somatic mosaic mutation in the GNAQ gene. This gene located at 9q21, is responsible for coding a guanine nucleotide-binding protein (a member of the G protein family). [40] This mutation is present in both SWS and in isolated facial port-wine stains without the underlying syndrome. [4, 6]

Von Hippel-Lindau Syndrome

The details of the genetic basis of the disease and the lesion in its namesake gene was discovered in 1993. [41] VHL is primarily an autosomal dominant, inherited disease. It is caused by germline inactivating mutations (through hypermethylation of CpG island) of the tumor suppressor gene VHL, which is located at 3p25-26. However, approximately 20% of VHL disease patients have no confirmed family history and are thought to be due to de novo mutation. [8] The product of the VHL gene product is a constituent of a protein complex which is responsible for protein degradation and holds a vital role in cellular oxygen sensing. [7, 42, 41]

Neurofibromatosis

NF1 occurs in 1 / 3,000-4,000 people worldwide. NF 1 is inherited in an autosomal dominant fashion. However, approximately half of individuals affected are the result of de novo NF1 gene mutations. [9, 43] Heterozygous loss-of-function mutations of NF1 are the culprit for the disease, however, the specific molecular variants responsible are truly heterogeneous. In approximately 30% of cases, mutations are due to splicing mutations. [9]

NF2 is caused by a mutation in the neurofibromin 2 gene (NF2), also known as Merlin. NF2 is located on the long arm of chromosome 22 at position 12.2 (22q12.2). Merlin is a tumor suppressor gene. NF2 is caused, in 90% of cases, by the production of an abnormally shortened neurofibromin 2 (merlin) protein. More than 200 pathologic mutations of the NF2 gene. [44]

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Prognosis and Predictive Factors

Tuberous sclerosis complex

Surgical resection has become the mainstay of treatment for intractable seizures due to cortical tubers, especially in patients who have few lesions or only a single identifiable seizure focus. Controversy exists as to the optimal treatment in those patients who suffer from multiple seizure foci, although in many cases resection of one of more of the foci can still offer significant, although sometimes partial, relief from symptoms. Bollo et al have seen success with a multistage technique in which 3 surgeries are performed during the same hospitalization. [45] Good presurgical selection has greatly improved outcomes for patients in whom surgery is performed.

Variables that can positively impact the expected success of surgical intervention include consistent unilateral interictal and/or ictal activity, clearly lateralized and localized seizure focus, tuberous sclerosis complex (TSC) patients with isolated or predominant brain involvement, and epileptiform activity limited to 1 or 2 cortical tubers. [46]

In recent years, knowledge about the insulin signaling pathway in tuberous sclerosis complex has provided a possible nonsurgical therapy for subependymal giant-cell tumors (SGCTs)/subependymal giant cell astrocytomas (SEGAs). Because tumor cells from patients with tuberous sclerosis complex activate mTOR, sirolimus/rapamycin—a potent mTOR inhibitor—has been suggested as a possible therapeutic agent to treat SGCTs/SEGAs. Preliminary studies indicate that sirolimus treatment indeed leads to regression of SGCTs/SEGAs, although its value as a long-term treatment for SGCTs/SEGAs remains under debate, given its potential to activate other signaling pathways (eg, AKT) that may be tumorigenic. [37, 47]

Sturge-Weber syndrome

Treatment of Sturge-Weber syndrome (SWS) is based on controlling the multiple manifestations of the disease (ie, glaucoma and seizures). Glaucoma control is lifelong, using multiple surgeries and medical treatments to decrease ocular pressure and prevent optic nerve damage. [18] Laser therapy is used to treat the facial cutaneous vascular malformations, with best results achieved with treatment beginning soon after diagnosis. [18] Medications and surgery are used for seizure control, with the definitive surgery being hemispherectomy. [18]

Von Hippel-Lindau Syndrome

The prognosis for patients with VHL largely depends on the location and type of tumors that they have. Hemangioblastomas may not need clinical intervention depending on the site and tumor size. Some tumors may not progress while others may develop enlarging cysts or begin to cause clinical symptomology.

Neurofibromatosis

Neurofibromas and plexiform neurofibromas have the potential to undergo malignant transformation into malignant peripheral nerve sheath tumor (MPNST). Approximately 50% of MPNSTs occur in the background of neurofibromatosis. The diagnosis of MPNST carries a poor prognosis and contributes to the decreased lifespan of NF patients.

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