The Diverse Clinical Manifestations of Tuberous Sclerosis Complex: A Review

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he Diverse Clinical Manifestationsf Tuberous Sclerosis Complex: A Review

ena Rosser, MD,* Ashok Panigrahy, MD,† and William McClintock, MD‡

Tuberous sclerosis complex (TSC) is an autosomal dominant multisystem neurocutaneousdisorder. TSC results in hamartomatous lesions primarily involving the skin, central ner-vous system, kidneys, eyes, heart, and lungs. The clinical findings and severity of TSC arehighly variable. Recent advances in our understanding of the complexities of the TSC1 andTSC2 genes are making genotype-phenotype correlations possible. While managing sei-zures, cognitive dysfunction, and behavioral abnormalities are the primary responsibility ofthe neurologist, familiarity with all aspects of this disease helps provide better compre-hensive care for affected individuals.Semin Pediatr Neurol 13:27-36 © 2006 Elsevier Inc. All rights reserved.

KEYWORDS tuberous sclerosis, epilepsy, infantile spasms, autism, subependymal giant cellastrocytoma, angiomyolipoma, cardiac rhabdomyoma

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uberous sclerosis complex (TSC) is a multisystem ge-netic disorder that occurs in approximately 1 in 6,000 to

0,000 individuals.1,2 TSC may cause hamartomatous lesionsf all organs but primarily affects tissues of the skin, centralervous system, kidneys, eye, heart, and lung.3,4 The currentlinical diagnostic criteria for TSC were revised by a consor-ium in 1998, and recommendations for the diagnostic eval-ation of TSC were proposed in 1999.3,4 The diagnosis ofefinite, probable or possible, TSC is based on the presencef major and/or minor features of the disease (Table 1).3

The recent discovery of the underlying genetic defects inSC has furthered our understanding of this complex geneticisorder and genotype-phenotype correlations are becomingossible. TSC occurs by a spontaneous mutation in approx-

mately 70% of affected individuals. Interestingly, mutationsn the TSC1 gene, on chromosome 9q34, and the TSC2 gene,n chromosome 16p13.3, result in a similar phenotypic pre-entation.5,6 At this time, it appears that TSC1 is more com-on in familial cases and results in less severe disease.5 Theathogenesis of TSC lies in the expression and function of the

Department of Neurology, Children’s Hospital Los Angeles, University ofSouthern California Keck School of Medicine, Los Angeles, CA.

Department of Radiology, Children’s Hospital Los Angeles, University ofSouthern California Keck School of Medicine, Los Angeles, CA.

Department of Neurology, Center for Neuroscience and Behavioral Medi-cine, Children’s National Medical Center, The George Washington Uni-versity, Washington, DC.

ddress reprint requests to Tena Rosser, MD, Children’s Hospital Los An-geles, Department of Neurology, MS# 82, 4650 Sunset Boulevard, Los

zAngeles, CA 90027. E-mail: [email protected]

071-9091/06/$-see front matter © 2006 Elsevier Inc. All rights reserved.oi:10.1016/j.spen.2006.01.008

ene products, tuberin in TSC2 and hamartin in TSC1, inissue. The interaction between these 2 proteins, the tuberin-amartin complex, has been shown to be critical to multiple

ntracellular-signaling pathways, especially those in controlf cell growth.6

entral Nervousystem Manifestations

he neurologic complications of TSC are the most commonnd often the most impairing aspect of this disease. In brainissue, mutations in the TSC1 and TSC2 genes cause abnor-al neuronal and glial differentiation and proliferation asell as abnormal cellular migration. The neocortex forms

hrough a complex, highly organized process. Glial and neu-onal precursor cells develop from pluripotent stem cells thatriginate in the subependymal/periventricular germinal ma-rix. Neuronal precursors then migrate outward to form theix layers of the cortex along radial glial fibers, most activelyuring the third to fifth month of gestation. Cerebral malfor-ations, such as those found in TSC, result from perturba-

ions during this process.7

The classic TSC central nervous system findings of corticalubers, subependymal nodules (SENs), subependymal giant-ell astrocytomas (SEGAs), and white-matter abnormalitiesre now easily identified by modern neuroimaging tech-iques. These structural brain abnormalities are likely re-ponsible for the common neurologic manifestations of sei-
ures, mental retardation, and behavioral abnormalities.3,7
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28 T. Rosser, A. Panigrahy, and W. McClintock

adiographic FindingsSC derives its name from cortical tubers, so called for theirross pathologic “potato-like” appearance.8 They occur in asany as 95% of patients.9,10 Tubers most commonly involve

urface cortical and subcortical areas but may also be seen inhe cerebellum. Their architecture expands the gyri and dis-upts the gray-white matter junction.9,10 Tubers vary in sizerom millimeters to centimeters and are frequently multiple.istologically, they are composed of disorganized pyramidaleurons and dysmorphic giant astrocytes. Areas of gliosisnd dysmyelination may also be seen. These cellular struc-ural abnormalities destroy the normal 6-layered cortical grayatter lamination pattern11 (Fig 1). Although they may be

oted by computed tomography (CT) scans, tubers are bestvaluated by magnetic resonance imaging (MRI). They areypointense on T1-weighted images and hyperintense on2-weighted images as well as on fluid attenuation inversionecovery (FLAIR) images.9 FLAIR sequences can greatly en-ance the sensitivity of MRI and may identify more tubershan spin-echo imaging12 (Fig 2). In infants and young chil-ren, a reverse pattern occurs. Tubers are hyperintense on1-weighted images and hypointense on T2-weighted im-

able 1 Diagnostic Criteria for Tuberous Sclerosis Complex3

Major featuresFacial angiofibroma or forehead plaqueNontraumatic ungual or periungual fibromaHypomelanotic macules (more than 3)Shagreen patch (connective tissue nevus)Cortical tuber*Subependymal noduleSubependymal giant cell astrocytomaMultiple retinal nodular hamartomasCardiac rhabdomyoma, single or multipleLymphangiomyomatosis†Renal angiomyolipoma†

Minor featuresMultiple, randomly distributed pits in dental enamelHamartomatous rectal polyps‡Bone cysts§Cerebral white-matter radial migration lines*§Gingival fibromasNonrenal hamartoma‡Retinal achromic patch‘Confetti’ skin lesionsMultiple renal cysts‡

Definite TSC: either 2 major feature or 1 major featureplus 2 minor feature

Probable TSC: 1 major plus 1 minor featurePossible TSC: either 1 major feature or 2 or more minor

features

When cerebral cortical dysplasia and cerebral white matter migra-tion tracts occur together, they should be counted as one ratherthan two features of tuberous sclerosis.

When both lymphangiomyomatosis and renal angiomyolipomas arepresent, other features of tuberous sclerosis should be presentbefore a definitive diagnosis is assigned.

Histologic confirmation is suggested.Radiographic confirmation is sufficient.

ges when compared with immature, premyelinated white j

atter. They are then most easily seen with T1-weightedmages.7,13 It is not unusual for tubers to enhance with gad-linium.10 Tubers may also calcify or contain degenerativeystic regions8,9 (Fig 2).

White-matter radial or migration lines can be identified in0% to 30% of individuals with TSC. These lesions representeterotopic neuronal and glial cells that have arrested alonghe path of cortical migration. They may extend from the wallf the lateral ventricle or from a SEN to the cortex or to anssociated tuber. Wedge-shaped lesions and curvilinear linesay also be noted.13,14 White-matter migration lines have a

imilar appearance to tubers. They are isointense to hypoin-ense on T1-weighted images and hyperintense on T2-eighted images.9 Only a minority of these abnormalities

nhance with contrast.10

Subependymal nodules are also seen in the majority ofSC patients. They can be identified early in infancy and

ncrease in number through the first decade of life.9,13,15 His-ologically, they are hamartomatous lesions formed from dys-lastic astrocytic and neuronal cells.8 Radiographically, SENsppear as small protrusions into the walls of the lateral ven-ricles, giving the pathologic appearance of “candle gutter-ng.” SENs are most commonly found around the area of theoramen of Monro.9,13 They tend to calcify with time and forhis reason are often more easily identified on CT imagingFig 3). On MRI, SENs are isointense to hyperintense on1-weighted images and isointense to hypointense on T2-eighted images when compared with cortical gray matter,hich is again likely a reflection of the calcium content of

hese lesions.9,13 It is also not unusual for SENs to enhanceith gadolinium.10

SEGAs are benign tumors that occur in approximately

igure 1 Coronal section of the brain shows a large right frontalortical tuber that expands the gyri and disrupts the gray-white
unction (black arrow).

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Clinical manifestations of TSC 29

0% of patients with TSC.16 They are thought to arise fromENs at the origin of the foramen of Monro, and histologi-ally these 2 lesions are indistinguishable (Fig 4). Their nat-ral history is poorly understood. They may develop rela-ively quickly in patients without evidence of SENs on priormaging but are unlikely to enlarge in patients over 21 yearsf age.16 SEGAs are currently classified as astrocytomas, buthis pathologic designation may require revision given thatEGAs consist of mixed glioneuronal cells.16,17 Recent re-earch has shown that tubers and SEGAs express similar neu-oglial markers and thus likely originate from a defect inrogenitor cell differentiation during brain development.17

EGAs are clinically significant because enlargement of theseesions may obstruct the flow of cerebrospinal fluid at theoramen of Monro, causing obstructive hydrocephalus16

Fig 4).The radiographic distinction between SENs and SEGAs is

ontroversial. Signal intensity, contrast enhancement, andize have all been used, but reports are inconsistent. How-ver, SEGAs are generally thought to enhance, whereas SENsften do not. In addition, lesions that have documentedrowth, become symptomatic, or are greater than 10 mm iniameter are also typically considered to be SEGAs.16

Less common intracranial findings in TSC may include

igure 2 Cortical and subcortical tubers on brain MRI. (Top left)xial T2-weighted image, (top right) axial FLAIR image, (bottom

eft) axial apparent diffusion coefficient map, and (bottom right)xial fractional anisotropy-diffusion tensor map. The FLAIR andiffusion tensor imaging improve the ability to delineate the extentf the subcortical hamartomatous lesions when compared with thexial T2-weighted imaging. Also note the presence of subependymalodules.

orpus callosum agenesis/dysgenesis, transmantle cortical c

ysplasia, linear and gyriform cerebellar folia calcifica-ions, cerebellar nodular white-matter calcifications, cere-ellar hemisphere/vermis agenesis/hypoplasia, cerebellaremisphere enlargement, and brainstem/fourth ventricle

igure 3 (A) Noncontrast head computed tomography scan showsalcification of multiple subependymal nodules and (B) a subcorti-
al tuber.

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ubependymal nodules and tubers. Small numbers of pa-ients have also been reported to have cerebral vascularbnormalities such as intracranial aneurysms and moya-

igure 4 (A) Postcontrast axial MRI T1-weighted image and (B) axialRI T2-weighted image show an enhancing lesion in the region of

he Foramen of Monro, which was pathologically proven to be aubependymal giant-cell astrocytoma.

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eurologic Complicationseizures are the presenting symptom in 92% of individualsith TSC, making epilepsy a significant cause of morbidity

ssociated with this disease. Seizure onset usually occurs dur-ng infancy or early childhood but may happen at any age.lthough classic absence seizures have not been reported inatients with TSC, all other seizure types, including clonic,onic, tonic-clonic, myoclonic, atonic, atypical absence, andomplex partial, have been seen. Partial motor and complexartial with or without generalization are most common,

ikely because of focal cerebral pathology.18 As discussed ear-ier, tubers consist of dysplastic neurons and glial cells thatistort the normal cortical architecture, causing them to beighly epileptogenic.7 The relationship between the numberf tubers and the severity of epilepsy has been investigated. Aeta-analysis of 5 independent studies showed that individ-als with poor seizure control and moderate to severe mentaletardation are 6 times more likely to have a tuber count overhe median count for a population of TSC patients. The au-hors conclude that cortical tuber count is a biomarker thatay be used to predict the severity of cerebral dysfunction inSC.19

Infantile spasms develop in approximately one third ofSC patients and may be the initial symptom in almost 70%f affected infants that come to medical attention.20 TSC maylso account for as many as 25% of cases of symptomaticnfantile spasms.20 Infantile spasms in TSC usually have theirnset between 4 to 5 months of age. They may appear asexor-, extensor-, or mixed-type spasms, but focal featuresuch as head turning, nystagmus, tonic eye deviation, ornilateral limb movement differentiate them from classic in-antile spasms. The majority of patients with TSC and infan-ile spasms unfortunately go on to develop other seizureypes.20,21

With the exception of the treatment of infantile spasms,he approach to medical management of epilepsy in TSC doesot differ from that of epilepsy from other causes and in-olves the use of traditional anticonvulsants. Although theres a range of clinical severity, intractable epilepsy in TSCequiring polypharmacy is frequently seen in this patientopulation. Recent research has shown the expression ofultidrug resistance and multidrug resistance-associatedrotein-1 in resected cortical tubers, suggesting that theseellular mechanisms may contribute to the development ofefractory epilepsy in TSC patients.22

For reasons that are poorly understood, vigabatrin appearso be more effective than adrenocorticotropic hormoneACTH) in managing infantile spasms in children with TSC.igabatrin produces its antiepileptic effect by irreversibly in-ibiting the enzyme gamma-aminobutyric acid-aminotrans-erase. This results in increased brain and spinal fluid con-entrations of the inhibitory neurotransmitter gamma-minobutyric acid.23 Practice parameters for the treatment ofnfantile spasms have recently been published.24 On reviewf the available literature, cessation of infantile spasms maye seen in 91% to 96% of TSC patients treated with vigaba-rin, which is considerably higher than in patients with idio-
athic or other symptomatic forms of infantile spasms.23-26

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here is no consensus on vigabatrin dosing, but 100 to 200g/kg/d has been used.23

The treatment of TSC patients with vigabatrin may beomplicated by the fact that its use in the United States hasot been approved by the Food and Drug Administrationecause of the incidence of retinal toxicity. Vigabatrin haseen shown to cause progressive, irreversible concentric vi-ual field defects in 40% to 50% of adults, and vision lossssociated with vigabatrin has also been reported in chil-ren.23 There is insufficient evidence at this time to makeecommendations regarding the type or frequency of visioncreening for children taking vigabatrin, but regular electro-etinograms have been used for this purpose.24

When anticonvulsant therapy options have been ex-austed, alternative treatments such as the ketogenic diet,agus nerve stimulator implantation, and focal surgical tuberesection may be tried. There are no specific published stud-es evaluating the use of the ketogenic diet in patients withSC, but it has been shown to be efficacious in refractorypilepsy from multiple causes.27 An open-label, retrospectiveulticenter study investigated the use of vagus nerve stimu-

ation (VNS) in children with TSC and intractable seizures.ine of the 10 patients experienced at least a 50% reduction

n seizure frequency, and 5 children experienced 90% orreater reduction in seizure frequency. When compared withn age-matched control population, there was a trend towardmproved seizure control with the VNS, but statistical signif-cance was not achieved. Thus, VNS may be an effectivedjunctive therapy in medically intractable cases when resec-ive surgery is not an option.28

Surgical resection of focally epileptogenic tubers can behallenging but may be beneficial in improving seizure con-rol as well as quality of life in select patients.29,30 It is fre-uently difficult to identify ictal onset and to localize a singleausative lesion in TSC patients because multiple corticalubers are usually present.29-31 Identification of appropriateandidates for epilepsy surgery begins with video electro-nchephalogram monitoring in an attempt to find an epilep-ogenic focus that is concordant with a tuber seen on MRI. Ifhis is not possible, invasive monitoring with subdural elec-rodes may be required.31 In the future, novel imaging mo-alities such as single-voxel proton spectroscopy, single-hoton emission computed tomography, positron emissionomography, and diffusion-weighted MRI may improve ourbility to identify epileptogenic tubers.32-36 The best outcomes obtained in individuals with a single epileptogenic lesion inhe noneloquent cortex.29,30 However, when bilateral or mul-ilobar foci are present, a more aggressive, multistaged eval-ation and surgical approach may hold promise for patientsraditionally believed to be inoperable.37

Cognitive dysfunction has long been recognized as a com-on neurologic complication of TSC. It was previously as-

umed that mental retardation was inevitable, but more re-ent studies have shown that many affected individuals mayave normal intelligence. Early population-based studiesound cognitive abnormalities in 50% to 65% of patients, buthe results in these studies were not based on standardized
sychometric evaluations.38 T
Addressing the shortcomings of prior reports, Joinson andoworkers38 performed standardized testing in 108 individ-als with TSC and their unaffected siblings. Over half ofatients (55.5%) had an IQ in the normal range. Forty-fourercent had an IQ less than 70, whereas 30.5% were pro-oundly disabled with an IQ less than 21. Thus, this studyupports earlier findings that TSC is associated with a bi-odal IQ distribution, with the majority of affected patients

alling into either a normal or profoundly affected range.ndividuals with TSC and an IQ in the normal range also hadmean IQ 12 points lower than their unaffected siblings,

uggesting that TSC still may adversely affect one’s intellec-ual potential.38 Other authors have also found a variety ofognitive impairments on detailed neuropsychological eval-ation in normally intelligent adults and children withSC.39

It is hypothesized that several interrelated factors likelyccount for the cognitive dysfunction seen in TSC. First,euroimaging with MRI has allowed investigators to evaluatehe relationship between cortical tubers and cognition. Theajority of studies show that a high tuber count correlatesith a more severe degree of mental impairment.19,38,40 Epi-

epsy is also highly associated with cognitive abnormalities inSC. Intractable epilepsy is seen most commonly in patientsith multiple cortical tubers, and these patients are also typ-

cally the most profoundly mentally retarded.19,38,40 A historyf infantile spasms may put individuals particularly atisk.19,21,38,40 Moderate to severe mental retardation has beeneported in as many as 85% to 100% of patients with a historyf infantile spasms. However, a recent retrospective studyeported a much lower incidence of mental retardation64%) in this patient population and found that the risk ofental retardation increased with prolonged duration of in-

antile spasms, delayed treatment of infantile spasms, andoor seizure control after resolution of infantile spasms.41

Finally, with the discovery of the TSC1 and TSC2 genes hasade genotype-phenotype correlations possible. For reasons

hat are not yet understood, TSC2 seems to result in a moreevere phenotype. Specifically, patients with TSC2 mutationsave recently been found to have a higher number of tubers,ore frequent seizures, and a higher incidence of moderate-

o-severe mental retardation.5,42 In 1 study, a low IQ wasndependently associated with TSC2 mutations as well asith infantile spasms.5

Autistic spectrum disorders are also highly prevalentmong individuals with TSC. These developmental disordershare a variety of symptoms including impairment of social-zation, impairment of communication, restricted interestsnd repetitive behaviors.43 Estimates vary widely because dif-erent methods and populations have been used to ascertainhe prevalence of autistic spectrum disorders in TSC but itppears that 17 to 61% of individuals with TSC may beffected. This represents a significant increase when com-ared with the general population.44 Among autistic popula-ions, TSC occurs in 1 to 4% of patients.45 It remains unclearhether autism in TSC is the direct result of a mutation in the
SC gene or whether it is a secondary effect from other fac-

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ors such as the associated structural brain abnormalities orpileptic encephalopathy.45

Mental retardation and epilepsy are comorbid risk factorshat may contribute to the development of autistic spectrumisorders in TSC. A history of infantile spasms may pose anven higher risk but is neither necessary nor sufficient tondependently cause autistic spectrum disorders.44,45 Manytudies have also evaluated the association between autismnd tuber location. The presence of tubers in the temporalobes is most frequently reported to be associated with au-ism.46-48 One recent study found that a more complex rela-ionship may exist. Temporal lobe tubers, temporal lobe ep-leptiform discharges, and a history of infantile spasms placedndividuals at highest risk for the development of autisticpectrum disorders.46 However, other studies have shownhat frontal, posterior, parietotemporal, and cerebellar tubersay be related to autistic symptoms.49,50 In summary, autism

n TSC, like cognitive dysfunction, likely arises from multiplenterrelated factors.

utaneous Manifestationshe cutaneous manifestations in TSC are common and are

ypically the first clue to the diagnosis. They include hy-omelanotic macules, facial angiofibroma, forehead plaques,hagreen patches, and ungual fibromas.3

Hypomelanotic macules or ash leaf spots occur in 61% to7.2% of individuals with TSC.51,52 They are often present atirth, and they may become more numerous with time. Aood lamp or ultraviolet light may be required to see them

n lighter-skinned individuals. They typically occur on therunk and buttocks. They are less common on the face.51,52

heir name derives from their typical shape with a roundednd a tapered end, resembling the leaves of a European ashree52 (Fig 5). Hypomelanotic macules are not specific forSC, however, because 1 or 2 may occur in healthy individ-als.53 Poliosis, hypomelanosis of patches of hair, may occur.kin hypopigmentation is also frequently noted in the “con-etti lesions ” seen on the anterior surface of the arms of manySC patients.51,52

Facial angiofibromas (adenoma sebaceum) are pathogno-onic for TSC and are seen in over 70% of patients. They first

ppear during the preschool years and with time develop intoiscrete, papular, pink, or erythematous lesions in a symmet-ical malar distribution on the face. They may also involve thehin.51,52 Forehead plaques are similar lesions that appear asarger, flesh-colored or erythematous, raised, areas on theorehead or scalp. They occur at later ages and are somewhatess common, seen in only 18.9% of patients.52 Pathologi-ally, angiofibromas are caused by the hamartomatous devel-pment of dermal connective tissue, and vascular elements.ermal fibrosis and vasodilitation are seen, but sebaceouslands are absent or atrophic in these lesions. Foreheadlaques have a similar fibrotic appearance but lack the vas-ular elements of angiofibromas.54

The incidence of shagreen patches varies depending on thege of the patient population studied but occur in approxi-
ately 50% of patients. They may be noted in early child- h
ood. These lesions are typically found in the lumbosacralrea and other dorsal surfaces but may also occur anteriorlyn the trunk. They are irregular, elevated areas of varying sizeith an orange peel texture and rubbery consistency. Histo-

ogically, shagreen patches are hamartomas of the connectiveissue.51,52

Ungual fibromas grow as flesh-colored or pink nodules inhe finger or toenail beds in patients with TSC. A linear linerising from the nail bed may be a clue to an underlyingubungual fibroma. Although they may be seen earlier, theyypically appear during adolescence. Ungual fibromas occurn the majority of adult TSC patients.52 More than 1 ungualbroma is required to meet the major criteria for TSC becausehey can be seen as an isolated posttraumatic lesion.3

enal Manifestationshe renal manifestations of TSC are found in a majority ofatients. They include angiomyolipomas (AMLs), simpleysts, polycystic kidney disease, and renal-cell carcino-a.4,55,56 These lesions likely arise in infancy or early child-ood, increasing in size and number with age.55,57 After neu-ologic complications, renal involvement is the second mostommon cause of morbidity and mortality in TSC.56

AMLs are found in as many as 80% of patients with TSCut are typically asymptomatic.56,57 They are formed fromariable amounts of smooth-muscle cells, fat, and abnormalascular components. AMLs are most often multiple and bi-ateral.56-58 They may cause clinical symptoms in 2 ways.irst, their growth may encroach on normal renal tissue re-ulting in renal failure and/or hypertension, although this isore common with renal cysts. Second, as AMLs enlarge,

hey can form micro- and macroaneurysms that are at risk for

igure 5 Hypomelanotic macule.

emorrhage.56,58 Lesions greater than 4 cm in diameter are

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ore likely to become symptomatic and may warrant closeonitoring.4 Clinical trials are now underway using the drug

apamycin to slow growth or promote regression of AMLs.apamycin is an immunosuppressant that inhibits cellrowth through modulation of the mammalian target of rapa-ycin and may prove to be a promising new therapy in the

reatment of these lesions.59,60

Renal cysts are also very common in TSC, occurring in7% of children and as many as 47% of adults. Like AMLs,hey are frequently multiple and bilateral. However, renalysts are more likely to become symptomatic than AMLs.55,57

olycystic kidney disease may also occur. It is a more severe,istinct entity with innumerable cysts that enlarge, replaceenal parenchyma, and cause renal insufficiency and hyper-ension typically at an early age (Fig 6). Polycystic kidneyisease in TSC results from a contiguous gene syndromeecause the adult polycystic kidney disease (APKD) gene liesdjacent to the TSC2 gene on chromosome 16p13.3.61

An association between TSC and renal carcinoma has beenecognized but is mostly anecdotal. A meta-analysis of caseeports in the literature did not find an increased risk of renalell carcinoma in this patient population.62

ardiac Manifestationsardiac rhabdomyomas are the most common intracardiac

umor of infancy and childhood and are highly associatedith TSC. They are found in 30% to 50% of affected individ-als.63 Rhabdomyomas are an early manifestation of the dis-ase, appearing at 22 to 28 weeks of gestation. Thus, it isossible to make the diagnosis of TSC in utero using fetalltrasound.64

Histologically, these benign, hamartomatous lesions areomposed of large, irregular cardiac myocytes with centrallylaced glycogen-filled cytoplasm and nuclei. The radiatingtrands of cytoplasm that stretch from the central nucleus tohe cell membrane give the cells a “chickenwire” appear-nce.63,65,66

Cardiac rhabdomyomas have a predilection for the ventri-les but may also occur in the atria. In TSC, they are usuallyultiple.63,64 These lesions are asymptomatic in the majority

f patients, but larger intracavitary rhabdomyomas mayresent with obstruction of outflow or inflow tracts and sub-equent congestive heart failure. Intramural rhabdomyomasay interfere with conduction pathways, causing a variety ofysrhythmias including supraventricular tachycardia, persis-ent sinus bradycardia, Wolff-Parkinson-White syndrome,nd premature atrial or ventricular beats.63,64,67 Intramuralesions can also mimic a cardiomyopathy, replacing the heartall with noncontractile muscle tissue. In certain cases, ex-

ensive obstructive or infiltrative lesions can result in nonim-une fetal hydrops.66

Cardiac rhabdomyomas have a unique ability to regressnd completely resolve during the first years of life. Theechanism behind the natural history of these lesions isoorly understood. Given their tendency to regress, rhab-omyomas should be conservatively managed with symp-
omatic treatment. Surgical excision is reserved for life- U
hreatening situations, typically intracavitary lesions causingevere obstruction and hemodynamic instability.67

ulmonary Manifestationsymphangiomyomatosis (LAM) is a rare disorder of un-nown etiology caused by proliferation of atypical smooth-uscle cells in the peribronchial, perivascular, and perilym-hatic tissues of the lung.68 LAM occurs almost exclusively inoung women, typically presenting between 30 to 35 years ofge.69,70 Rare cases of LAM have been reported in men, buthe occurrence of LAM in men is controversial.71,72 LAM mayccur sporadically but is also closely associated with TSC.

igure 6 (A) Transaxial contrast-enhanced computed tomographymage of the kidneys and (B) coronal spin-echo T1-weighted MRImage show multiple cystic lesions throughout 2 enlarged kidneysonsistent with polycystic kidney disease.

ntil recently, LAM was believed to be a relatively uncom-

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on manifestation of TSC, occurring in 1% to 2.3% ofomen with the disease.70,73 A more recent study reports that

t may affect up to 26% of female patients.73

Clinically, LAM is a progressive disorder of the lung, caus-ng dyspnea, spontaneous pneurothorax, hemoptysis, cough,hylothorax cor pulmonale, and chest pain.70 Symptomsave been reported to begin or worsen during pregnancy,uggesting that LAM may be hormonally influenced.70,73 Thisonnection has been debated because 1 large national case-ontrolled study failed to find an association between pulmo-ary symptoms and the use of oral contraceptive pills.74

Histopathologically, LAM causes diffuse cystic destructionf the tissues of the lung by abnormal spindle-shaped, closelyacked smooth-muscle cells. Multifocal, micronodularneumocyte hyperplasia and clear-cell lung tumors have alsoeen found in patients with TSC.69,75 LAM is associated withermline mutations in both the TSC1 and TSC2 genes.76 Re-al AMLs are present in most patients with TSC and in 50%f individuals with sporadic LAM. Current research has led tohe theory that pulmonary LAM and renal AML cells have aommon genetic basis and cellular origin. It has been hypoth-sized that LAM is the result of metastatic spread of benignML smooth-muscle cells.77

LAM eventually leads to progressive respiratory failure andeath. Treatment options for women with LAM are limited.he discovery of estrogen and progesterone receptors onAM cells has led to the use of antiestrogen therapies such asophorectomy, progesterone, luteinizing hormone–releasingormone agonists and tamoxifen. However, response to in-ervention with hormone manipulation has been variable.ung transplantation has been used in patients with end-tage lung disease.69 Early studies reported that the medianurvival time from the onset of symptoms to death was ap-roximately 5 years, but more recently, 10-year survival fromhe onset of symptoms has been documented to be as high as1%.72,78

phthalmologic ManifestationsSC is associated with both nonretinal and retinal findings.onretinal abnormalities such as eyelid angiofibromas, stra-ismus, cataracts, colobomas, and iris depigmentation haveeen reported.79,80 A dilated fundascopic examination by anxperienced ophthalmologist may be required to fully iden-ify retinal lesions.

Hamartomas are the most common retinal manifestationf TSC and are identified in approximately 40 to 50% ofndividuals. They may be bilateral in 34% to 50% of cases.hree morphologic types of retinal hamartomas are tradition-lly described: (1) relatively flat, smooth, noncalcified trans-ucent, gray lesions; (2) elevated, calcified mulberry-like le-ions; (3) transitional lesions with features of lesionsescribed in 1 and 2. The noncalcified hamartomas are theost common and are usually found in the posterior retinalole. Calcified, nodular, mulberry lesions are typically foundt or near the disc margin (Fig 7). Pigmentary retinal abnor-
alities are also frequently identified. Punched-out areas of
etinal depigmentation, plaque-like lesions in the deep ret-na, and pigment clumping may be seen.79,80

The natural history of retinal abnormalities associated withSC has not yet been adequately characterized, but they areenerally believed to be static lesions. Fortunately, they rarelyause vision loss. However, cases involving decreased visionr blindness associated with hamartoma enlargement, mac-lar involvement, retinal detachment, and vitreous hemor-hage have been reported.80

onclusionhe systemic manifestations of TSC are numerous. Whileanaging seizures, cognitive dysfunction and behavioral ab-ormalities are the primary responsibility of the neurologist,amiliarity with all aspects of this disease helps provide betteromprehensive care for affected individuals.

Guidelines for the evaluation of newly diagnosed patients,stablished patients, and family members of TSC patientsave been published.4 At presentation, all children with sus-ected TSC should be thoroughly screened for seizures, de-elopmental delay, and autistic spectrum disorders. Formaleurodevelopmental testing should be requested. An oph-halmologic examination, brain imaging (brain computed to-ography scan or MRI), electrocardiogram, and renal ultra-

ound should also be performed. Subsequent evaluationsepend on the patient’s age and extent of organ involve-ent.4 Gene mutational analysis is now commercially avail-

ble and may be helpful in the diagnosis of atypical cases asell as for genetic counseling. Treatment of the complica-

ions of TSC is primarily symptomatic at this time. In theuture, improved understanding of the genetic underpin-ings and molecular pathogenesis of TSC may lead to morepecific, biologically based therapies for this complex disor-er.

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igure 7 Elevated, multinodular, calcified retinal hamartoma adja-ent to the optic disc.

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Documents

The Diverse Clinical Manifestations of Tuberous Sclerosis Complex: A Review