Tuberous Sclerosis Lancet 2008

8/14/2019 Tuberous Sclerosis Lancet 2008

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www.thelancet.com Vol 372 August 23, 2008 657

Tuberous sclerosis

Paolo Curatolo, Roberta Bombardieri, Sergiusz Jozwiak

Tuberous sclerosis is a genetic multisystem disorder characterised by widespread hamartomas in several organs,including the brain, heart, skin, eyes, kidney, lung, and liver. The affected genes are TSC1 and TSC2, encodinghamartin and tuberin respectively. The hamartintuberin complex inhibits the mammalian-target-of-rapamycinpathway, which controls cell growth and proliferation. Variations in the distribution, number, size, and location oflesions cause the clinical syndrome to vary, even between relatives. Most features of tuberous sclerosis become evidentonly in childhood after 3 years of age, limiting their usefulness for early diagnosis. Identification of patients at risk forsevere manifestations is crucial. Increasing understanding of the molecular abnormalities caused by tuberoussclerosis may enable improved management of this disease.

IntroductionTuberous sclerosis is a genetic, variably expressed,

multisystem disorder that can cause circumscribed,benign, non-invasive lesions in any organ.1,2 The termtuberous sclerosis of the cerebral convolutions was usedmore than a century ago to describe the distinctivefindings at autopsy in some patients with seizures andmental subnormality. The term tuberous describes thepotato-like consistency of gyri with hypertrophicsclerosis.3 The wide range of organs affected by thedisease4 implies an important role for TSC1 and TSC2genes, encoding hamartin and tuberin,in the regulationof cell proliferation and differentiation.

In a series of patients reported by the Mayo Clinic(Rochester, MN, USA), more than 90% had skin lesions,

about 90% had symptoms of cerebral pathology,7090% had renal abnormalities, and about 50% hadretinal hamartomas5 (figure 1). Tuberous sclerosis is aprotean disease: the random distribution, number, size,and location of lesions cause varied clinical mani-festations. Some lesions, such as renal angiomyolipomas,do not occur until a certain age; by contrast, cardiacrhabdomyomas appear in the fetus, and almost alwaysregress spontaneously in infancy.6 The frequency ofmost clinical signs in the prenatal period is unknown.Few data are available for the rate of clinical signs thatneed imaging examinations (ie, subependymal nodules,retinal hamartomas) in young children.

DiagnosisMajor and minor criteria exist to diagnose tuberoussclerosis (panel). The diagnosis is made when two majorfeatures, or one major and two minor ones, can beshown. Sometimes, an antenatal diagnosis can be madebased on fetal ultrasound and MRI, which show cardiacand brain lesions. Most patients are diagnosed in infancyor early childhood, making early therapeutic interventionsand treatments possible.7

EpidemiologyPopulation-based studies in UK reported a frequencyof 1 in 12 000 to 1 in 14 000 in children under 10 years ofage.8However, improved methods of ascertainment haveidentified individuals who are not severely affected by

tuberous sclerosis, increasing the estimates of itsfrequency.9The disorder has a birth rate of 1 in 6000.10

PathophysiologyTuberous sclerosis is an autosomal dominant disorder,although two-thirds of patients have sporadic mutations.The genes in which abnormalities are found are calledTSC1 and TSC2. Both genes have been studied bymultigenerational linkage analysis.11,12 TSC1 is located atposition 9q34, and encodes a transcript of 86 kb,containing 23 exons and encompassing 55 kb of DNA. 13

TSC2 is located at position 16p13.3, and encodes atranscript of 55 kb, containing 41 exons and encom-passing 40 kb of DNA.14Table 1 shows features of thesegenes. 307 allelic variants of TSC1and 1061 of TSC2have

been reported so far.Recent studies, carried out on small families, indicatedthat mutations of TSC1 account for 1530% of thefamilies.15,16 In preponderance of mutations of TSC2 iseven higher in sporadic cases, where mutations of TSC1are found in1020% of families.15,1720More severe diseasein cases with new mutations of TSC2 would reduce thechance of these people having a family.21

Mutational studies have shown no hotspots (ie,preferred sites of mutation) in these genes. Largedeletions or rearrangements are present in TSC2 morefrequently than in TSC1.22 In 23% of patients, largegenomic deletions in TSC2also affect the adjacent gene,polycystic kidney disease type 1 (PKD1).23 Missense

Lancet2008; 372: 65768

Department of Neurosciences,

Paediatric Neurology Unit,

Tor Vergata University, Rome,

Italy(Prof P Curatolo MD,

R Bombardieri MD);and

Department of Neurology and

Epileptology, Childrens

Memorial Health Institute,

Warsaw, Poland(S Jozwiak MD)

Correspondence to:

Prof Paolo Curatolo, Paediatric

Neurology Unit, Tor Vergata

University of Rome,via Montpellier 1, 00133 Rome,

Italy

[email protected]

For allelic variantssee http://

chromium.liacs.nl/LOVD2/TSC/

home.php

Search strategy and selection criteria

Information in this Seminar is mainly based on peer-

reviewed medical publications from 1985 to 2007

(PubMed). Selection criteria are the novelty and importance

of studies, and their relevance to general medical doctors

and paediatricians. Search terms included tuberous

sclerosis, clinical features, molecular genetics, medical

and surgical treatment, and sirolimus. Only articles

published in English were reviewed. All articles were read by

the authors, and references were reviewed to identify any

additional relevant studies. Further references were included

according to referee suggestions.


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658 www.thelancet.com Vol 372 August 23, 2008

mutations are more common in TSC2than in TSC1, and

tend to cluster in the GTPase-activating protein (GAP)binding domains.24

The overall mutation detection rate in patients withtuberous sclerosis is around 8590%, even when newimplemented diagnostic techniques are used (eg,multiplex ligation-dependent probe amplification).22

Therefore, mutations are not identified in 1015% ofpatients.20 The low detection rate could be due to:(1) methods (eg, denaturing high-pressure liquid chroma-tography and direct sequencing) that are not sensitiveenough; (2) mutations in intronic and promoter regions,which might disrupt gene expression, and be missed bymost mutation screening methods: (3) diffi culty ofdetecting mutations by any conventional method in

patients with diagnostic features of tuberous sclerosisand low rate of mosaicism for either TSC1 or TSC2mutations;25 and (4) additional causative loci that couldaccount for a few patients with tuberous sclerosis.

After the discovery of TSC1 andTSC2and their encodedproteins (hamartin and tuberin), several downstreamprotein cascades that might be affected by thepathogenesis of the disease, such as the pathway ofmammalian target of rapamycin (mTOR), have beenidentified.2628 mTOR is stimulated by Ras homologueenriched in brain (RHEB), a small G protein of the Rasfamily. RHEB is active when bound to GTP. Tuberin andhamartin form an intracellular complex which activatesGTPase, reducing stimulation of mTOR.2931 mTORdetects signals of nutrient availability, hypoxia, or growthfactor stimulation32,33 (figure 2), and is part of many cellprocesses, such as cell-cycle progression, transcriptionand translation control, and nutrient uptake. Itphosphorylates, among other proteins, S6K1 andeukaryotic translation initiation factor 4E bindingprotein 1 (4E-BP1). S6K1 is a kinase that activates

ribosomal subunit protein S6, leading to ribosome

recruitment and protein translation. 4E-BP1 inhibitsactivity of eukaryotic translation initiation factor 4E(eIF4E) and, when phosphorylated by mTOR, releaseseIF4E from its control.34Tuberin and hamartin also bind,independently of the tuberinhamartin complex, toseveral other proteins; however, the physiologicalrelevance of these interactions is unclear35 (figure 3).

Inactivation of both alleles of TSC1or TSC2is neededfor tumour development. Loss of heterozygosity isfrequent in renal angiomyolipomas, less in sub-ependymal giant-cell astrocytomas, and almost absentin cortical tubers.36,37 Haploinsuffi ciencyie, minorsignalling or biochemical effects due to the presence ofonly one functional gene, manufacturing 50% of the

usual quantity of proteinmight contribute to thepathological effects of tuberous sclerosis in someorgans. According to Knudsons theory, the second hit iscaused by a somatic, independent mutation: somatic,second-hit mutations of TSC1 or TSC2, detectable byloss-of-heterozygosity analysis, might synergise withfirst-hit, systemic mutations of TSC1or TSC2, to causecomplete loss of TSC1TSC2 function. Identification ofloss of heterozygosity at different markers in anastrocytoma and angiomyolipoma from the same patientsuggested the multifocal origin of a second-hitmutation.38By contrast, identical somatic mutations ofTSC2have been described in abnormal lung and kidneycells, but not in healthy cells, of patients with sporadiclymphangiomyomatosis and renal angiomyolipoma.The hypothesis of benign metastasis has been proposedto explain this phenomenon: perhaps benign cells withmutations in TSC1 or TSC2 could travel to the lungsfrom renal angiomyolipomas.39,40 This hypothesis issupported by the finding that TSC2-deficientsmooth-muscle cells have higher migration potentialthan normal cells in vitro, and most patients withtuberous-sclerosis-associated pulmonary lymph-angioleiomyomatosis have large, potentially meta-statogenic renal angiomyolipomas.Understanding therole of hamartin and tuberin in cell adhesion andmigration through ezrinradixinmoesin proteins, and

small GTP-binding protein Rho, might expand theknowledge of benign metastasis.41,42

Individuals with the same genotype can have differentclinical phenotypes. Wide variation in the extent andseverity of clinical manifestations, even within the samefamily, shows that no strict correlation exists between amutation and its clinical outcome.43 Individuals withmutations in TSC2 have on the whole more severesymptoms than those with mutations in TSC1:15,16,1820,44,45specifically, more frequent and severe epilepsy, mentalretardation (moderate and severe), cortical tubers, renalangiomyolipomas, retinal hamartomas, and advancedfacial angiofibromas.15 However, some missensemutations in TSC2 might cause a mild clinicalphenotype.4649

100

Age

Expressionp

ercentage

9080

7060

5040

3020

100

Pren

atally

Atbirth

1yea

r

5yea

rs

10years

15years

25years

40years

60years

Hypomelanotic maculesSubependymal nodules

EpilepsyFacial angiofibroma

Renal angiomyolipomaCardiac rhabdomyoma

Ungual fibromaLiver hamartoma

Retinal hamartoma

Figure :Age-dependent expression of clinical manifestations


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Patients with no evident mutations have, on average,

milder manifestations than patients with mutations inTSC2 and sometimes even milder than those withmutations in TSC1. Mosaicism is a possible explanationfor this finding in sporadic patients. In familial cases, thepossibility of a distinct mutational spectrum, or mutationsin an unknown gene, should be considered.15 Thereported association between a high-expression allele ofthe gene encoding interferon gamma and a low frequencyof renal angiomyolipomas in patients with mutations inTSC2suggests that modifier genes might have importanteffects on the phenotype.50

Organ dysfunctionAbout 85% of children and adolescents with tuberous

sclerosis have CNS complications, including epilepsy,cognitive impairment, challenging behavioural problems,and autism.51

Progress in structural and functional imaging has ledto further characterisation of brain lesions, such ascortical tubers, subependymal nodules, subependymalgiant-cell tumours, and white matter abnormalities.52,53Intracranial aneurysms, especially implicating theinternal carotid artery, have also been seen in tuberoussclerosis.54Widespread anatomical abnormalities of greyand white matter structure have been noted, even inpatients with average intelligence.55

Cortical tubers are characterised by proliferation ofglial and neuronal cells, and loss of the six-layeredstructure of the cortex. Tubers are variable in size andmultiple in number, and can be detected by fetal MRI asearly as 26 weeks of gestation56,57 (figure 4). The mostprominent abnormal cell types in tubers are largedysplastic neurons, giant cells, and bizarrely shapedastrocytes. Dysplastic neurons have disrupted radialorientation in the cortex and abnormal dendriticarborisation, showing -aminobutyric acid (GABA)-transporter defect and low GABAergic inhibition.58Subependymal nodules are hamartomas, typically seenin the subependymal wall of the lateral ventricles. Somenodules protrude into the ventricular cavity.Subependymal nodules develop during fetal life, are

present in most patients with tuberous sclerosis, and areusually asymptomatic (figure 5).

Nodules bigger than 5 mm, which are located near theforamen of Monro, not calcified, and enhanced bygadolinium, have a high probability of evolving into asubependymal giant-cell tumour, particularly in familialcases of tuberous sclerosis59(figure 5). Transformation of asubependymal nodule into a subependymal giant-celltumour is usually a gradual process, of which the highestrate is in the first two decades of life.60 Growth over12 months has rarely been reported.59 Subependymalgiant-cell tumours are slow-growing tumours and of mixedglioneuronal lineage, and are the most common braintumours in patients with tuberous sclerosis, occurring inabout 10% of cases.5962 Growth of these lesions at the

foramen of Monro can block circulation of the cerebrospinal

fluid, leading to progressive lateral ventricular dilatationand increased intracranial pressure.60

Neonatal subependymal giant-cell tumours areextremely rare; however, large subependymal giant-celltumours have been identified in utero at 19 weeks ofgestation.63

Epilepsy associated with tuberous sclerosis generallybegins during the first year of life and, in most patients, in

TSC TSC

Chromosomal location 9q34 16p13.3

Size 55 kb 40 kb

Number of exons 23 41

Transcript size 86 kb 55 kb

M utation occurr ence 10 15% of sporadic cases 7580 % of sp or adic ca ses

Prevailing mutations Small truncations (mostly nonsensemutations and small deletions), lack of

hotspots

Large deletions and/or rearrangementsinvolving PKD, small truncations

(mostly missense mutations or

deletions), lack of hotspots

Phenotype Less severe More severe

LOH in affected organs Rare Frequent

Protein Hamartin Tuberin

Protein size 1164 aminoacids, 130 kDa 1807 aminoacids, 180 kDa

Protein function Together with tuberin, hamartin

regulates mTORS6K, and cell adhesion

through interaction with ezrin and Rho

Together with hamartin, tuberin

regulates mTORS6K and GTPase-

activating proteins. Tuberin has a role in

cell cycle

PKD1=polycystic kidney disease 1. LOH=loss of heterozygosity. mTOR=mammalian target of rapamycin. S6K=kinase

that activates ribosomal subunit protein S6.

Table :Characteristics of TSCand TSC

Panel:Diagnostic criteria for tuberous sclerosis7

Major features

Facial angiofibromas or forehead plaque pits in dental

enamel

Non-traumatic ungula or periungual fibroma Hypomelanotic macules (three or more)

Shagreen patch (connective tissue nevus) migration lines

Multiple retinal nodular hamartomas

Cortical tuber

Subependymal nodule

Subependymal giant-cell astrocytoma

Cardiac rhabdomyoma, single or multiple

Lymphangiomyomatosis, renal angiomyolipoma, or both

Minor features

Multiple, randomly distributed

Hamartomatous rectal polyps

Bone cysts

Cerebral white matter radial Gingival fibromas

Non-renal hamartoma

Retinal achromic patch

Confetti-like skin lesions

Multiple renal cysts


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the first few months. Focal seizures precede, coexist with,or evolve into infantile spasms. Focal or multifocalepileptiform abnormalities might be present when an EEGis done between the neonatal period and the developmentof spasms (figure 6). During non-rapid eye movement(REM) sleep, multifocal and focal EEG abnormalities tendto generalise.64Several children who have partial seizures orspasms at onset later develop intractable seizures withmultifocal EEG abnormalities, which are associated withbilateral and synchronous slow spikewave complexes.65,66Epileptogenic foci can shift from one epileptogenic tuber to

another during the course of the disease due to maturational

phenomena; different regions can become epileptogenicover time.67However, in many patients one localisation isconsistently present, especially in the frontotemporalregions, in a topographic relation with a major tuber.51,68

Epileptogenesis in tuberous sclerosis is caused bydiminished neuronal inhibition, secondary to molecularchanges of GABA receptors in giant cells and dysplasticneurons, and enhanced excitation, which is secondary tomolecular changes of glutamate receptors in dyplasticneurons.69 The deficiency of GABAergic interneuronsmight explain the early onset and severity of seizures intuberous sclerosis.70,71 Impaired extracellular potassiumuptake by astrocytes contributes to neuronal hyper-excitability and epileptogenesis in a mouse model.72The

importance of the GABA inhibitory system in tuberoussclerosis has been confirmed by studies of vigabatrin, aninhibitor of GABA transaminase, which can stop spasmsin up to 95% of infants affected by tuberous sclerosis.7375Prompt seizure control is crucial, and could prevent thedevelopment of an epileptic encephalopathy.76Treatmentwith vigabatrin seems to prevent spread of paroxysmalactivity outside the cortical dysplasia.77A clinical responseis often present after one or two doses. In our experience,low doses (50 mg/kg, once daily) are rapidly effective ininfants, if the treatment is started shortly after onset offocal seizures or spasms.78

The risk of visual-field loss caused by vigabatrinprogressively rises with increased duration of treatmentand mean dose.78,79Therefore, administration of low dosesof vigabatrin for brief periods minimises the chance ofophthalmological toxicity.80Several techniques, includingelectroretinography (ERG), electro-oculography (EOG),multifocal electroretinography (mfERG), and ocularcoherence tomography are used to identify possibleretinal damage in children treated with vigabatrin.79,8183

Tuberous sclerosis has a striking variability of neuro-cognitive manifestations and psychopathological features.84

In the same family, some individuals can be impaired andhave severe autism and challenging behaviours, whereasothers lead normal lives.85 A bimodal distribution ofintelligent quotient (IQ) exists between a population of

severely disabled patients (mean IQ=3040) and apopulation of less severely disabled patients (meanIQ=93).86About 30% of individuals with tuberous sclerosisare profoundly impaired, and show little or no newimprovements. More than 50% of individuals withtuberous sclerosis have average intelligence (IQ>70),86butmight be prone to specific cognitive deficits of memory,attention, or executive skills.76,85,87,88 Most important vari-ables associated with poor cognitive outcome include ahistory of refractory seizures, mutations of TSC2, and thepresence of cortical tubers in certain regions.89 Data ofmonozygotic twins indicate that non-genetic factors alsocause differences in neurological and psychiatric out-come.90Individuals with learning disabilities usually havea history of early-onset seizures, which often present as

AMPK

Nutrients

Ribosome biogenesis, translation, and cell growth

Rapamycin

AKT

REDD1CDK1

TSC1

GTP

PI3KIII

S6K1 4E-BP1

mTOR

Raptor

GL

RHEB

TSC2

GSK3RSK1

ERK

ERCalmodulinp27SMAD214-3-3PAM

c-Myc, cyclin D1transcription

-catenin

Cell-cycle progression

Figure :The hamartintuberin complex: central regulator of cell-signallingpathways

After growth-factor stimulation, the hamartintuberin complex is

phosphorylated and its GTPase-activating protein activity is decreased, whereas

in response to stimuli such as hypoxia or low energy it is phosphorylated and its

GTPase-activating protein activity increased. The complex deactivates RHEB by

causing GTP to be cleaved from it. Activated RHEB stimulates mTOR, which has

a crucial role in the translation of proteins such as c-Myc or ornithine

decarboxylase, and participates in cell-cycle control. mTOR binds to raptor and

GL to exert its effect, which is mediated by S6K1 and 4E-BP1, proteins that

participate in ribosome biogenesis and translation initiation, respectively.

Nutrients might boost translation through PI3KIII, which phosphorylates mTOR.

TSC1 and TSC2 interact also with other proteins, such as ER, calmodulin, p27,

SMAD2, 14-3-3 proteins, and PAM. 4E-BP1=eukaryotic translation initiation

factor 4E binding protein 1. AKT=protein kinase B. AMPK=AMP-activated

protein kinase. CDK1=cyclin-dependent kinase 1. ERK=extracellular

signal-regulated protein kinase. GL=G protein -subunit like. GSK3=glycogen

synthase kinase 3. PAM=protein associated with Myc. PI3KIII= PtdIns 3-kinase.REDD1=regulated in development and DNA damage responses. RHEB=Ras

homologue enriched in brain. RSK1=ribosomal S6 kinase 1. S6K1=kinase that

activates ribosomal subunit S6.


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infantile spasms.86 Seizure onset during early stages of

brain development can be temporally associated withautistic regression.91,92Frequency of autism in infants withtuberous sclerosis might be significantly higher thanfrequency of cardiac or renal abnormalities, for whichscreening is routinely done.93 Children with cognitiveimpairment are significantly more likely to have an autisticspectrum disorder and attention deficit hyperactivity dis-order.84Seizure-related sleep disorders, such as prolongedsleep latency and night waking, are routinely seen.94

Hypomelanotic macules are the most common dermato-logical manifestation, being present in 9098% of patientswith tuberous sclerosis (figure 7).95,96The hypopigmentedmacules are best seen under ultraviolet light (Woodslamp) particularly on the trunk and buttocks.

Hypomelanotic macules can be the only skin lesions ininfants: if the child also has focal seizures or infantilespasms, a diagnosis of tuberous sclerosis should beconsidered. Bilateral facial angiofibromas are hamar-tomatous nodules of vascular and connective tissue, witha butterfly pattern over the malar eminences and nasallabial folds of the face (figure 7). Their frequency is about80% in children with tuberous sclerosis who are olderthan 5 years of age.97They generally appear in children of34 years of age, giving a ruddy appearance to the cheeks,which become rougher and cobblestoned thereafter.Rarely, these lesions are unilateral: in such cases, theymight represent a segmental form of tuberous sclerosis.98

Another common dermatological feature of tuberoussclerosis is the shagreen patch (figure 7). These patches areconnective tissue naevi, generally located on thelumbosacral flank; they can also be scattered across thetrunk or thighs. The frequency of these lesions rises withage. Webb and colleagues97showed that these lesions arepresent in 54% of children with tuberous sclerosis who areolder than 5 years of age, and are usually evident by 10 yearsof age, typically with an irregular border, a raised,roughened surface, and a generally pigmented skin overthe lesion. Molluscum fibrosum pendulum is common onthe neck, groins, axillae, and near flexory surfaces of limbs,especially in adults.99

The forehead fibrous plaque is a yellowbrown or

flesh-coloured patch of raised skin of variable size andshape, with a diameter from a few millimetres to severalcentimetres. These lesions are found in around 36% ofpeople with tuberous sclerosis. They are classifiedhistologically as angiofibromas, although the vascularcomponent is not pronounced. In some children,forehead fibrous plaques develop in the neonatal period,and are the first skin lesions of tuberous sclerosis.

Ungual fibromas, also called Koenen tumours, areconnective tissue hamartomas close to or underneathnail beds. They are generally more common on toes thanon fingers, and develop at 1529 years and are morecommon in women than in men. When present at thebase of the nail, they can produce a groove. They can beinduced by nail-bed trauma.

Dental abnormalities (dental pits) are seen in 90% ofpatients with tuberous sclerosis, but only in 9% of thegeneral population.100

A

B

T417(CDK1)

S584(CDK1)

S357/S390(GSK3)

T1047(CDK1)

1164Hamartin

Hamartininteraction

GAPdomain

T1227(AMPK)

S1345(AMPK)

Tuberin 1807

S664(ERK2)

S939(AKT)

S1210(MK2)

T1462(ATK)

S1798(RSK1)

Tuberin

interaction

Figure :Structure of hamartin and tuberinDomains of hamartin (A) and tuberin (B) that bind to other proteins are shown. Only inhibitory phosphorylation

sites on both proteins are shown, together with the respective kinases.

Figure : Axial fetal MRI

This MRI, which was done at 27 weeks of gestation, shows subependymal

nodules and tubers. The left-pointing arrow indicates a tuber; the right-pointing

arrows indicate nodules.

A B

Figure :Progressive growth of a lesion at the foramen of Monro

Coronal T1-weighted image with gadolinium (A) shows a small enhancing lesion; marked growth is visible at

3-year follow-up (B).


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Cardiac rhabdomyomas are the main feature of the

disease in the fetus and newborn baby. 96% of infantswith cardiac rhabdomyomas will ultimately bediagnosed with tuberous sclerosis.101Although patients

typically have several, these tumours are rarely

symptomatic. Nonetheless, they can manifest prenatallyas arrhythmia, non-immune hydrops, or death. Thesetumours are usually 325 mm in diameter, are mostcommonly located within the ventricles, and within thewalls more often than the septum (figure 7). In a smallpercentage of patients, supraventricular tachycardia,secondary to a ventricular pre-excitation syndrome suchas WolffParkinsonWhite syndrome, can be associatedwith these septal lesions. Large lesions can obstructcardiac outflow or cause cardio-embolic disease. 101How-ever, lesions usually recede over time, with completeregression in childhood.102

Renal complications are the most frequent cause oftuberous-sclerosis-related death.103 Multiple, bilateral

angiomyolipomas are found in about 7090% of adultpatients, and are more often symptomatic in women.104,105Their frequency is lower in children than in adults, but upto 16% of patients below the age of 2 years can be affected.95These tumours consist of abnormal blood vessels, smoothmuscle, and adipose tissue. They tend to grow slowly.However, ultrasonography may reveal dramatic pro_

gression of tumour size (34 cm every 2 years) inadolescents.106Spontaneous bleeding is the most commoncomplication in patients with tumours larger than 4 cm indiameter. Surgical resection should be nephron-sparing,to preserve renal function, and done only if clinicallysuggested. If tumours are more than 4 cm in diameter, thepreferred method of treatment is tumour embolisation,107109which can be used as a prophylactic treatment. Theprocedure is especially recommended in patients withcentrally located tumours, when surgery is likely to causeloss of function of the kidney.110 Angiogenesis inhibitorscould have a role in preventing the development of renalangiomyolipomas, and could improve the prognosis forpatients with tuberous sclerosis.111

As well as angiomyolipomas, patients with tuberoussclerosis develop renal cysts and renal-cell carcinomas.Renal cysts are usually asymptomatic, unless they are inpatients with contiguous deletions in TSC2 and PKD1.In these individuals, cysts can be large and multiple,leading to end-stage renal failure by early adult life.23

Renal-cell carcinoma is seen in 23% of patients withtuberous sclerosis. This carcinoma is usually diagnosedduring childhood, but symptoms appear only after manyyears.112114 Smooth-muscle cell carcinomas usually stainfor cytokeratin and are negative for HMB45, which is amarker of renal angiomyolipomas.

Retinal hamartomas are present in about 4050% ofpeople with tuberous sclerosis. They can be found at anyage (figure 7);115 they have been described in smallchildren and even newborn babies.116

Different morphological types of hamartomas exist. Themost common type is a subtle, flat, smooth-surfaced,salmon-coloured, semitransparent, circular or oval lesion,on the superficial part of the retina, usually near or at theposterior pole. The second most common type is an easily

A

C

E

B

D

F

Figure :Dermatological, cardiac, and pulmonary manifestations of tuberous sclerosis

Hypomelanotic macules (A). Facial angiofibromas (B). Shagreen patch (C). Hyperechoic rhabdomyoma detected byechocardiography (D). Retinal hamartoma (E). Lymphangiomyomatosis (F).

Fp2-T4

T4-O2

Fp2-C4

C4-O2

Fpl-C3

C3-O1

Fp1-T3

T3-O1

T4-C4

C4-Cz

Cz-C3

C3-T3ECO-RF

A B

Figure :Epilepsy

Ictal EEG showing epileptic spasms (A). Axial MRI showing cortical tubers in a 20-month-old boy (arrows) (B).


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recognised, opaque, white, elevated, multinodular,

calcified lesion that is frequently described as resemblinga mulberry. The third most common type of lesioncontains features of the other two, being calcified andnodular centrally, but having a semitranslucent, smooth,and salmon-coloured perimeter.117Progression from a flatto an elevated shape of lesion has been reported. 118

Lesions referred to as mulberry are seen in about50% of patients with tuberous sclerosis, and arefrequently bilateral.117 They are composed of glial andastrocytic fibres, and can be evident by 2 years of age.Unless these lesions affect the macula or optic nerve,they are typically asymptomatic. Sometimes, an achromicpatch is seen on the retina, similar to the hypopigmentedmacules on the skin.

Pulmonary lymphangiomyomatosis is characterisedby alveolar smooth-muscle proliferation, and cysticdestruction of lung parenchyma. No study has yet definedthe frequency of the disease symptomatically within thegeneral population, but it probably affects 13% of peoplewith tuberous sclerosis.119

Pulmonary lymphangiomyomatosis is usually general-ised and progressive, extremely diffi cult to treat, and witha poor prognosis. This disease predominantly affectspremenopausal women and is exceptionally rare in men(figure 7).120122 The onset in childhood has been rarelyreported.119 First manifestations are shortness of breath,lung collapse, coughing, and chest pain. Pulmonarylymphangiomyomatosis can take place as an isolated form(sporadic) or as a pulmonary manifestation of tuberoussclerosis (tuberous-sclerosis-associated). Most tuberous-sclerosis-associated cases are caused by mutations inTSC2; few are caused by mutations in TSC1.123,124Sporadicpulmonary lymphangiomyomatosis typically results fromtwo somatic mutations in TSC2.124,125

Renal angiomyolipomas are present in 32% of patientswith sporadic pulmonary lymphangiomyomatosis and in93% of patients with tuberous-sclerosis-associatedpulmonary lymphangiomyomatosis:126 renal tumoursmight be a source of metastatic cells.39 Pulmonarylymphangiomyomatosis is present almost exclusively inwomen: perhaps oestrogens regulate cell-signalling

pathways of tuberous sclerosis (figure 2) and migrationof TSC2-deficient cells. In-vitro studies have shown thatthe carboxy terminal of TSC2 interacts with the oestrogenreceptor , and functions as a transcriptional corepressorof the receptor.127

Hepatic multiple, bilateral angiomyolipomas havebeen reported in patients with tuberous sclerosis onlyrarely, perhaps because they are usually asymptomatic.In two ultrasonographic studies of individuals withtuberous sclerosis, the proportion of patients who hadhepatic angiomyolipomas was 24% and 16%.128,129Theseangiomyolipomas are more common in adults(2345%) than in children, and more frequent inwomen than in men.130Renal angiomyolipomas usuallyprecede development of hepatic angiomyolipomas in

patients with tuberous sclerosis. Hepatic angio-

myolipomas grow more slowly than renal angio-myolipomas, and do not cause death. 131

Diagnosis and managementAt the onset of tuberous sclerosis, diagnostic studies arecommonly done, to confirm the presence of the diseaseor to find the cause of symptoms. When symptomssuggesting tuberous sclerosis arise, brain MRI is usuallydone.7 EEG is useful when the initial presentationincludes seizures; children or adolescents who have neverhad seizures generally do not need to have an EEG. Thediagnosis of tuberous sclerosis is made before the onsetof seizures in an increasing group of newborn babies andsmall infants, with techniques such as routine fetal

echocardiography and fetal MRI. In our experience, thispopulation should be closely monitored by EEG recordingsto detect subtle focal seizures at an early stage. For everypatient, renal ultrasonography is carried out at the time ofdiagnosis. Adolescents and adults have a greater chanceof developing symptomatic renal angiomyolipomas thanchildren. Cardiac arrhythmia can be present at birth, ordevelop later. Therefore, investigations must be done atthe time of diagnosis. Echocardiography shows one ormore cardiac rhabdomyomas in most newborn babieswith tuberous sclerosis.132 However, as noted above, suchlesions spontaneously regress; the most rapid reductionin lesion size takes place during the first 3 years of life.133

Children usually do not suffer from facial angiofibromasor ungual fibromas at the time of initial diagnosis. Typicalhypomelanotic macules can be recognised early by mostclinicians who have knowledge of tuberous sclerosis.Generally, dermatological examination is importantwhen skin lesions are atypical or when diagnosis oftuberous sclerosis is uncertain. Once diagnosis is made,scrupulous, regular, age-dependent screening forbehavioural, cognitive, and neurodevelopmentaldysfunction is strongly recommended.95,134 Children withapparently normal initial findings and developmentalmilestones can have mild deficits that, nonetheless,diminish their learning abilities.

Genetic testing enables patients with tuberous sclerosis

to know exactly what mutation caused the disorder.Mutation detection could identify patients with differentdegrees of risk of particular complications. DNA testingcan be useful in several settings. First, it can be helpful inconfirming a clinical diagnosis of tuberous sclerosis,especially in young patients.135Second, in many familiesaffected by tuberous sclerosis in which a sporadic caseexists, genetic testing can provide reassurance to parentsand other family members that they do not have amutation. However, about 2% of unaffected parents mighthave a gonadal mosaicism, bearing the risk of the nextchild with tuberous sclerosis.136 Third, DNA testing isuseful for prenatal diagnosis. In families with either achild or a parent with a known mutation, prenatalmutational analysis can be easily done.


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Long-term surveillance testing should be directedtowards lesions that are frequent, can be treated if

identified early, and have a high risk of causing dys-function or death. A surveillance protocol based on thehistory of tuberous sclerosis provides some practicaladvice for follow-up testing. Any effort should be madeto keep to a minimum costly testing of asympto-matic patients and to maximise the likelihood of earlyidentification of potentially life-threatening compli-cations. Renal angiomyolipomas, subependymal giant-cell tumours, pulmonary and cardiac complications arethe major causes of shortened life expectancy.103

MRI of the brain should be done before the patient is2 years old, and repeated every year until the patient is21 years old, if the patient has clinical or neuroimagingrisk factors for developing astrocytomas.59,60The diagnosis,at an asymptomatic stage, of subependymal giant-celltumours that are likely to cause problems later, is not yetpossible. Careful clinical surveillance during childhoodand adolescence, and close monitoring with MRI of thebrain in the presence of changing clinical symptoms orrapidly growing lesions, are strongly recommended tofacilitate early intervention against subependymal giant-cell tumours.137

Despite the use of all available antiepileptic drugs,many patients with tuberous sclerosis have intractableseizures.138140 Multimodality imaging, including MRIscans, positron emission tomography, and magneto-encephalography has been used to localise epileptogenic

tubers and associated epileptogenic regions: results arepromising.141145Tailored surgical resection of epileptogenicfoci have yielded excellent results: seizures have beenstopped in 57% of drug-resistant patients. Surgery canreduce deterioration of cognitive functioning, andbehavioural regression.140,146 Multistage surgery is anoption for patients with several epileptogenic tubers.147

Clear guidelines for screening, surveillance, andtreatment of angiomyolipomas in patients with tuberoussclerosis are needed. These guidelines should includethe appropriate frequency of surveillance for patients indifferent age groups and at different stages ofangiomyolipoma development; growth of renal angio-myolipomas can be rapid and asymptomatic. CT or MRImight be needed to detect complications, such as

bleeding and rupture in large lesions. Angiogenesis

inhibitors could have a role in the prevention ofdevelopment of angiomyolipomas, and improve prog-nosis for patients with tuberous sclerosis.111

In patients affected by the disease, symptomaticpulmonary lymphangioleiomyomatosis is infrequent,but causes great morbidity and mortality. No predisposingfactors, other than sex, have yet been identified. Malepatients with apparent pulmonary lymphangioleio-myomatosis should be rigorously investigated. Clinicalsymptoms, such as visual impairment, take place rarelyin retinal hamartomas. Lesions causing secondaryexudative changes need continuing eye care, and mightbe treated with photocoagulation. Although in thesepatients visual stabilisation is possible after argon laser

photocoagulation, vision-threatening complications canoccur as a result of the disease. Current treatmentstrategies for exudative retinal hamartomas includephotodynamic therapy based on favourable anatomicaland functional results.118 Table 2 summarises recom-mendations for long-term clinical management ofasymptomatic patients, when a definite diagnosis ismade.148

Future developmentsAt present, the management of tuberous sclerosis issymptomatic. However, the discovery of mTOR pathwayupregulation in tuberous-sclerosis-associated tumourspresents new possibilities for treatment strategies.149Interferon gamma and interferon alpha interact withmTOR, leading to deactivation of the translationalrepressor 4E-BP1, which could be beneficial for thetreatment of tuberous sclerosis.150

Sirolimus makes the dysregulated mTOR pathwayreturn to normal in cells that lack TSC1 or TSC2. Severalresults from in-vitro or in-vivo animal studies suggestthat sirolimus or its analogues might be effective in thetreatment of various manifestations of tuberoussclerosis (eg, skin lesions,151 lymphangioleiomyoma-tosis,152renal angiomyolipomas,153renal-cell carcinoma,154or even polycystic kidney disease155). Sirolimus iseffective in diminishing the volume of lesions in

patients with renal angiomyolipomas,156,157 subependy-mal giant-cell astrocytomas,158and sporadic lymphangioleiomyomatosis.159 However, angiomyolipomas in-creased in volume after the therapy was discontinued,156,157and some patients taking sirolimus experienced seriousadverse events.159

Conflict of interest statement

We declare that we have no conflict of interest.

Acknowledgments

We thank Romina Moavero for her technical assistance.

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Initial testing Repeated testing

Neurodevelopmental testing At diagnosis and at school entry As clinically indicated

Ophthalmic examination At diagnosis As clinically indicated

Electroencephalography At diagnosis As clinically indicated

Electrocardiography At diagnosis As clinically indicated

Ech ocardiograph y If cardiac sympt oms t ake place If cardiac dysfu nction takes place

Renal ultrasonography At diagnosis Ever 13 years

Chest computed tomography In adulthood (women only) If pulmonary dysfunction takes place

Cranial MRI At diagnosis Children and adolescents: every 13 years

Table :Testing recommendations of asymptomatic patients


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Tuberous Sclerosis Lancet 2008