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Informații şi înregistrări: vezi primul anunț 


Autor: Carmen Burloiu
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Tuberous sclerosis complex is an autosomal dominant inherited multisystemic disorder characterized by the presence of multiplehamartomas in different organs mainly in brain, skin, kidney, liver, eyes and heart. The estimated frequency of the disease is1:10.000. Representative series of studies on patients with tuberous sclerosis has led to the improvement of the diagnostic criteriaand allowing early positive diagnosis of the disease. Even many clinical features have high specifi city for TS some of themtend to appear later in life, in childhood or adult age. Mildly or asymptomatic cases are rarely diagnosed in childhood. Th osepatients who do not meet the diagnostic criteria for positive diagnosis of TS need periodic reevaluation for confi rmation. The diagnostic signifi ance of the criteria is different at different ages because the clinical features are age dependent.Th e objective of this paper is to review the literature data on the evolution of diagnostic criteria for tuberous sclerosis, their practicalusefulness in early diagnosis of TS according to age and the actualities about recomandations for diagnostic and follow-upevaluation of these patients.




Being a multi-system genetic disease with dominantautosomal transmission, Tuberous Sclerosis(TS) is characterized by the presence of numeroustumour lesions with hamartomatous character thatcause non-malignant tumours to grow predominantlyin the brain and on other vital organs such as the skin,kidneys, liver, eyes, and heart. The estimated frequencyof this disease is 1:10.000 but its real prevalence is1:6800 (1). Early recognition of TS signs is importantfor diagnosis and implicitly for the appropriatetreatment of the different types of lesions in order to prevent their severe complications. The clinical phenotypeof TS has a great variability of expression,being influenced by the number, the size, location oflesions and of the organs aff ected. The first diagnosticcriteria of the disease have been developed in 1908by Voght. Over time, diagnostic criteria have beenmodified several times, based on the fi nding that onlysome clinical signs have high specifi city for the disease.Studies on large groups of patients showed that asignificant number of patients with mild TS or clinicallyasymptomatic did not meet the clinical criteriafor positive diagnosis and remained undiagnosed untiladulthood. Adults who have only one or two clinicalsigns of reduced significance for TS may be wronglyconsidered as asymptomatic. Careful physical examinationcan detect other clinical signs, too and goingfurther with laboratory investigations: neuroimaging,radiological and ultrasound examinations can detectnew characteristic lesions allowing the positive diagnosisof the disease. On the other hand, the presenceof only one clinical sign, even if it is one with greaterspecifi city for TS, does not automatically imply apositive diagnosis of the disease. In this situation afull evaluation is necessary, periodically, including allclinical signs due to the fact that they occur graduallyover time, with age (2) (see Table 1).


Table no. 1. Lesion type in TS according to the age of occurrence (after Crino2006, modified):


The earliest lesions are the cardiac rhabdomyomasand the cortical tubers that are developing in thewomb, during embryogenesis. The detection of cardiacrhabdomyomas is useful for diagnosing cardiac TSin infancy and even during the prenatal period. Th ehypomelanotic macules are precociously present inmost patients during the infant or young child stage,their diagnostic significance being much greater inthis age group since the other clinical signs appearlater in evolution (3). The shagreen patches and thefacial angiofi bromas are detected more frequentlyafter 4 -5 years of age and occur more frequentlywhile the periungual fi bromas occur more frequentlyduring pubertal period and in adulthood, havinggreater diagnostic importance over the age 5.

Subependymal nodules, occasionally degenerating tosubependymal giant cell astrocytomas (SEGA) alsooccur in children and adolescents. Renal cysts maybe present in infants and children; while renal angiomyolipomas(AML) develop especially in the olderchildren, adolescents and adults, and the lymphangioleiomyomatosis(LAM) occurs only in females duringadolescence or adulthood.

Although inactivating mutations in one of the twodistinct TSC genes (TSC 1 or TSC2) responsible forthe occurrence of TS causes the same basic syndrome,the degree of disorder, the general clinical aspect andalso the neurological one are different depending onthe aff ected gene (4).

Clinical impairment seems to be more severe inpatients with TSC2 mutations compared with thosewith TSC1 disease (5). Despite the research studiesand the progress of molecular genetics concerning TS,there was no evidence was obtained so far, of a biochemicalmarker for the clinical detection of geneticdefects (6; 7). About 96% of patients with TS have atleast one skin lesion, 90% have signs of brain damage,84% have epileptic seizures, 60% have renal impairmentand about 50% have retinal damage (6). The mostimportant diagnostic modalities are represented bycareful clinical examination of any patient suspected ofhaving TS and para-clinical evaluation for the detectionof still asymptomatic lesions in different organs.A.



The first diagnostic criteria for TS were prepared in1908 by Voght and constituted the classical diagnostictriad (Voght triad) consisting of: epileptic seizures,mental retardation and facial “sebaceous ade-nomas”(angiofi bromas) (6 and 7). With a better understandingof the TS and the ability to recognize various clinicalsigns as part of the same disease, it was found thatnot all patients with TS had all three signs of the Voghttriad. Examining large series of TS patients, Gomezfound that only 29% of cases displayed the presence ofthe Voght triad, 6% of patients having no clinical signsbelonging to this diagnostic triad (8). Thus, the necessityto establish new criteria for the diagnosis of TSemerged. In 1979, the paediatric neurologist Gomezwas able to improve these criteria which he divided intotwo categories: primary and secondary (8, 9) (see Table no. 2). The classification allowed a certain TS diagnosisin patients who had one of the primary criteria. In theabsence of primary criteria, the secondary diagnosis forTS was accepted on condition that two secondary criteriawere present.

Subsequently, the introduction of methods such asultrasound imaging examination, the examination ofthe brain using roentgen-ray computed tomography(CT) and magnetic resonance imaging (MRI) has allowedthe detection of new evidence, showing at thesame time that the anatomopathological presence ofthe subependymal nodules and of the cortical tubers(primary criteria), was not necessary to be demonstratedbecause these anomalies might be easily highlightedduring examinations using CT and brain MRI. In addition,it was found that some clinical signs of TS havea higher specifi city than others, giving greater diagnosticcertainty than the less specifi c ones (10). Based onthis fi nding, in 1992, Roach and his colleagues reviewed the diagnostic criteria for TS, dividing the clinical signsaccording to their importance for diagnosis into threecategories: primary, secondary and tertiary criteria.Primary criteria were considered pathognomonic. TSpositive diagnosis was possible if the following criteriawere present: one primary criterion, or two secondarycriteria, or a secondary criterion plus two tertiary criteria(10) (see Table no. 3). The practical use of thisclassification has proved to be quite cumbersome. Furtherstudies showed that specifi city of certain clinicalcriteria was not as great as it had been initially thought,some clinical signs being present in individuals withoutTS. For example, hypomelanotic macules (tertitertiarydiagnostic criterion in the classification of 1992)may be present in small numbers (up to 3) in healthypersons, too. The renal angiomyolipoma and the lunglymphangioleiomyomatosis can occur simultaneouslyin patients where the tuberous sclerosis is apparentlyabsent while focal cortical dysplasia and ungual fi bromasmay exist in patients without evidence of TS (11).According to the 1992 classification, hypomelanoticmacules were considered tertiary diagnostic criteria,having a low diagnostic significance compared withfacial angiofi bromas and periungual fi bromas that wereconsidered pathognomonic signs for TS with the valueof primary diagnostic criteria (3, 10).


Table nr. 2. TS Diagnostic Criteria (after Gomez 1979, modified ):


Table nr. 3. Primary, secondary and tertiary diagnosis criteria (Roach 1992)


Starting from the observation of the specifi citiesof different clinical signs in TS, in 1998, a new revisionof diagnostic criteria took place. These criteriaare now grouped into two broad categories: major andminor criteria (see Table no. 4) making up a classification that is still currently used for the TS diagnosisand allowing TS to be defined by the presence of twomajor criteria or of a major criterion in combinationwith two minor criteria (11) (see Table 4). The advantageis that this classification allows the diagnosis ofcases that have not yet met all the diagnostic criteriaof certainty, but which are likely to be TS and requireregular monitoring and inspection to confi rm the diagnosis.Thus, we may speak of probable TS and possibleTS (Table no. 5) (12). Despite improvements in diagnostic criteria and their large number, early diagnosisat the age of newborn, infant and young child isoften diffi cult and a challenge given the fact that atthis age most visceral lesions are not present yet, clinicalsigns appearing later in childhood or even in adolescenceand adulthood (6, 7). Associating infantilespasms or partial seizures in infants with hypomelanoticmacules is suggestive but not suffi cient for thediagnosis of TS (6).


Table nr. 4. Revised diagnostic criteria (major and minor) (after Roach 1998 modified):


Table no 5. TS (after Franz 2007)


The significance of diagnostic criteria is differentat different ages. Jozwiak and colleagues noted thathypomelanotic macules, cardiac rhabdomyomas, infantilespasms and the subependymal nodules havethe greatest diagnostic usefulness in infants andyoung children under 2 years old (3). Analyzing the frequency of various clinical signs by age group (0-2years, > 2-5 years, > 5-9 years, > 9-14 years and respectively> 14 to 18 years), in a series of 106 childrenwith TS, he found that hypomelanotic macules werethe most frequent sign of TS (in 89.6% cases) in childrenaged under 2 years preceding the emergence ofother specifi c signs such as facial angiofi bromas andepileptic seizures. Cardiac rhabdomyomas, epilepsyand subependymal nodules had a similar frequency(about 83% cases). In children with TS aged 2 to 5 years, subependymal nodules were the most commonaspect (97.3%) followed by hypomelanotic macules(95.3%) (3).



According to the recommendations of the 1998Consensus Conference on Tuberous Sclerosis, thediagnostic approach in TS aims at assessing patientssuspected of suff ering from TS, those already diagnosedwith TS and the patient’s potentially aff ectedfamily members (13, 6, 7). The prenatal assessment ofthe disease in mothers already diagnosed with TS isalso important.

1. Assessment of patients suspected of TS

The assessment of patients suspected of TS aims todetect the presence of different characteristic lesionsattempting to fi nd out major and minor diagnosticcriteria (13). The order of diagnostic investigations isdictated by clinical signs and the patient’s age, the occurrenceof TS lesions being dependent on age (see Table 1).

The first step in the diagnostic approach is to obtaincomplete a medical history followed by the patient’sgeneral examination (paying particular attention tothe examination of the skin) and the neurological examination(4). If the patient has a history of infantilespasms or seizures, or if he has an autistic aspect, thenext step will be to conduct a brain MRI exam in orderto look for additional evidence of TS (4, 6). The electroencephalogram (EEG) is useful in the initialinvestigation only if the patient suff ers from epilepticseizures; in their absence, there is no need for itin a routine examination. Recently, a group of Polishauthors have raised also the issue of EEG usefulnessin patients with confi rmed TS who do not have crisesclinically. Detecting electroencephalographic abnormalitiesin young infants without epilepsy couldpredict the onset of seizures (14). If suggestive skinlesions and MRI changes are present but not suffi -cient to support the diagnosis of TS according to thediagnostic criteria, the investigation should continuewiTheye examination in order to detect any retinalhamartomas (4). Renal ultrasound evaluation will bemade at the moment of the initial diagnosis in anypatient suspected of TS. Although they appear inchildhood, renal cysts may be present at a young agetoo (a minor diagnostic criterion). Later in childhood,in adolescence and in adult age patients may developkidney AML (major criterion for diagnosis). Cardiacultrasound is especially useful in infants and youngchildren up to the age of 2, cardiac rhabdomyomashaving the fastest rate of regression in the first yearsof life (6). Nevertheless, at the moment of the initialdiagnosis Cardiac ultrasound is recommended inall patients suspected of having TS, regardless of age,given the fact that, in some cases, rhabdomyomas canappear or reappear in adolescence (15). Dermatologicexamination is not required in the initial approach ifthe patient is young, an infant or a young child, exceptingsituations where the presence of atypical skinlesions is noted or there is an uncertain diagnosis ofTS (6). Initial psychological examination is mandatoryin all patients using age-appropriate tests to detectneuro – developmental, cognitive and behaviouraldefi cits (13) (table 6).

The genetic test remains the last step in makingthe initial diagnosis and can be performed but onlyselectively, in patients with risk for particular complications,in order to reduce the number of investigations(6). The utility of routine genetic test for initialdiagnosis has not been demonstrated so far. Currentevidence does not yet allow the establishment ofa strict correlation between the type of gene defi citand the clinical phenotype. Genetic counselling isimportant for family planning. In families, the estimatedrisk of having a child with TS is 50% for eachpregnancy. For sporadic cases with novo mutations,where the parents are apparently healthy, excludingwith certainty the emergence of a new case is diffi cult.In these situations, the risk of recurrence is estimatedat 1-2% and is due to germ-line mosaicism, whichcan not be detected by genetic testing. In addition, theusefulness of diagnostic genetic test is controversialbecause about 30% of patients with TS had negativeresults in genetic tests so that a negative genetic testwill not exclude the disease (4, 6).

2. Evaluation of patients already diagnosed with tuberous sclerosis

Patients diagnosed with TS require long-termclinical and imaging observation. Based on the informationknown about the natural progression of thedisease, attention should be directed to the supervisionof most common injuries, of those which mightbenefi t from early treatment if they are identifi ed indue time and of lesions at risk for major dysfunctionor even death (6, 11). The growth of these lesions will be monitored, particularly renal AML and SEGA.Guidelines for overseeing the development of thisdisease have not been set up yet. The revaluation planwill be based on the results of initial evaluation (Tableno. 6), (7).


Table no. 6. Recommendations for initial and evolution assessment (Roach 1998 modified):


EEG is recommended to be performed in all patients with epileptic seizures where the aspect of the seizures has changed and also in those who, in theabsence of a history of seizures display inexplicablecognitive or behavioural decline. (6).

Neuro-developmental tests will be made compulsorilyat school age regardless of the outcome ofinitial testing (4). For those who have had changesto the initial tests, the neuro-developmental tests willbe repeated whenever signifi cant behavioural – cognitivechanges occur. But in case of a teenager or anadult with normal and stable social pattern from acognitive point of view, routine testing is not required(6). In an attempt to establish clinical guidelines forthe management of cognitive behavioural problemsof patients with TS, a consensus group consisting ofpsychiatrists, psychologists and parents, following aworkshop held in 2003 in Cambridge recommendsevaluating the cognitive-behavioural profi le of thesepatients at regular intervals in time in a planned mannerand consistent with the diffi culties associated withthis disease. Evaluation should include standardizedneuropsychological and behaviour tests in order todetermine the needs of these people at different levels:educational, social and concerning clinical management strategies (16).

Subependymal giant cell astrocytoma (SEGA) requiresregular monitoring of brain CT or MRI neuroimaging.It is known that SEGA typically occur inchildhood and only rarely after puberty, their growthrate being higher in the first and second decades oflife. Clinical signs of intracranial hypertension causedby obstructive hydrocephalus secondary to SEGAgrowth are diffi cult to see in patients with mentalretardation or autistic behaviour. Thus, for the earlydetection of SEGA, it is considered useful to performbrain imagery at regular intervals until puberty andeven in adolescence (17). General Recommendationssupport the repeated CT scan or brain MRI in childrenand adolescents every three years and annuallyif the initial examination has revealed a lesion with apotential for rapid growth and for developing complications(4). Brain neuroimaging will be repeatedevery time new neurological signs occur. If, during thebrain neuroimaging examinations, an evolving lesion is evidenced with the potential to cause obstructionby its location and size, it will suggest the diagnosis ofSEGA probable. SEGA clinical diagnosis is requiredif subependymal lesions associate neurological signs,papilledema and radiological signs of hydrocephalusor obvious increase in size (18). The diagnosis ofSEGA probable or SEGA involves more frequentneuroimaging monitoring in order to assess accuratelythe optimal timing of neurosurgical intervention.Annual MRI screening should be made with orwithout administration of contrast substance until theage of 20 years (18). In patients over 20 years of age,neuroimaging can be done at an interval of 2-3 years(7). Emergency brain imaging will be performed ifnew neurological signs appear.

Tracking the evolution of renal lesions is done byultrasonography. A normal initial ultrasound does notexclude subsequent occurrence of renal lesions (3). Itis recommended to repeat renal ultrasound every 1-3years, depending on the degree of disorder and the resultsof previous investigations (11). The repetition ofrenal ultrasound will be performed more frequently ifrenal lesions were large (more than 4 cm diameter) orwith high risk for growth. In case of new clinical signsof kidney distress, it will be completed with urgency.The specifi cation of the extension of renal damage canbe done by kidney MRI (6).

Cardiac rhabdomyomas are attributes of infantsand toddlers being present in about 75% of TS casesat this age. For TS patients for whom the initial cardiacevaluation revealed cardiac rhabdomyomas andclinical signs of cardiac dysfunction, echocardiographywill be repeated periodically according to theirclinical condition. In patients who showed no abnormalitieson initial testing, in the absence of clinicalsigns of cardiac dysfunction it is not necessary to repeatthe routine cardiac ultrasound examination (13).Most patients with TS and have Cardiac rhabdomyomasremain asymptomatic clinically, evolving towardsa progressive remission during the first years of life(6.19). But the cardiac ultrasound will be repeatedat any time if signs of cardiac dysfunction appear, irrespectiveof the patient’s age. Recent data point tothe possibility of occurrence or recurrence of cardiacrhabdomyomas in some TS cases in adolescence, thusregular repetition of cardiac ultrasound may be usefulat this age, especially when a teenager with TS showsunexplained signs of cardiac dysfunction (15).

Given that pulmonary lymphangioleiomyomatosis(LAM) occurs predominantly in adult womenwith TS, CT examination at this age is recommendedat least once (6, 13). The repetition of the examinationwill be made if signs of pulmonary dysfunction occuror if at the initial examination changes have beendetected.

Ophthalmic examination in TS will be repeatedafter three years of age if the patients develop signs ofeye disease. Repeated ophthalmologic assessment isnot required under the age of 3 years because retinalhamartomas are rarely present in this age group andhave a slow growth tendency over time (6).

3. Evaluation of relatives of the patients with tuberoussclerosis

In the presence of a child diagnosed with TS, parentalgenetic counselling should not be overlooked.The first step is to determine the modality of influencefrom the genetic point of view: familial or sporadic(de novo). Detecting TS signs in parents of analready aff ected individual is often a challenge due tothe diffi culty to diagnose the raw forms of disease,from subtle clinical signs. Sometimes even carefulclinical examination, investigations or neuroimaging(brain MRI), renal ultrasound, ophthalmic examinationcan not rule out the suspicion of TS. Even sporadiccases in which parents have no signs of diseaseat a rate of 1-2%, there is a risk of recurrence due toparental germ-line mosaicism.

Regarding the diagnostic value of different investigationsof subtle forms of TS, Cranial Magnetic ResonanceImaging examinations were found to be onlyoccasionally useful for diagnosis in parents with subtleclinical signs of TS and for other negative diagnostictests for the disease (20.6). In the study by Roach in1991 on parents of children with TS, out of 120 parentsinvestigated with cranial MRI (60 couples) only 8were diagnosed with TS. A single parent who had nosuggestive clinical examination for TS was confi rmedas having the disease after cranial MRI (20). Renalultrasonography is a more accessible method for thedetection of renal AML in these situations, being lessexpensive and easier to perform. Although no studyhas shown the advantage of using ultrasonographyin detecting the least aff ected individuals with TS, itis recommended for diagnostic testing of potentiallyaff ected family members (6). Molecular genetic testscould be used to identify potentially aff ected familymembers who do not meet clinical diagnostic criteria(11). But parental germ-line mosaicism can not beidentifi able either by using routine diagnostic tests or by genetic tests performed on DNA extracted fromleucocytes so that the indication of genetic testing inthese cases is limited (6).

4. Prenatal diagnosis of tuberous sclerosis.

The earliest visceral injuries in TS are cardiac rhabdomyomas.They emerge during the life in the womb,developing during embryogenesis and can be detectedbefore birth by routine foetal ultrasound starting with22nd gestation week. The detection of foetal TS lesionsraises suspicion, especially when multiple, even withouta family history of TS and requires a careful assessmentof foetal structures, especially the brain andkidneys in order to detect other signs of TS.

Prenatal highlighting of cortical tubers or SEGA has become possible with the development of neuroimagingmethods (21, 22, 23). They can be detected with ultrasonography since the 22nd gestation week. Some authors support the idea that they may be detected even in the second trimester of pregnancy (22).Brackley reports a case of antenatal diagnosis of TS by evidencing suggestive brain lesions since the 14th gestation week that was subsequently confirmed by foetal MRI examination performed at 28th gestation weekand by postnatal ultrasonographic examination (24), the disease being later confirmed by genetic testing.

The presence of foetal cerebral lesions in TS seems to be associated with adverse postnatal neurological development. Unlike cardiac rhabdomyomas that have the highest growth rate in utero and in the firstyear of life with subsequent, most often full regression,the cortical tubers and subependymal nodulesdetected before birth grow in number and size during childhood and are correlated with epilepsy, mental retardation and behavioural disorders associated withTS (23). Specialist literature reports only 21 casesof TS diagnosed before birth by associating cardiacrhabdomyomas with cerebral lesions. Prenatal adviceis diffi cult in these conditions. But parents should beinformed about the suspected diagnosis and possiblepostnatal development.



Although current TS diagnostic criteria are basedon their increased specifi city, for this disease, theirdiagnostic significance is different in different agegroups. ST clinical signs are age dependent, which restrictstheir usefulness in the diagnosis of ST in somepaediatric patients. The easiest method of diagnosis isa careful clinical examination for specific signs of theskin. From the multitude of skin signs in infants andyoung children hypomelanotic macules have greaterdiagnostic value. The other clinical signs are usually undetectable at this age, thus the ST-positive diagnosisin newborns and infants is often difficult. Inolder children it is easier to diagnose ST because theclinical examination, renal ultrasonography and neuroimaginghighlight various brain lesions characteristicof the disease. Patients suspected with ST, whodo not meet diagnostic criteria for certain, requireclinical and para-clinical periodic review to confi rm.Although TS evaluation guides are still to be compiled,the current data recommend regular assessmentof patients diagnosed with ST in order to track theprogress of the lesions detected at initial testing andprevent the complications.



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Correspondence to:
Carmen Burloiu “Al. Obregia” Hospital, Pediatric Neurology Clinic, Bucharest