Diagnosis Of Tuberous Sclerosis Complex Research Articles

Molecular and Functional Assessment of TSC1 and TSC2 in Individuals with Tuberous Sclerosis Complex

Tuberous sclerosis complex (TSC) is an autosomal dominant neurodevelopmental disorder and multisystem disease caused by pathogenic DNA alterations in the TSC1 and TSC2 tumor suppressor genes. A molecular genetic diagnosis of TSC confirms the clinical diagnosis, facilitating the implementation of appropriate care and surveillance. TSC1 and TSC2 encode the core components of the TSC, a negative regulator of the mechanistic target of rapamycin (MTOR) complex 1 (TORC1). Functional analysis of the effects of TSC1 and TSC2 variants on TORC1 activity can help establish variant pathogenicity. We searched for pathogenic alterations to TSC1 and TSC2 in DNA isolated from 116 individuals with a definite clinical diagnosis of TSC. Missense variants and in-frame deletions were functionally assessed. Pathogenic DNA alterations were identified in 106 cases (91%); 18 (17%) in TSC1 and 88 (83%) in TSC2. Of these, 35 were novel. Disruption of TSC activity was demonstrated for seven TSC2 variants. Molecular diagnostics confirms the clinical diagnosis of TSC in a large proportion of cases. Functional assessment can help establish variant pathogenicity and is a useful adjunct to DNA analysis.

Subependymal giant cell astrocytoma in the absence of tuberous sclerosis: a case report and literature review

Introduction and Importance: Subependymal giant cell astrocytoma (SEGA) is a benign intraventricular tumor classically arising near the Foramen of Monro. SEGAs almost always present as a component of tuberous sclerosis complex (TSC), an autosomal dominant disorder characterized by lesions in multiple organs. Case Presentation: A 16-year-old male with no significant past medical history presented with headache and dizziness. Imaging revealed intraventricular mass within the left lateral ventricle; the post-contrast image showed a contrast-enhanced lesion suggestive of SEGA. Following resection, histopathological analysis identified the lesion as a SEGA. However, on further workup, the patient was found not to meet the clinical criteria of TSC, which exemplifies a rare case of SEGA in the absence of a TSC diagnosis. Clinical Discussion: Tuberous sclerosis Complex (TSC) is a neurocutaneous disorder with a classical triad of seizures, mental retardation, and hamartomas in multiple organs and tissues. SEGA without TSC does not have multiorgan problems and hence doesn’t need ancillary testing but despite having a good outlook still needs follow-up for interval growth or recurrence. However, overall prognosis of isolated SEGA is better than SEGA associated with TSC. Conclusion: SEGA is commonly found to be associated with TSC. Although it is challenging to diagnose isolated SEGA, hence it is essential for physicians to be aware of the possibility of SEGA in the absence of other characteristics of TSC, which has many implications for a patient’s clinical course. This case report adds to current knowledge regarding isolated SEGA.

Molecular diagnosis of tuberous sclerosis complex in fetuses and infants: an institutional case series

ObjectiveWe describe the clinical and genetic characteristics of fetuses and infants diagnosed with tuberous sclerosis complex (TSC) in our centre, prenatally or neonatally, for a better understanding of the benefits...

When Epilepsy Takes Center Stage in Tuberous Sclerosis Complex: A Case Report from the Dermatology Hospital of Bamako

Tuberous Sclerosis Complex (TSC) is a multi-organ genetic disorder characterized by numerous hamartomas found in several organs, including the brain, heart, skin, eyes, kidneys, lungs, and liver. The responsible genes are TSC1 and TSC2, encoding hamartin and tuberin, respectively. The hamartin-tuberin complex inhibits the mammalian target of rapamycin pathway, which controls cell growth and proliferation. Variations in the distribution, number, size, and location of lesions lead to variations in the clinical syndrome, even among family members. Most features of Tuberous Sclerosis Complex become evident only in childhood, after the age of 3, limiting their usefulness for early diagnosis. Identifying patients at risk of severe manifestations is crucial. We report a case of Tuberous Sclerosis Complex inaugurated by epilepsy. It is a 10-year-old girl, a student, who came for consultation for a black spot on her left cheek evolving continuously for seven years. Two months later, this spot, asymptomatic solid lesions appeared on her face, gradually increasing in size and number. In her medical history, she has had convulsive seizures since the age of three, occurring at least five times a year, confirmed by an electroencephalogram. There is an oblong-shaped skin plaque measuring approximately 7x3 cm, erythematous, on the left cheek. Additionally, there are multiple normochromic angiofibromas affecting the nasal pyramid, nasolabial folds, and cheeks. The rest of the dermatological examination is unremarkable. The diagnosis of Tuberous Sclerosis Complex was made. In the presence or absence of cutaneous lesions, when faced with epilepsy in young children, we must always consider Tuberous Sclerosis Complex before ruling out other causes.

Have epilepsy outcomes changed for children with tuberous sclerosis complex in Queensland, Australia?

Historically, epilepsy has been the most frequently presenting feature of tuberous sclerosis complex (TSC). Advances in TSC health care have occurred over the past decade; thus, we studied whether TSC epilepsy outcomes have changed. A retrospective chart review was undertaken for all children with TSC in Queensland, Australia. Epilepsy outcome and TSC diagnosis data were extracted, and data were compared between children born before 2012 with those born in or after 2012. In this retrospective cohort, TSC diagnosis in children born in or after 2012 is now predominantly antenatal (51%, p < .05). Most patients with epilepsy are now known to have TSC before they develop epilepsy. Despite earlier TSC diagnosis, the frequency of epilepsy (85%) has not changed (p = .92), but diagnosis trends toward an earlier age (median = 3 months for patients born in or after 2012 vs. 5.5 months for those born before 2012, p = .23). Most (95%) patients had focal seizures as their initial clinical seizure type; it was rare (5%) for epileptic spasms (ES) to be the initial seizure type. The frequency of ES was lower in patients born in or after 2012 (36% vs. 50%, p = .27). Infantile (<24 months) onset ES was not associated with worse epilepsy outcome. Late onset ES was seen in 14%, and these patients hada lower rate of epilepsy remission. Lennox-Gastaut syndrome was seen in 7%. Febrile/illness-related status epilepticus occurred in 12% of patients, between 1 and 4 years of age. Despite many (78%) patients having multiple daily seizures at maximal seizure frequency, and 74% meeting criteria for treatment-refractory epilepsy, most patients achieved epilepsy remission (66%), either with epilepsy surgery (47%) or with age (53%). At the time of inclusion in this study, only 21% of patients had uncontrolled frequent (daily to 3 monthly) seizures and 14% had uncontrolled infrequent (3 monthly to <2 yearly) seizures. This study provides updated information that informs the counseling of parents of newly diagnosed pediatric TSC patients.

Delayed diagnosis of tuberous sclerosis complex: unveiling low-level TSC2 mosaicism using targeted next-generation sequencing.

Our case illustrates the clinical and diagnostic challenges presented by tuberous sclerosis complex (TSC), notably when the clinical signs are few and subtle, and the molecular pathology involves mosaicism and presence of a low percentage of the mutant variant in target tissues. The result aligns with previous findings that a significant number of individuals exhibit low-level mosaicism for a TSC1/TSC2 pathogenic variant without clinical recognition, and underscores the utility of next-generation sequencing technologies in the genetic study of TSC. Moreover, a deeper understanding of the molecular pathology of TSC-associated tumours improves genetic counselling and disease management.

Diagnosis of tuberous sclerosis in the prenatal period: a retrospective study of 240 cases and review of the literature.

Tuberous sclerosis complex (TSC) is a rare multisystemic disorder caused by a pathogenic variant in the TSC1 or TSC2 gene. A great phenotypic variability characterises TSC. The condition predisposes to the formation of hamartomas in various tissues, neurologic and neurodevelopmental disorders such as epilepsy, psychiatric disorders, as well as intellectual disability in 50%. TSC may be responsible for cardiac rhabdomyomas (CRs), cortical tubers, or subependymal nodules during foetal life. Detecting multiple CRs is associated with a very high risk of TSC, but the CR could be single and isolated. Few data exist to estimate the risk of TSC in these cases. We report the largest series of prenatal genetic tests for TSC with a retrospective study of 240 foetuses presenting with suggestive antenatal signs. We also provide a review of the literature to specify the probability of clinical or genetic diagnosis of TSC in case of detection of single or multiple CRs. Indeed, an early diagnosis is crucial for the counselling of the couple and their families. In this series, a definite diagnosis was assessed in 50% (41/82) of foetuses who initially presented with a single CR and 80.3% (127/158) in cases of multiple CRs. The prevalence of parental germinal mosaicism was 2.6% (3/115).

Incidence and Characteristics of Cerebellar Atrophy/Volume Loss in Children with Confirmed Diagnosis of Tuberous Sclerosis Complex.

Objectives: The goal of our study was to determine the incidence of cerebellar atrophy, assess the imaging findings in the posterior fossa and determine the incidence of hippocampal sclerosis in a cohort of pediatric patients with confirmed tuberous sclerosis complex (TSC). Material and methods: MRI studies of 98 TSC pediatric patients (mean age 7.67 years) were evaluated for cerebellar atrophy, cerebral/cerebellar tubers, white matter lesions, subependymal nodules, subependymal giant cell astrocytomas, ventriculomegaly, and hippocampal sclerosis. Clinical charts were revisited for clinical symptoms suggesting cerebellar involvement, for seizures and treatment for seizures, behavioral disorders and autism. Results: Cerebral tubers were present in 97/98 cases. In total, 97/98 had subependymal nodules, 15/98 had SEGA, 8/98 had ventriculomegaly and 4/98 had hippocampal sclerosis. Cerebellar tubers were found in 8/98 patients (8.2%), whereas cerebellar atrophy was described in 38/98 cases (38.8%). In 37/38 patients, cerebellar volume loss was mild and diffuse, and only one case presented with left hemi-atrophy. Briefly, 32/38 presented with seizures and were treated with anti-seizure drugs. In total, 8/38 (21%) presented with behavioral disorders, 10/38 had autism and 2/38 presented with seizures and behavioral disorders and autism. Conclusions: Several studies have demonstrated cerebellar involvement in patients with TSC. Cerebellar tubers differ in shape compared with cerebral tubers and are associated with cerebellar volume loss. Cerebellar atrophy may be focal and diffuse and one of the primary cerebellar manifestations of TSC, especially if a TSC2 mutation is present. Cerebellar degeneration may, however, also be secondary/acquired due to cellular damage resulting from seizure activity, the effects of anti-seizure drugs and anoxic-ischemic injury from severe seizure activity/status epilepticus. Further, prospective studies are required to identify and establish the pathogenic mechanism of cerebellar atrophy in patients with TSC.

Multiple recurrent supraventricular tachycardia in infantile tuberous sclerosis complex: management requiring triple-drug therapy.

We report the case of a female neonate admitted to the neonatal ICU with a rapid, narrow-complex tachyarrhythmia determined to be supraventricular tachycardia. Multimodality imaging and genetic testing confirmed a diagnosis of tuberous sclerosis complex with multiple cardiac rhabdomyomas. At 13 days of age, the patient was readmitted, exhibiting recurrent supraventricular tachycardia non-responsive to first-line treatment. Management required triple-drug therapy, whereafter the patient remained stable without recurrences. This is a rare report of supraventricular tachycardia in a functionally normal heart with the occurrence of supraventricular tachycardia due to structural abnormalities, with the possibility of multiple concealed accessory pathways.

Early Subclinical Status Epilepticus May Contribute to Developmental Delays in Infants With Tuberous Sclerosis Complex

We present a case of a newborn with a prenatally discovered cardiac rhabdomyoma leading to early genetic diagnosis of tuberous sclerosis complex (TSC). This early diagnosis prompted a presymptomatic electroencephalography (EEG) that revealed subclinical seizures meeting the definition for status epilepticus on day 1 of life. Antiseizure medications (ASMs), including vigabatrin, were started. The EPISTOP and PREVeNT trials demonstrated that early life initiation of vigabatrin may reduce the degree of refractory epilepsy and epileptic spasms (ES) in this population (TSC). Although neonatal seizures are a known entity in TSC, continuous neonatal EEG monitoring is not standard at birth. This case supports early consideration for neonatal EEG monitoring to identify and treat neonatal seizures, reduce risk for infantile spasms, and potentially improve neurodevelopmental outcomes.

Prevalence of Liver Steatosis in Tuberous Sclerosis Complex Patients: A Retrospective Cross-Sectional Study.

Introduction: Tuberous sclerosis complex (TSC) is a genetic disease caused by pathogenetic variants in either the TSC1 or TSC2 genes. Consequently, the mechanistic target of the rapamycin complex 1 (mTORC1) pathway, a regulator of cell growth, metabolism, and survival, becomes inappropriately activated, leading to the development of benign tumors in multiple organs. The role of mTORC1 in lipid metabolism and liver steatosis in TSC patients has not been well-studied, and clinical data on liver involvement in this population are scarce. Methods: We conducted a retrospective, cross-sectional study to compare liver steatosis in TSC patients with age-, sex-, BMI-, and diabetes status-matched controls. Participants with a definite diagnosis of TSC were recruited from the TSC clinic at UZ Brussel. Liver steatosis was quantified using the fat signal fraction from in-phase and out-of-phase MRI, with a threshold of ≥5% defining the presence of steatosis. We also evaluated the prevalence of liver angiomyolipomata in the TSC group and analyzed risk factors for both liver steatosis and angiomyolipomata. Results: The study included 59 TSC patients and 59 matched controls. The mean fat signal fraction was 4.0% in the TSC group and 3.9% in the controls, showing no significant difference (two-tailed Wilcoxon signed ranks test, p = 0.950). Liver steatosis was observed in 15.3% of TSC patients compared to 23.7% of the controls, which was not statistically significant (two-tailed McNemar test, p = 0.267). Liver angiomyolipomata were identified in 13.6% of the TSC cohort. Conclusions: Our study, describing in detail the liver phenotype of TSC patients, did not reveal a significant difference in the prevalence of MRI-assessed liver steatosis in a large cohort of TSC patients compared to a closely matched control group.

Neuropsychiatric Manifestations of Tuberous Sclerosis in a young adult male in a Psychiatry Hospital in Botswana: a case report

IntroductionTuberous sclerosis complex (TSC) is a disorder that affects multiple systems and was first described in 1880. Its symptoms include seizures, intellectual disability, and adenoma sebaceum. TSC is caused by mutations in the TSC1 and TSC2 genes and is inherited in an autosomal dominant manner.ObjectivesThis report highlights a case of a patient with an unusual psychological presentation evaluated in a psychiatric hospital.MethodsThe patient presented with psychotic features and abnormal behavior. A physical examination showed neurocutaneous lesions. After assessment a diagnosis of Tuberous sclerosis complex was confirmed through MRI Brain and genetic testing. Some of his relatives also showed similar neuropsychiatric symptoms.ResultsTuberous sclerosis complex is diagnosed based on TSC Clinical Consensus Group guidelines of 2012. Our patient fulfilled 4 of the major criteria and genetic testing also yielded a pathogenic variant. A TAND checklist (TSC-Associated Neuropsychiatric Disorders) is used to guide clinicians on areas to prioritize when managing TSC patients.Image:Image 2:Image 3:ConclusionsGiven that psychiatry may be the first contact for TSC patients, especially in low-resource settings. Patients referred to psychiatry, therefore, need to be thoroughly examined to exclude neuropsychiatric disorders, and a multidisciplinary team approach is vital in investigating and managing these cases.Disclosure of InterestNone Declared

The effect of pregnancy on renal angiomyolipoma; a world of knowledge to gain, specifically in women with TSC

BackgroundWomen are counseled preconceptionally about the potential risks of rAML progression and chance of complications during and due to pregnancy. However, a systematic search investigating the evidence on which this advice is based does not exist. The aim of this systematic review is to determine the effect of pregnancy on renal angiomyolipoma (rAML) size and risk of haemorrhage in patients with tuberous sclerosis complex (TSC).MethodsWe searched PubMed, EMBASE, Medline and ClinicalTrials.gov using terms for “renal angiomyolipoma” and “pregnancy”. English-language articles published between January 1st 2000, and December 31st 2020 of which full-text was available were included. The initial search resulted in 176 articles. After the screening process we included 45 case reports and 1 retrospective study. For the retrospective study we assessed the risk of bias using the Newcastle–Ottawa Scale. We included articles about renal AML and pregnancy with and without an established diagnosis of TSC. From these articles we recorded the rAML sizes and rAML complications.ResultsSeven case reports, from a total of 45 case reports, provided follow-up data on renal AML size (these were all cases of renal AML without a known diagnosis of TSC). Of these cases, renal AML size decreased in one patient, was stable in one patient, increased in three patients and fluctuated in two others. Renal AML size of women who suffered a haemorrhage were significantly larger (12.1 ± 4.6 cm) than rAMLs of women who did not suffer a haemorrhage (8.3 ± 3.2 cm). Data from the retrospective study showed no difference in renal complications between the women with and without a history of pregnancy. Haemorrhage occurred in 30% of the women with a history of pregnancy (n = 20) and in 11% in the patients without a history of pregnancy (n = 2), however this retrospective study had methodological limitations.ConclusionThe effect of pregnancy on renal AML size and complications in patients with TSC is unclear. More research is needed to determine the risk of pregnancy on TSC-associated kidney disease in TSC patient.

Identification of a complex intrachromosomal inverted insertion in the long arm of chromosome 9 as a cause of tuberous sclerosis complex in a Korean family.

Tuberous sclerosis complex (TSC) is an autosomal dominant multisystem disorder, caused by a loss-of-function of either TSC1 or TSC2 gene. However, in 10%-15% TSC patients there is no pathogenic variant identified in either TSC1 or TSC2 genes based on standard clinical testing. In this study, genome sequencing was performed for families with clinical diagnosis of TSC with negative results from TSC1 and TSC2 single-gene tests. Herein, we report a family presenting a classical TSC phenotype with an unusual, complex structural variant involving the TSC1 gene: an intrachromosomal inverted insertion in the long arm of chromosome 9. We speculate that the inverted 9q33.3q34.13 region was inserted into the q31.2 region with the 3'-end of the breakpoint of the inversion being located within the TSC1 gene, resulting in premature termination of TSC1. In this study, we demonstrate the utility of genome sequencing for the identification of complex chromosomal rearrangement. Because the breakpoints are located within the deep intronic/intergenic region, this copy-neutral variant was missed by the TSC1 and TSC2 single-gene tests and contributed to an unknown etiology. Together, this finding suggests that complex structural variants may be underestimated causes for the etiology of TSC.

Tuberous sclerosis complex, Clinic and pathology manifestations, Mini -review

Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous syndrome that affects almost all of the organs of the body, including the brain, heart, lungs, liver, and kidneys. Brain tumors in TSC patients include cortical tubers, subependymal nodules (SENs), and Subependymal giant cell astrocytomas (SEGAs). Seizures that occur in 92% of patients with TSC are an important cause of sudden deaths in them. Other organ involvement includes renal angiomyolipomas, lymphangioleiomyomatosis, cardiac rhabdomyomas, and cutaneous manifestations (hypomelanotic macules, angiofibroma, ungual fibromas, shagreen patch, and ‘confetti’ skin lesions). There is a criterion for tuberous sclerosis complex that consists of 11 major and 6 minor clinical features that diagnosis occurs based on it. The best way for a definitive diagnosis of TSC in a patient is by using genetic tests and histopathology. Immunohistochemistry is a helpful method in confirming the diagnosis of brain tumors in TSC. Immunostaining of SEGA shows positivity for GFAP and S-100 protein while neurofilament and synaptophysin are negative. Ki-67, which indicates nuclear proliferation, has a low proliferation index in immunostain. In an aggressive tumor, hydrocephalus, rising intracranial pressure and focal neurologic deficit, surgery is a necessity and can improve outcomes. Brain and kidney involvement in this disease is life-threatening. Brain involvement in these patients can lead to extensive neuropsychological complications, so the aim of this study is a concise review of the variable manifestations of this disease with a focus on the histopathological findings of brain involvement.

Subependymal giant cell astrocytoma, report of a rare case

Tuberous sclerosis complex (TSC) is a rare genetic disease that is inherited autosomal dominantly and may be associated with subependymal giant cell astrocytoma (SEGA) in 10-20% of cases. Different phenotypes are related to the form of lesions in different parts of the body, including skin, brain, kidneys, lungs, and heart. The age of the patient, the location of the tumor, and associated skin or neurological lesions may guide the pathologist for a definite diagnosis. Here we report a case of SEGA in an adolescent with TSC. Neurological clues including seizure and mental retardation, facial angiofibroma, renal mass, and histopathology examination of the brain tumor culminated in the diagnosis of TSC and SEGA.

Solitary atrial Rhabdomyoma in an infant with tuberous sclerosis: a case report and review of the literature

BackgroundDespite its rare incidence of 1/40,000, fetal cardiac rhabdomyoma (CR) represents the prevailing type of benign cardiac fetal tumors, which commonly affects the ventricles. Fetal CRs rarely occur in the right atrium. Thus, the presentation of atrial fibrillation and premature atrial contractions (PAC) due to a solitary cardiac rhabdomyoma is an extremely rare scenario. Our literature review found that only 2% (1 out of 61) of rhabdomyoma cases were found in the right atrium. The majority of fetal cardiac rhabdomyomas are associated with tuberous sclerosis complex (TSC).Case presentationA 7-day-old male neonate presented with arrhythmias and an atrial mass for further evaluation. Echocardiography revealed a hyperechoic, round, uniform right atrial mass (25 mm). An abdominal and testicular ultrasound showed multiple thin-walled cortical cysts in both kidneys and a scrotal hydrocele, respectively. His laboratory workup was insignificant except for hypomagnesemia. Electrocardiography revealed junctional rhythm and PACs with wave distortions. A brain magnetic resonance imaging scan revealed multiple subependymal lesions on the frontal and occipital horns of the lateral ventricles. These findings (Fig. 1), along with a family history of TSC, confirmed the diagnosis of TSC with associated CR. The patient was treated symptomatically with an anti-convulsant and monitored with regular follow-ups. Surgical resection was not required.ConclusionDespite CR’s predominance in the ventricles, a diagnosis of rhabdomyoma should be kept in mind in the presence of a solitary atrial mass and PACs. Physicians should evaluate systemic findings related to TSC and provide appropriate follow-up and family screening. Surgical resection is not always required, and symptom management can be achieved through medical treatment alone.

Is tuberous sclerosis complex-associated autism a preventable and treatable disorder?

Tuberous sclerosis complex (TSC) is a genetic disorder caused by inactivating mutations in the TSC1 and TSC2 genes, causing overactivation of the mechanistic (previously referred to as mammalian) target of rapamycin (mTOR) signaling pathway in fetal life. The mTOR pathway plays a crucial role in several brain processes leading to TSC-related epilepsy, intellectual disability, and autism spectrum disorder (ASD). Pre-natal or early post-natal diagnosis of TSC is now possible in a growing number of pre-symptomatic infants. We searched PubMed for peer-reviewed publications published between January 2010 and April 2023 with the terms "tuberous sclerosis", "autism", or "autism spectrum disorder"," animal models", "preclinical studies", "neurobiology", and "treatment". Prospective studies have highlighted that developmental trajectories in TSC infants who were later diagnosed with ASD already show motor, visual and social communication skills in the first year of life delays. Reliable genetic, cellular, electroencephalography and magnetic resonance imaging biomarkers can identify pre-symptomatic TSC infants at high risk for having autism and epilepsy. Preventing epilepsy or improving therapy for seizures associated with prompt and tailored treatment strategies for autism in a sensitive developmental time window could have the potential to mitigate autistic symptoms in infants with TSC.

Updated Genotype-Phenotype Correlations in TSC

Paolo Curatolo MD, Romina Moavero MD, Denis Roberto, Federica Graziola Seminars in Pediatric Neurology Volume 22, Issue 4, December 2015, Pages 259-273 Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by the development of widespread hamartomatous lesions in various organs, including brain, skin, kidneys, heart, and eyes. Central nervous system is almost invariably involved, with up to 85% of patients presenting with epilepsy, and at least half of patients having intellectual disability or other neuropsychiatric disorders including autism spectrum disorder. TSC is caused by the mutation in one of the 2 genes TSC1, at 9q34, and TSC2, at 16p13.3. They respectively encode for hamartin and tuberin, which form an intracellular complex inhibiting the mammalian target of rapamycin. Mammalian target of rapamycin overactivation following the genetic defect determines the cell growth and proliferation responsible for TSC-related lesions, as well as the alterations in neuronal excitability and synaptogenesis leading to epilepsy and neuropsychiatric disorders. A causative mutation for the disorder is identified in about 85% of patients with a clinical diagnosis of TSC. Mosaicism and technology limits likely explain most of the no mutation identified cases. This review confirms that patients with TSC2 mutations considered as a group usually present a more severe phenotype, characterized by higher number of tubers, earlier age at seizure onset and higher prevalence of intellectual disability. However, the clinical phenotype of the disease presents a high variability, thus making the prediction of the phenotype on an individual basis still challenging. The increasing application of new molecular techniques to subjects with TSC has the potential to significantly reduce the rate of patients with no mutation demonstrated and to identify an increasing higher number of mutations. This would hopefully allow a better characterization of higher risk mutations, which might help clinicians to plan individualized surveillance plans. Furthermore, the increasing availability of disease registries to collect clinical and genetics data of patients help to define more valid and clinically oriented genotype or phenotype correlations.

Early Diagnosis of Tuberous Sclerosis Complex: Prenatal Diagnosis.

Strong emphasis has been placed recently on early (4 postnatal months) detection of tuberous sclerosis complex and the introduction of antiepileptic treatment before seizure onset. This objective can be achieved prenatally: Cardiac rhabdomyomas and the major diagnostic tuberous sclerosis complex sign are detected during fetal ultrasound, and prenatal MR imaging allows detection of cerebral major manifestations: cortical tubers, subependymal nodules, and subependymal giant cell astrocytomas. We retrospectively reviewed 50 fetuses with ultrasound-detected cardiac tumors at 19-36 gestational weeks (median, 31 weeks). MR imaging with the use of 1.5T scanners was performed at 24-37 gestational weeks (median, 34 weeks). In 11 fetuses (22%), cardiac tumors remained the only criterion. In remaining 39 fetuses (78%), MR imaging revealed a prenatal diagnosis of tuberous sclerosis complex, having shown an additional 1-3 major criteria: subependymal nodules in all cases (39/39 = 100.0%), subependymal giant cell astrocytomas in 6 (6/39 = 15.4%), and cortical tubers in 24 (24/39 = 61.5%). Radial migration lines and cerebellar tuber, not published so far, were shown in 1 case each. A schedule of proper care of children with tuberous sclerosis complex can be established during the perinatal period due to education of women to report for mandatory ultrasound examinations during pregnancy, the good quality of ultrasound, and referral to MR imaging if a cardiac tumor is depicted on ultrasound. Gynecologists and pediatric cardiologists performing fetal ultrasound and radiologists performing prenatal MR imaging are a key to early diagnosis of tuberous sclerosis complex in many cases.