Phenotypic distinctions between mosaic forms of tuberous sclerosis complex.

PURPOSE: To determine if mosaic tuberous sclerosis complex (TSC) can be stratified into subtypes that correspond with prognosis and extent of disease. METHODS: Next-generation sequencing of skin tumor and other samples was used to identify patients with mosaic pathogenic variants in TSC1 or TSC2. Extent of disease, onset age, and family history of TSC were determined through retrospective analysis of patient records. RESULTS: The median number of disease findings and age at penetrance differed between mosaic patients with asymmetrically distributed facial angiofibromas (4 findings, 24 years, n = 7), mosaic patients with bilaterally symmetric facial angiofibromas (8 findings, 10 years, n = 12), and germline TSC patients (10 findings, 4 years, n = 29). Cutaneous and internal organ involvement positively correlated in mosaic (R = 0.62, p = 0.005), but not germline (R = -0.24, p = 0.24) TSC. Variant allele fraction (VAF) in the blood (range: 0-19%) positively correlated with the number of major features (R = 0.55, p = 0.028). Five had a TSC2 variant identified in the skin that was below detection in the blood. One of 12 children from a mosaic parent had TSC. CONCLUSION: The phenotype of mosaic TSC ranged from mild to indistinguishable from germline disease. Patients with mosaicism and asymmetric facial angiofibromas exhibited fewer findings, later onset, and lower VAF in the blood.

Is It Feasible to Identify Natural Clusters of TSC-Associated Neuropsychiatric Disorders (TAND)?

BACKGROUND: Tuberous sclerosis complex (TSC) is a genetic disorder with multisystem involvement. The lifetime prevalence of TSC-Associated Neuropsychiatric Disorders (TAND) is in the region of 90% in an apparently unique, individual pattern. This "uniqueness" poses significant challenges for diagnosis, psycho-education, and intervention planning. To date, no studies have explored whether there may be natural clusters of TAND. The purpose of this feasibility study was (1) to investigate the practicability of identifying natural TAND clusters, and (2) to identify appropriate multivariate data analysis techniques for larger-scale studies. METHODS: TAND Checklist data were collected from 56 individuals with a clinical diagnosis of TSC (n = 20 from South Africa; n = 36 from Australia). Using R, the open-source statistical platform, mean squared contingency coefficients were calculated to produce a correlation matrix, and various cluster analyses and exploratory factor analysis were examined. RESULTS: Ward's method rendered six TAND clusters with good face validity and significant convergence with a six-factor exploratory factor analysis solution. The "bottom-up" data-driven strategies identified a "scholastic" cluster of TAND manifestations, an "autism spectrum disorder-like" cluster, a "dysregulated behavior" cluster, a "neuropsychological" cluster, a "hyperactive/impulsive" cluster, and a "mixed/mood" cluster. CONCLUSIONS: These feasibility results suggest that a combination of cluster analysis and exploratory factor analysis methods may be able to identify clinically meaningful natural TAND clusters. Findings require replication and expansion in larger dataset, and could include quantification of cluster or factor scores at an individual level.

Different MRI-defined tuber types in tuberous sclerosis complex: Quantitative evaluation and association with disease manifestations.

BACKGROUND: Tuberous sclerosis complex (TSC) is a rare genetic disorder with multisystem involvement. A magnetic-resonance (MRI) based classification of tubers into types A, B and C has been proposed. However, the relationship between different tuber types and their quantitative characteristics, also the non-neurological manifestations of TSC remains unknown. AIMS: To quantitatively evaluate different MRI-defined tuber types and to explore their relationships with major disease manifestations in patients with tuberous sclerosis complex. METHODS: We performed quantitative manual assessment of tubers visible on T1W, T2W/FLAIR images and DW/ADC maps of 20 patients with TSC. Tubers were classified into types A, B and C based on their signal intensity on MRI. General clinical information and quantitative tuber characteristics were evaluated. Between-group comparisons were made using the nonparametric Mann-Whitney U test with Bonferroni correction. RESULTS: In total, 20 patients with 770 tubers were evaluated. Type A tubers were most numerous followed closely by Type B tubers, whereas Type C tubers were relatively rare. Tuber size was markedly different among the three tuber types: it increased from Type A to Type B to Type C. Infantile spasms, generalized-tonic clonic seizures, poor seizure control, cardiac rhabdomyomas, SEGA and developmental delay were not associated with quantitative tuber characteristics. Increased total Type B tuber load was associated with early onset epilepsy, while individually larger Type A and Type B tubers were associated with the presence angiomyolipoma (AML) and renal cysts. CONCLUSIONS: MRI-defined tuber types differ significantly in their size and number. Larger total Type B tuber load and larger individual Type A and Type B tubers were found to be most associated with early seizure onset and renal angiomyolipomas, respectively. One possible explanation for the observed differences in the clinical phenotype based on MRI-defined tuber types is not the intrinsic qualitative distinctions between different tuber types, but rather their individual size and total tuber load.

Tuberous sclerosis complex: Imaging characteristics in 11 cases and review of the literature.

Tuberous sclerosis complex (TSC) is an uncommon multiorgan disorder that may present many and different manifestations on imaging. Radiology plays an important role in diagnosis and management, and can substantially improve the clinical outcome of TSC. Therefore, a comprehensive understanding of this disease is essential for the radiologist. The manifestations of TSC on computer tomography (CT) and magnetic resonance (MR) images were analyzed. Eleven patients with a clinical diagnosis of TSC were retrospectively reviewed. Central nervous system lesions included subependymal nodules (SENs) (11/11), subependymal giant cell astrocytomas (SEGAs) (2/11), cortical and subcortical tuber lesions (5/11), and white matter lesions (4/11). Of the 6 patients with abdominal scans, there were 6 cases of renal angiomyolipomas (AMLs), and one case of hepatic AMLs. Of the 4 patients undergoing chest CT, lung lymhangioleiomyomatosis (LAM) (2/4), and multiple small sclerotic bone lesions (2/4) were observed. Different modalities show different sensitivity to the lesion. Analysis of images should be integrated with patients' history in order to diagnose TSC.

RETINAL ASTROCYTIC HAMARTOMA: Optical Coherence Tomography Classification and Correlation With Tuberous Sclerosis Complex.

PURPOSE: To propose a classification of retinal astrocytic hamartoma based on spectral domain optical coherence tomography and correlate each class with systemic manifestations of tuberous sclerosis complex. METHODS: Retrospective chart review conducted at four international referral medical retina centers. There were 43 consecutive patients with an established diagnosis of tuberous sclerosis complex based on presence of at least 2 major or 1 major and 2 minor features of the diagnostic criteria. Clinical and spectral domain optical coherence tomography features regarding retinal astrocytic hamartoma were documented. RESULTS: The mean patient age at presentation was 16.2 years. The retinal astrocytic hamartoma was classified as Type I (n = 41), Type II (n = 25), Type III (n = 20), or Type IV (n = 12). Patients with Type II showed greater number of cutaneous fibrous plaques (odds ratio = 64.8; 92% confidence interval: 64.2-65; P < 0.001); those with Type III displayed higher incidence of subependymal giant-cell astrocytomas (odds ratio = 43.2; 95% confidence interval: 43.0-43.3; P < 0.001); and those with Type IV showed higher incidence of pulmonary lymphangiomyomatosis (odds ratio = 126; 95% confidence interval: 122-128; P < 0.001). CONCLUSION: Retinal astrocytic hamartoma can be classified into four morphologic groups, based on spectral domain optical coherence tomography. There are important systemic tuberous sclerosis complex correlations with each class.

Epilepsies associated with hippocampal sclerosis.

Hippocampal sclerosis (HS) is considered the most frequent neuropathological finding in patients with mesial temporal lobe epilepsy (MTLE). Hippocampal specimens of pharmacoresistant MTLE patients that underwent epilepsy surgery for seizure control reveal the characteristic pattern of segmental neuronal cell loss and concomitant astrogliosis. However, classification issues of hippocampal lesion patterns have been a matter of intense debate. International consensus classification has only recently provided significant progress for comparisons of neurosurgical and clinic-pathological series between different centers. The respective four-tiered classification system of the International League Against Epilepsy subdivides HS into three types and includes a term of "gliosis only, no-HS". Future studies will be necessary to investigate whether each of these subtypes of HS may be related to different etiological factors or with postoperative memory and seizure outcome. Molecular studies have provided potential deeper insights into the pathogenesis of HS and MTLE on the basis of epilepsy-surgical hippocampal specimens and corresponding animal models. These include channelopathies, activation of NMDA receptors, and other conditions related to Ca(2+) influx into neurons, the imbalance of Ca(2+)-binding proteins, acquired channelopathies that increase neuronal excitability, paraneoplastic and non-paraneoplastic inflammatory events, and epigenetic regulation promoting or facilitating hippocampal epileptogenesis. Genetic predisposition for HS is clearly suggested by the high incidence of family history in patients with HS, and by familial MTLE with HS. So far, it is clear that HS is multifactorial and there is no individual pathogenic factor either necessary or sufficient to generate this intriguing histopathological condition. The obvious variety of pathogenetic combinations underlying HS may explain the multitude of clinical presentations, different responses to clinical and surgical treatment. We believe that the stratification of neuropathological patterns can help to characterize specific clinic-pathological entities and predict the postsurgical seizure control in an improved fashion.

MRI findings reveal three different types of tubers in patients with tuberous sclerosis complex.

Cortical tubers are very common in tuberous sclerosis complex (TSC) and widely vary in size, appearance and location. The relationship between tuber features and clinical phenotype is unclear. The aim of the study is to propose a classification of tuber types along a spectrum of severity, using magnetic resonance imaging (MRI) characteristics in 35 patients with TSC and history of epilepsy, and to investigate the relationship between tuber types and genetics, as well as clinical manifestations. Three types of tubers were identified based on the MRI signal intensity of their subcortical white matter component. (1) Tubers Type A are isointense on volumetric T1 images and subtly hyperintense on T2 weighted and fluid-attenuated inversion recovery (FLAIR); (2) Type B are hypointense on volumetric T1 images and homogeneously hyperintense on T2 weighted and FLAIR; (3) Type C are hypointense on volumetric T1 images, hyperintense on T2 weighted, and heterogeneous on FLAIR characterized by a hypointense central region surrounded by a hyperintense rim. Based on the dominant tuber type present, three distinct patient groups were also identified: Patients with Type A tuber dominance have a milder phenotype. Patients with Type C tuber dominance have more MRI abnormalities such as subependymal giant cell tumors, and were more likely to have an autism spectrum disorder, a history of infantile spasms, and a higher frequency of epileptic seizures, compared to patients who have a dominance in Type B tubers, and especially to those with a Type A dominance.

Tuberous sclerosis complex: a review of the management of epilepsy with emphasis on surgical aspects.

OBJECTIVE: To review the management of epilepsy in patients with tuberous sclerosis complex (TSC) with an emphasis on surgical aspects, neuropathology, and pathogenesis. METHODS: Review of the literature and presentation of the authors' experience of surgery for refractory epilepsy in patients with TSC. RESULTS: TSC is a multisystem genetic disorder with variable phenotypic expression. TSC results from a mutation in the TSC1 gene on chromosome 9, which codes for hamartin, or in the TSC 2 gene on chromosome 16 which codes for tuberin. The majority of the patients have TSC as a result of spontaneous genetic mutations while in one-third of the patients, the disorder is inherited in an autosomal dominant manner. Epilepsy is the most common neurological complication, and up to 80-90% of individuals with TSC develop epilepsy at some point in their lifetime. The onset of epilepsy is typically in early childhood. Infantile spasms are a very common early seizure type although partial seizures may occur. Developmental delay, intellectual impairment, autism, behavioral problems, and neuropsychiatric disorders occur commonly in individuals with TSC and may be associated with poorly controlled epilepsy. Antiepileptic drugs are the first-line management for epilepsy but the ketogenic diet, resection of one or more tubers, corpus callosotomy, and vagus nerve stimulation are other therapeutic options for individuals with poorly controlled epilepsy.

Mutational analysis of TSC1 and TSC2 in Korean patients with tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by a broad phenotypic spectrum that includes seizures, mental retardation, renal dysfunction and dermatological abnormalities. TSC is caused by mutations affecting either of the tumor-suppressor genes TSC1 and TSC2. At least 495 mutations of TSC1 and TSC2 have been reported. Twenty-two males and 22 females who were diagnosed with TSC at the Seoul National University Children's Hospital between 1982 and 2002 were enrolled in the study. Forty-four patients were from different families and included nine familial cases and 35 sporadic cases. Denaturing high performance liquid chromatography and DNA sequencing analysis of TSC1 and TSC2 revealed 13 types of mutations (30%). One novel mutation of TSC1 and nine novel mutations of TSC2 were identified. The TSC1 mutation and one of the nine TSC2 mutations were missense mutations and seven of the nine TSC2 mutations caused truncation of proteins. One novel single nucleotide substitution was identified at the consensus splicing donor site of exon 39 (c.5,069-1G>A). This mutation is predicted to cause a splicing error. Of the TSC2 mutation loci, the correlation with cardiac rhabdomyoma was more significant when the mutation was in the C-terminal part of tuberin than the N-terminal part. This is the first extensive mutational analysis of TSC1 and TSC2 in Korean TSC patients.

Síndrome de Brooke-Spiegler simulando esclerosis tuberosa / Brooke-Spiegler Syndrome simulting tuberose sclerosis

Se presenta una mujer de 18 años de edad sin antecedentes familiares ni personales de interés que consulta por tricoepiteliomas en cara y cilindromas en cuero cabelludo. En el examen físico hallamos máculas hipomelanóticas en abdomen y en muslo, y un fibroma periungueal en el 5º dedo de pie derecho que obligaron a descartar otras entidades. Se realizó el diagnóstico de síndrome de Brooke-Spiegler, y se revisan los diagnósticos diferenciales de papulosis faciales

[Clinical and molecular epidemiology of lymphangioleiomyomatosis and pulmonary pathology in tuberous sclerosis]. / Epidémiologie clinique et moléculaire de la lymphangioleiomyomatose et de l'atteinte pulmonaire de la sclérose tubéreuse.

Pulmonary lymphangioleiomyomatosis is characterized by a proliferation of abnormal smooth muscle cells in peribronchial, perivascular and perilymphatic areas leading to cystic destruction of the pulmonary parenchyma. Recent clinical series of LAM have been helpful in better describing the various clinical and radiological forms of the disease, although our understanding of the pathophysiological mechanisms of LAM remains very limited. Significant progress has been noted in recent years with the discovery of probable antigenic and genetic similarities between pulmonary lymphangioleiomyomatosis, Bourneville tuberous sclerosis and renal angiomyolipoma. The proliferating cells in LAM share with normal smooth muscle cells their reactivity with desmine, vimentin and actin but certain are different by their reactivity with the monoclonal antibody HMB45, a common antigen marker of melanocyte differentiation cells, clear-cell lung carcinomas or renal angiomyolipomas. A loss heterozygosity in the region of the TSC2 gene in renal angiomyolipomas has been demonstrated in association with pulmonary lymphangioleiomyomatosis. The TSC2 gene is particularly implicated in the pathogenesis of Bourneville tuberous sclerosis.

[Birt-Hogg-Dubé syndrome as an expression of tuberous sclerosis. Apropos of 2 personal cases in 2 sisters]. / El síndrome de Birt-Hogg-Dubé como forma de expresión de la esclerosis tuberosa. A propósito de dos observaciones personales en dos hermanas.

Two familial observations of Birt-Hogg-Dubé syndrome are reported. In fact they were cases of tuberous sclerosis. The authors comment that probably this syndrome is an expression form of tuberous sclerosis.

[Phacomatoses. Pathogenesis - Classification - Vascular aspects]. / Les phacomatoses. Pathogénie - Classification - Aspects vasculaires.

The pathogenesis of the phacomatoses, developmental diseases of the embryonic plates, permits an understanding of the different manifestations which characterize these disorders. This pathogenesis also constitutes the best basis for a rational classification. The author sets out the main features of this pathogenesis and its practical applications, and then considers the principal vascular aspects of the phacomatoses, especially in Osler-Rendu disease, Blue Rubber Bleb Naevi, Mafussi's syndrome, the haemangioblastomatoses, Bailey's glomangiomatosis, the Louis-Bar syndrome, Struge-Weber angiomatosis, the syndrome of Bonnet-Dechaume and Blanc, Cobb's syndrome, the angio-osteo-hypertrophic syndromes, von Recklinghausen's neurofibromatosis, Bourneville's tuberous sclerosis, and the melanic phacomatoses.

[General classification and limited nosology of the phacomatoses]. / Classification générale et limites nosologiques des phacomatoses

The authors suggest a new classification of phacomatoses based on the dysembryoplastic concept of these disorders, which are blastomas of the germ layers. Three main groups are described : ectoblastic, mesoblastic and entoblastic phacomatoses. The diffuse forms are often familial and very evolutive and are contrasted with the regional forms which are commonly sporadic and not very evolutive. The limits of the phacomatoses are finally specified.