Tuberous Sclerosis Complex Consensus Conference Research Articles

Cutaneous and neurological profile of tuberous sclerosis complex in children: A case series and literature review

Tuberous sclerosis complex (TSC) is a rare genetic disease, belongs to the group of neurocutaneous syndrome. The consequence of genetic mutation is inadequate inhibition of the mammalian target of rapamycin (mTOR) signal pathway that results in inactivation of regulated cells growth and formation of dysgenic tissues/ hamartomas in multiple systems. The updated version of diagnostic criteria for TSC and management has been laid down after second International Tuberous Sclerosis Complex Consensus Conference (2012). To describe the clinico-neuroradiological profile and aspects of antiepileptic treatment of “ definite” TSC casesWe report a case series of four TSC cases attended in a teaching hospital. The “ definite” TSC cases are diagnosed by updated diagnostic criteria (2012) and data obtained retrospectively from records. We discuss the present series in the light of the current literature.We report three female and one male TSC patients. The “definite” TSC diagnosed by two major criteria - one or more cutaneous lesions and neuropathological lesion by neuroimaging. No family history of TSCs have been reported in the series.Hypomelanotic macules were observed in all (n=4) patients. Two TSC patients (n=2) had facial angiofibroma and one TSC had (n=1) shagreen patch. In neuroimaging studies, subependymal nodules were reported in three TSC patients (n=3) and one TSC had cortical dysplasias.The most common neurological manifestation in the TCS series is epilepsy; three TSC patients (n=3) had epilepsy. One TSC patient (n=1) did not present with epilepsy. Infantile spasms, tonic-clonic seizure and focal seizure were the phenotype of seizures. Vigabatrin, valporate and phenobarbitone have been prescribed in TSC patients. Scholastic performance was normal in one TSC patient (n=1) and subnormal in another patient(n=1).TSC -associated cutaneous lesions, the major features for diagnosis, develop in age-dependant manner. The prospective evaluation with a neuroimaging is an integral part of TSC management. Infantile spasm, focal seizure are the first manifested seizures with subtle presentation. First-contact physician must be well knowledgeable about updated 2012 diagnostic criteria, so timely management could be advocated. Vigabatrin is the first choice for infantile spsams in TSC patients as well as for focal seizures. Cognitive outcome/ scholastic performance may varies in TSC patients.

Clinical case of manifestation of tuberous sclerosis in a child

We have provided information about prevalence, etiology and pathogenesis of the tuberous sclerosis complex, a rare hereditary disease, caused by genetic mutation in TSC1 and TSC2 genes. Clinical and morphological manifestations of the disease were considered, according to updated diagnostic criteria, approved by the 2012 International Tuberous Sclerosis Complex Consensus Conference, as well as management of patients and prognosis were briefly described. Given that tuberous sclerosis is a rare disease with a polymorphic clinical picture (may affect the skin, central nervous system, kidneys, cardiovascular system, other organs and systems) and the manifestation at different times, and taking into account a low awareness of primary care physicians (especially pediatricians, who are more likely to face a child with the first signs of tuberous sclerosis) and specialist physicians, the correct diagnosis may often require years from the emergence of the first symptoms and lead to a deterioration in the health of patients and reducing the overall quality of life due to the development of complications that could be avoided. Our own clinical observation was performed of the tuberous sclerosis complex in a girl, who was treated in the MNPE “Children’s Regional Hospital” at Kirovohrad Regional Council, with a detailed description of the course of the disease, starting before the patient’s birth when the first symptoms were suspected during ultrasound screening, as well as the child’s current state; we have also presented the results of additional instrumental researches. Given that the disease in the girl was suspected before her birth, establishing the correct diagnosis did not require a lot of time, but not in all patients the disease manifests so early, therefore, it is important to preserve the alertness regarding tuberous sclerosis complex and other hereditary diseases.

Tuberous sclerosis complex patient fulfilling the criteria set by the 2012 international tuberous sclerosis complex consensus conference

Tuberous sclerosis complex (TSC) is a rare multisystem neurocutaneous disorder associated with the growth of benign tumors in different organs such as the brain, lungs, kidneys, heart, and eyes. The dermatological findings of this disorder are very common, present at early age and not easy to miss. The neurological manifestations of TSC include seizures, autism, and intellectual disabilities. Furthermore, intracranial abnormalities and hamartoma formation in the heart and other organs are found among sufferers. The clinical diagnostic criteria have been critically evaluated and updated in the 2012 International Tuberous Sclerosis Conference. The diagnosis is based on genetic criteria, clinical criteria, and various manifestations of skin, kidneys, lungs, and brain. The management involves multispecialty and multidisciplinary approaches. Here, we present a case of a 13-year-old female with characteristic clinical, radiological, and pathological features of TSC.

Tuberous Sclerosis Complex : A Case Report

Tuberous Sclerosis Complex (TSC) is an autosomal dominant inherited neurocutaneous disorder. Tuberous Sclerosis Complex is caused by mutations in tumor suppressor gene (TSC), both TSC1 and TSC2. In approximately two-thirds of cases neither parent has signs of TSC and the disease is caused by a de novo mutation. Tuberous Sclerosis Complex is classically identified by the Vort's triad in the presence of angiofibroma, mental retardation, and epilepsy. A 17-year-old woman with a major complaint of a facial bump that appeared at birth and got bigger when she reached puberty. There are white patches on the patient's body from birth. On the scalp obtained the presence of skin color plaque, while at the back and right knee obtained shagreen patch. Patientwas diagnosed with epilepsy and mental retardation by the pediatric department. No family history has the same complaints as patient. Histopathologic examination of facial bumps taken by shaving biopsy suggests the presence of hemangiomas. Based on the clinical diagnostic criteria from International Tuberous Sclerosis Complex Consensus Conference 2012, the patient meets two major criteria, macular hypopigmentation and shagreen patch so it is included in "definite diagnosis".

SPONTANEOUS PNEUMOTHORAX AS A PRESENTATION OF LYMPHANGIOLEIOMYOMATOSIS IN TUBEROUS SCLEROSIS COMPLEX

SESSION TITLE: Tuesday Medical Student/Resident Case Report Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: 10/22/2019 01:00 PM - 02:00 PM INTRODUCTION: Lymphangioleiomyomatosis (LAM) is a rare cystic lung disorder with a worldwide incidence of only 100,000 cases. However LAM is known to occur in 30 to 40% of adult women with Tuberous sclerosis. Tuberous sclerosis (TSC) is an autosomal dominant inherited disorder that occurs almost exclusively in women. While tuberous sclerosis is known to be associated with tumor development, seizures, intellectual disability and skin lesions in childhood, pulmonary lymphangioleimyomatosis is a finding that occurs primarily in adult patients and may go undiagnosed until serious complications occur. Here we present a case of acute hypoxic respiratory failure due to a large pneumothorax in an adult patient with known TSC prompting diagnosis of LAM. CASE PRESENTATION: 35 year old female with history of tuberous sclerosis complex with associated seizure disorder and cognitive disability who presents from home with complaints of dyspnea after suffering a seizure. Patient was in her usual state of health until that evening when she had a seizure that is not unusual for her. She then developed increased work of breathing that worsened throughout the night which prompted her mother to call EMS. At that time she had oxygen saturations in the 70s and was brought to the emergency department. She was found to have a left large spontaneous pneumothorax that was treated with a tube thoracostomy. After discharge, patient had a high resolution chest CT that showed bilateral diffuse cystic disease consistent with lymphangioleiomyomatosis and was diagnosed with TSC-LAM. DISCUSSION: LAM is a rare disorder characterized by abnormal proliferation of smooth muscle cells. Pulmonary disease associated with LAM presents with progressive dyspnea, pneumothorax and chylothorax. Symptoms of LAM in TSC patients typically occur in adulthood and onset may be slow and progressive, ultimately leading to respiratory failure. High resolution chest CT is recommended in symptomatic patients. Characteristic CT findings are bilateral, diffuse, thin-walled cysts. While spontaneous LAM is rare, LAM in TSC patients is a more common occurrence with reported total prevalence 1-3% and up to 35% in women with TSC. Some studies suggest screening asymptomatic women with TSC 18 years and older given its high prevalence in that population. Once a clinical diagnosis of TSC-LAM is made, obtaining VEGF-D level can confirm the diagnosis given its high specificity for TSC-LAM. 50% of LAM patients will have pneumothorax during the course of their disease with a high recurrence rate. CONCLUSIONS: This case highlights the importance of considering LAM in patients with TSC who present with spontaneous pneumothorax. Reference #1: Taveira-DaSilva AM, Pacheco-Rodriguez G, Moss J. The natural history of lymphangioleiomyomatosis: markers of severity, rate of progression and prognosis. Lymphat Res Biol. 2010;8(1):9-19. Reference #2: Cudzilo C.J., Szczesniak R.D. Lymphangioleiomyomatosis screening in women with tuberous sclerosis. Chest. 2013;144:578–585. Reference #3: Northrup H, Krueger DA, International Tuberous Sclerosis Complex Consensus Group. Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 Iinternational Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol. 2013;49(4):243-54. DISCLOSURES: No relevant relationships by Augusto Amaral Neto, source=Web Response No relevant relationships by Jack Amja, source=Web Response No relevant relationships by Jennifer Broess, source=Web Response

Tuberous sclerosis complex: review based on new diagnostic criteria

Tuberous sclerosis complex is a multisystemic, autosomal dominant genetic disorder with complete penetrance, that can evolve with hamartomas in multiple organs, such as skin, central nervous system, kidney and lung. Due to the wide phenotypic variability, the disease is often not recognized. Tuberous sclerosis complex affects one in 10,000 newborns and most patients are diagnosed during the first 15 months of life. The diagnostic criteria for tuberous sclerosis were reviewed in 2012, at the second International Tuberous Sclerosis Complex Consensus Conference. The diagnosis is based on genetic criteria, by the identification of inactivating pathogenic mutation of tumor suppressor genes TSC1 and TSC2, and clinical criteria, including cutaneous, renal, pulmonary, cardiac and neurological manifestations. The treatment of tuberous sclerosis complex consists, mainly, in management of the symptoms caused by hamartomas and in prevention of organ failure. Multidisciplinary approach is recommended, in order to obtain better clinical outcomes.

Tuberous Sclerosis Complex: An Update for Dermatologists.

Tuberous sclerosis complex is an autosomal dominant disorder that often manifests early in life with cutaneous features, and it is important that dermatologists who care for children remain up to date on its diagnosis and management. This article provides an update regarding the most recent guidelines for diagnosis published by the International Tuberous Sclerosis Complex Consensus Conference, which took place in 2012, and provides a brief literature review of the most recent developments in the treatment of skin findings.

Tuberous Sclerosis Complex Confirmed by Genetic Analysis: A Case Report

Tuberous sclerosis complex (TSC), also known as Bourneville disease, is an autosomal-dominant, neurocutaneous, multisystem disorder [1]. The underlying genetic cause is mutations in the TSC1 or TSC2 gene, which leads to overactivation of the mammalian target of rapamycin (mTOR) protein complex [2,3]. The main clinical features of the disease are facial sebaceous adenomas, epilepsy, and hypophrenia. Currently diagnosis is based on the criteria established at the 2012 International Tuberous Sclerosis Complex Consensus Conference [4]. mTOR inhibition is presently the main treatment [2,5]. It is still difficult to differentially diagnose TSC from other conditions such as neurofibromatosis, epilepsy, and mental disease, which makes genetic analysis important in its diagnosis.

Subependymal Giant Cell Astrocytoma: Diagnosis, Screening, and Treatment. Recommendations From the International Tuberous Sclerosis Complex Consensus Conference 2012

BackgroundTuberous sclerosis complex is an autosomal dominant disorder predisposing to the development of benign lesions in different body organs, mainly in the brain, kidney, liver, skin, heart, and lung. Subependymal giant cell astrocytomas are characteristic brain tumors that occur in 10% to 20% of tuberous sclerosis complex patients and are almost exclusively related to tuberous sclerosis complex. Subependymal giant cell astrocytomas usually grow slowly, but their progression ultimately leads to the occlusion of the foramen of Monro, with subsequent increased intracranial pressure and hydrocephalus, thus necessitating intervention. During recent years, secondary to improved understanding in the biological and genetic basis of tuberous sclerosis complex, mammalian target of rapamycin inhibitors have been shown to be effective in the treatment of subependymal giant cell astrocytomas, becoming an alternative therapeutic option to surgery. MethodsIn June 2012, an International Tuberous Sclerosis Complex Consensus Conference was convened, during which an expert panel revised the diagnostic criteria and considered treatment options for subependymal giant cell astrocytomas. This article summarizes the subpanel's recommendations regarding subependymal giant cell astrocytomas. ConclusionsMammalian target of rapamycin inhibitors have been shown to be an effective treatment of various aspects of tuberous sclerosis complex, including subependymal giant cell astrocytomas. Both mammalian target of rapamycin inhibitors and surgery have a role in the treatment of subependymal giant cell astrocytomas. Various subependymal giant cell astrocytoma–related conditions favor a certain treatment.

Tuberous Sclerosis Complex Surveillance and Management: Recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference

BACKGROUNDTuberous sclerosis complex is a genetic disorder affecting every organ system, but disease manifestations vary significantly among affected individuals. The diverse and varied presentations and progression can be life-threatening with significant impact on cost and quality of life. Current surveillance and management practices are highly variable among region and country, reflective of the fact that last consensus recommendations occurred in 1998 and an updated, comprehensive standard is lacking that incorporates the latest scientific evidence and current best clinical practices.METHODSThe 2012 International Tuberous Sclerosis Complex Consensus Group, comprising 79 specialists from 14 countries, was organized into 12 separate subcommittees, each led by a clinician with advanced expertise in tuberous sclerosis complex and the relevant medical subspecialty. Each subcommittee focused on a specific disease area with important clinical management implications and was charged with formulating key clinical questions to address within its focus area, reviewing relevant literature, evaluating the strength of data, and providing a recommendation accordingly.RESULTSThe updated consensus recommendations for clinical surveillance and management in tuberous sclerosis complex are summarized here. The recommendations are relevant to the entire lifespan of the patient, from infancy to adulthood, including both individuals where the diagnosis is newly made as well as individuals where the diagnosis already is established.CONCLUSIONSThe 2012 International Tuberous Sclerosis Complex Consensus Recommendations provide an evidence-based, standardized approach for optimal clinical care provided for individuals with tuberous sclerosis complex.

Clinical Correlates of Renal Angiomyolipoma Subtypes in 209 Patients: Classic, Fat Poor, Tuberous Sclerosis Associated and Epithelioid

Angiomyolipomas classically present radiographically as fat containing lesions but some fail to demonstrate fat content. Histologically confirmed angiomyolipomas uniformly follow a benign course but rare epithelioid variants of angiomyolipoma can recur and metastasize. We investigated the clinical, radiographic and histological characteristics of each angiomyolipoma subtype. Pertinent data were recorded for 209 patients surgically treated for angiomyolipoma in 219 kidneys from 1981 to 2007. Classic and fat poor angiomyolipomas were classified radiographically based on the presence or absence of fat and classified histologically based on the presence of triphasic, monophasic or epithelioid histology. Median radiographic size was 3.2, 4.9 and 10 cm in patients with a single angiomyolipoma (59% of patients), multiple angiomyolipomas and tuberous sclerosis (probable or definite), respectively. In these 3 groups 65%, 47% and 33% of lesions were not suspected radiographically (fat poor angiomyolipoma). Fat poor angiomyolipomas were more commonly single, smaller and in older patients. Triphasic histology was evident in 76% of angiomyolipomas with 16% demonstrating a predominance of 1 component and 8% containing epithelioid features. Despite potentially aggressive findings in 18% (eg presence within the perinephric fat, lymph node involvement) no angiomyolipoma recurred during a mean followup of 3.4 years (range 0 to 24). A total of 28 (13%) patients with angiomyolipoma had concomitant renal cell carcinoma. A surprisingly high number of resected angiomyolipomas was not suspected radiographically indicating the importance of precise radiographic characterization to minimize nephrectomy for fat poor angiomyolipoma, which should remain a research priority. In this sizeable single institution series no triphasic, monophasic or epithelioid angiomyolipoma recurred despite potentially aggressive findings in a substantial proportion of cases.

Value of fetal cerebral MRI in sonographically proven cardiac rhabdomyoma

Tuberous sclerosis complex (TSC) is an autosomal dominant phakomatosis associated with intracardiac rhabdomyomas. The aim of our study was to examine the value of cerebral MRI in diagnosing TSC in fetuses with intracardiac rhabdomyomas, applying the TSC Consensus Conference (TSCCC) criteria. In a prospective manner six consecutive fetuses with cardiac rhabdomyomas (21-34 weeks' gestation) underwent cerebral MRI. The MRI results were correlated with clinical follow-up at 10-34 months after birth, histology, and genetic data. In five of the six fetuses the diagnosis of TSC was established. In two of five fetuses MRI demonstrated cerebral manifestations of TSC that correlated well with severe epilepsy manifesting during the follow-up period. In another two of five fetuses MRI as well as clinical follow-up were normal. One of five pregnancies was terminated and histology demonstrated microscopically small subependymal nodules not demonstrated by MRI. The results of our study agree with the available literature that fetal MRI is sufficient for the detection of cerebral lesions in TSC and should be better promoted. The TSCCC criteria can also be applied to fetal MRI.

Renal manifestations in tuberous sclerosis complex

Purpose : The renal manifestations of tuberous sclerosis complex (TSC) are remarkably diverse, including polycystic kidney disease, simple renal cysts, renal cell carcinomas, and angiomyolipomas. All of these occur in children as well as adults in TSC. Angiomyolipomas, which can cause spontaneous life-threatening hemorrhages, are by far the most prevalent and the greatest source of morbidity. Here, we will address our experience, adding to the literature on pediatric patients with TSC requiring evaluation and treatment for renal manifestations. Methods : A retrospective analysis was made on 19 patients in whom TSC was diagnosed between May 2001 and Oct. 2005 at Severance Hospital. All patients had clinical diagnoses of TSC as defined by the 1998 tuberous sclerosis complex consensus conference. Results : The patients consisted of 13 boys and 6 girls with a mean age of 7.3 years (range 1 to 22). The renal disease associated with TSC included angiomyolipoma in nine patients (47.4 percent), renal simple cyst in one (5.3 percent), hydronephrosis in one (5.3 percent) patient. Eight patients (42.1 percent) presented with normal kidney contours at abdominal ultrasonography. One patient underwent renal replacement therapy due to chronic renal insufficiency after nephrectomy. Hemorrhage from angiomyolipoma was not detected. Conclusion : In our review of 19 cases of TSC, renal manifestations are reported in 57.9 percent of patients. Asymptomatic angiomyolipoma associated with TSC grow gradually, although severe hemorrhages are rare. So patients with TSC should be followed up with serial computerized tomography or abdominal ultrasonography. And also, renal function should be monitored conservatively.

LONG-TERM OUTCOME OF TRANSCATHETER EMBOLIZATION OF RENAL ANGIOMYOLIPOMAS DUE TO TUBEROUS SCLEROSIS COMPLEX

Complications from renal angiomyolipomas (AMLs) are common in patients with tuberous sclerosis complex (TSC) and tumors greater than 4 cm are more likely to cause symptoms. AMLs are the most common cause of death in adults with TSC. We present our long-term experience with transcatheter tumor embolization as a definitive treatment for AMLs due to TSC. A total of 16 patients with TSC between 7.5 and 47.2 years old with symptomatic or large (4 to 21 cm) AMLs underwent embolization. Followup consisted of periodic physician visits or telephone contacts and renal imaging. The 16 patients underwent 18 treatment sessions to embolize 27 tumors. There were no intraoperative complications. The post-embolization syndrome occurred in 11 individuals but all responded to medical management. Two individuals had an arterial aneurysm within a tumor. The AML size decreased in the 13 patients who were imaged 3 months after treatment, and the 7 patients who were imaged 3 to 9 years after treatment have shown no tumor regrowth. No renal failure or hemorrhage has developed in patients following embolization. Transcatheter embolization of symptomatic or large AMLs due to TSC prevents hemorrhage and renal loss. The treatment is minimally invasive, preserves renal function, and can be performed multiple times. All of the patients who underwent followup renal imaging after embolization showed decreased AML size, and none of the 16 patients has developed renal loss or renal insufficiency in these individuals. Embolization should be considered the initial treatment of choice for large or symptomatic AMLs.