Diagnostic Criteria For Tuberous Sclerosis Research Articles

Tuberous Sclerosis–Associated Renal Neoplasm

A man in his thirties presented with bilateral renal masses and well-controlled hypertension. He had a history of resection of a brain lesion in early childhood. Imaging studies did not reveal cystic lung disease. Bilateral nephrectomies were performed because of end-stage renal disease, and both kidneys were replaced by fibrotic and lobulated masses. Histopathological examination revealed extensive involvement by angiomyolipoma bilaterally. What syndrome should this patient be screened for, and what are some other common associated features?a.Birt-Hogg-Dubé syndrome: benign tumors of the skin and spontaneous pneumothorax secondary to cystic lung diseaseb.von Hippel-Lindau disease: central nervous system hemangioblastomas and pheochromocytomasc.Li-Fraumeni syndrome: osteosarcoma, adrenocortical carcinoma, and central nervous system tumorsd.Tuberous sclerosis complex: subependymal giant cell astrocytomas, cardiac rhabdomyomas, and lymphangioleiomyomatosis Answer: d. Tuberous sclerosis complex: subependymal giant cell astrocytomas, cardiac rhabdomyomas, and lymphangioleiomyomatosis Tuberous sclerosis complex is associated with renal manifestations including renal angiomyolipomas and a wide spectrum of renal neoplasia that have variable morphological features.1Guo J. Tretiakova M.S. Troxell M.L. et al.Tuberous sclerosis-associated renal cell carcinoma: a clinicopathologic study of 57 separate carcinomas in 18 patients.Am J Surg Pathol. 2014; 38: 1457-1467Crossref PubMed Scopus (129) Google Scholar Two major diagnostic features or a combination of 1 major and at least 2 minor diagnostic features are required to establish a clinical diagnosis.2Henske E.P. Jóźwiak S. Kingswood J.C. Sampson J.R. Thiele E.A. Tuberous sclerosis complex.Nat Rev Dis Primers. 2016; 2: 16035Crossref PubMed Scopus (214) Google Scholar Major diagnostic criteria for tuberous sclerosis include hypomelanotic macules (≥3 of ≥5 mm in diameter), angiofibromas (≥3) or fibrous cephalic plaques, ungual fibromas (≥2), shagreen patches, multiple retinal hamartomas, cortical dysplasias, subependymal nodules, subependymal giant cell astrocytomas, cardiac rhabdomyomas, lymphangioleiomyomatosis, and angiomyolipomas (≥2). Tuberous sclerosis complex is an autosomal dominant disorder associated with loss-of-function alterations in TSC1 and TSC2 genes (for expansion of gene symbols, use search tool at www.genenames.org). von Hippel-Lindau disease, secondary to germline alterations in the VHL gene, is associated with clear cell renal cell carcinoma, central nervous system hemangioblastoma, and pheochromocytoma. Li-Fraumeni syndrome, secondary to germline alterations in the TP53 gene, is associated with osteosarcoma, adrenocortical carcinoma, and central nervous system tumors. Finally, Birt-Hogg-Dubé syndrome, secondary to germline alterations in the FLCN gene, is associated with hybrid renal tumors, benign tumors of the skin, and spontaneous pneumothorax secondary to cystic lung disease.

Scalp EEG spikes predict impending epilepsy in TSC infants: A longitudinal observational study.

ObjectiveTo determine if routine electroencephalography (EEG) in seizure‐naive infants with tuberous sclerosis complex (TSC) can predict epilepsy and subsequent neurocognitive outcomes.MethodsForty infants 7 months of age or younger and meeting the genetic or clinical diagnostic criteria for tuberous sclerosis were enrolled. Exclusion criteria included prior history of seizures or treatment with antiseizure medications. At each visit, seizure history and 1‐hour awake and asleep video‐EEG, standardized across all sites, were obtained until 2 years of age. Developmental assessments (Mullen and Vineland‐II) were completed at 6, 12, and 24 months of age.ResultsOf 40 infants enrolled (mean age of 82.4 days), 32 completed the study. Two were lost to follow‐up and six were treated with antiepileptic drugs (AEDs) due to electrographic seizures and/or interictal epileptiform discharges (IEDs) on their EEG studies prior to the onset of clinical seizures. Seventeen of the 32 remaining children developed epilepsy at a mean age of 7.5 months (standard deviation [SD] = 4.4). Generalized/focal slowing, hypsarrhythmia, and generalized/focal attenuation were not predictive for the development of clinical seizures. Presence of IEDs had a 77.3% positive predictive value and absence a 70% negative predictive value for developing seizures by 2 years of age. IEDs preceded clinical seizure onset by 3.6 months (mean). Developmental testing showed significant decline, only in infants with ongoing seizures, but not infants who never developed seizures or whose seizures came under control.SignificanceIEDs identify impending epilepsy in the majority (77%) of seizure‐naive infants with TSC. The use of a 1‐hour awake and asleep EEG can be used as a biomarker for ongoing epileptogenesis in most, but not all, infants with TSC. Persistent seizures, but not history of interictal epileptiform activity or history of well‐controlled seizures, correlated with low scores on the Vineland and Mullen tests at 2 years of age.

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.

What's new with common genetic skin disorders?

Common genetic disorders such as neurofibromatosis type I (NF1), tuberous sclerosis, basal cell nevus syndrome (BCNS), incontinentia pigmenti, and X-linked ichthyosis have recognizable, cutaneous features. In children, cases often present without a prior diagnosis. This review highlights new information about diagnostic signs and care of affected patients. Disruption of key regulatory pathways causes disorders such as BCNS, NF1, and tuberous sclerosis. The discovery of associated mutations in these pathways has led to molecular targeted therapies. For example, use of drugs such as vismodegib in BCNS and rapamycin in tuberous sclerosis complex is being studied. Also, patient review has refined the diagnostic criteria for tuberous sclerosis and incontinentia pigmenti and expanded the phenotype of X-linked ichthyosis. Preimplantation genetic diagnosis for disorders such as NF1 and incontinentia pigmenti is available. Identification of nevus anemicus or juvenile xanthogranuloma in a young child may lead to an early diagnosis of NF1. Rapamycin offers noninvasive treatment for problematic skin lesions in pediatric patients with tuberous sclerosis. Providers can give early advice to affected families that reproductive technologies such as preimplantation genetic diagnosis are a consideration for future pregnancies.

P139 – 3023: First epileptic seizures in children followed for cardiac rhabdomyomas and tuberous sclerosis

Objective Tuberous sclerosis (TSC) is a congenital multisystemic disease affecting also nervous system; including early onset of epilepsy and risk of mental retardation. Cardiac rhabdomyoma (CR) is the earliest diagnostic criterion of TSC. It belongs to the major diagnostic criteria of TSC. Finding of CR enables prenatal/early postnatal identification of children at risk of TSC and allows to follow up these children from early neonatal period. Methods 29 children with CR were followed up from 01/2002 to 01/2015 from neonatal age. Several clinical, EEG and neuroimaging characteristics were evaluated including age at seizure onset, types of seizures and psychomotor development in these children. Results Our series included 15 boys and 14 girls. In 26/29 (90%) children with CR the diagnosis of TSC was established. Two children with TSC died. Twenty-three (23/26, 88%) children with TSC have developed epilepsy, 18/23 (70%) of them within the first year of life and seizure types consisted of partial motor seizures (13/23), infantile spasms (5/23) and other generalized types of seizures (5/23). Early administration of antiepileptic drug(s) resulted in complete seizure control in 13/23 patiens. Mental retardation was proven in 14/26 TSC children; always in subjects with early manifestation of epilepsy. In 3/29 children with CR, the diagnosis of TSC was not established; no one of them developed epilepsy. Conclusion 1) Epilepsy starts in children with TSC usually before the first year of life. Seizures most often include partial motor, less frequently infantile spasms and other generalized types of seizures. 2) Mental retardation dominates in TSC children with early manifestation and difficultto-compensated epilepsy. 3) Children with CR who did not fulfill diagnostic criteria for TSC, have not developed epilepsy. 4) We suppose positive impact of early initiated antiepileptic treatment on the psychomotor development of these children with TSC. Supported by project 00064203-IG6005, project EPISTOP

Self-assessment questions: Tuberous sclerosis: from gene to targeted therapy

1. The following are part of the current diagnostic criteria for tuberous sclerosis: 1. Seizures 2. Intellectual disability 3. Angiomyolipoma 4. Shagreen patch 5. Lymphangioleiomyomatosis 2. Which statement(s) describe the genetics of tuberous

Unilateral eyelid angiofibroma with complete blepharoptosis as the presenting sign of tuberous sclerosis

Tuberous sclerosis is a multisystem autosomal-dominant disease characterized by hamartomatous growths in the brain, skin, kidneys, eyes, and heart, but it may affect almost any organ. Retinal hamartomas are 1 of the major diagnostic criteria for tuberous sclerosis and occur in approximately 50% of patients. Nonretinal findings include angiofibromas of the eyelid, strabismus, and pseudo-colobomas of the lens and iris. We report a case of a newborn with congenital eyelid angiofibroma mimicking complete congenital blepharoptosis that was revealed by central nervous system imaging to be part of the tuberous sclerosis complex.

Common Genodermatoses: What the Pediatrician Needs to Know

Recognizing the patterns of the skin findings and establishing the correct diagnosis can also help avoid subjecting patients to unnecessary tests, such as lumbar punctures to rule out herpes simplex virus in neonates with a Blaschkoid distribution of vesicles in incontinentia pigmenti. The cutaneous features of genetic disorders provide important clues to the underlying diagnoses for conditions such as tuberous sclerosis, neurofibromatosis, incontinentia pigmenti, and help direct the diagnostic evaluation and health supervision in those individuals.

Pigmentary disorders: update on neurofibromatosis-1 and tuberous sclerosis.

Pigmentary disorders are a common finding in primary care pediatric practice. Tuberous sclerosis and neurofibromatosis type 1 are two pigmentary disorders that have had many changes in their diagnostic and therapeutic approach. This review focuses on the significant advances in the past few years in the genetics and diagnostic criteria of these disorders. A review of the clinical presentation of neurofibromatosis is provided along with the revised diagnostic criteria for tuberous sclerosis. A logical approach to testing the tuberous sclerosis patient and his or her family is included.

Tuberous Sclerosis in Western Sweden

To study the prevalence of tuberous sclerosis in children and adolescents. Previously published diagnostic criteria for tuberous sclerosis were used. All physicians likely to encounter young patients with tuberous sclerosis were contacted by way of a screening questionnaire. The study was performed in a circumscribed geographic area (western Sweden). The sample was population based. However, only patients with such severe and early symptoms that referral to a physician had been considered necessary and relatives of these patients with tuberous sclerosis could be included. This was because there is currently no diagnostic marker for tuberous sclerosis that could be used as a screening tool. The peak prevalence (one in 6800 individuals) for tuberous sclerosis was found in the 11- to 15-year-old age group. For the whole age cohort, 0 to 20 years, the prevalence was one in 12,900 individuals. The prevalence for the school-age group was the highest ever reported in the literature on tuberous sclerosis. However, it is likely that the true prevalence of tuberous sclerosis in the general population is even higher.

Diagnosis of Tuberous Sclerosis-Reply

In Reply.— Dr Steffen has raised several important points in his letter. We concur that the term adenoma sebaceum reflects more historical interest than histological accuracy. Angiofibroma is the more appropriate term. While Dr Steffen indicates that we claim that the [sic] adenoma sebaceum and periungual fibromas (ie, angiofibromas) are diagnostic of the tuberous sclerosis complex, we actually made no such specific statement ourselves but referred to the diagnostic criteria for tuberous sclerosis established and published by Gomez,1 which are the accepted standards. While these diagnostic criteria of Gomez may be viewed as arbitrary and subject to further studies for better definition, none of our probands had equivocal findings. All had involvement of at least two major organ systems; therefore, none had only angiofibromas or periungual fibromas. Similarly, all but one of the four previously unsuspected heterozygous parents had involvement of two or more organ systems. The only