Tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is a neurocutaneous syndrome that can affect the brain, skin, eyes, kidneys, heart, and lungs. TSC alters cellular proliferation and differentiation, resulting in hamartomas of various organs, tumor formation, and altered neuronal migration. The phenotype is highly variable. Most individuals have seizures, commonly including infantile spasms, and there is variable intellectual disability and autism. Neonates can present with cardiac failure due to intracardiac rhabdomyomas. The likelihood of renal angiomyolipomas increases with age, and renal disease is the most common cause of death in adults with TSC. Pulmonary involvement occurs predominantly in women and carries a high morbidity and mortality. TSC is inherited as an autosomal dominant trait, but spontaneous mutations are common. A mutation of either TSC1 on chromosome 9 or TSC2 on chromosome 16 leads to dysfunction of hamartin or tuberin, respectively. These two proteins form a functional complex that modulates the mammalian target of rapamycin (mTOR) pathway. Medications that inhibit mTOR are being used to treat TSC-related tumors, and current studies are investigating whether these agents could alleviate other TSC complications. Consensus statements guide identification and optimal management of many of the TSC-related complications at diagnosis and throughout the lifespan. A multidisciplinary approach is necessary for optimal management of individuals with TSC.

[1]  J. Stephenson,et al.  SEIZURES AND INTELLECTUAL DISABILITY ASSOCIATED WITH TUBEROUS SCLEROSIS COMPLEX IN THE WEST OF SCOTLAND , 1992, Developmental medicine and child neurology.

[2]  E. Roach,et al.  Detection of tuberous sclerosis in parents by magnetic resonance imaging , 1991, Neurology.

[3]  M. Tynan,et al.  Cardiac rhabdomyomata as a marker for the antenatal detection of tuberous sclerosis. , 1983, Journal of medical genetics.

[4]  M. Sahin,et al.  Clinical Presentation and Diagnosis of Tuberous Sclerosis Complex in Infancy , 2008, Journal of child neurology.

[5]  E. Walsh,et al.  Cerebral embolism resulting from an intracardiac tumor in tuberous sclerosis. , 1986, Pediatric neurology.

[6]  J. Wheless,et al.  Genotype/phenotype correlation in 325 individuals referred for a diagnosis of tuberous sclerosis complex in the United States , 2007, Genetics in Medicine.

[7]  C. Shepherd,et al.  A prevalence study of autism in tuberous sclerosis , 1993, Journal of autism and developmental disorders.

[8]  E. Roach Diagnosis and Management of Neurocutaneous Syndromes , 1988, Seminars in neurology.

[9]  H. Northrup,et al.  Tuberous Sclerosis Complex Consensus Conference: Revised Clinical Diagnostic Criteria , 1998, Journal of child neurology.

[10]  H. Vinters,et al.  Co‐Localization of TSC1 and TSC2 Gene Products in Tubers of Patients with Tuberous Sclerosis , 1999, Brain pathology.

[11]  David J. Kwiatkowski,et al.  Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[12]  J. Delleman,et al.  Tuberous sclerosis: The incidence of sporadic cases versus familial cases , 1980, Brain and Development.

[13]  J. Seward,et al.  Tuberous sclerosis and cardiac rhabdomyoma. , 1995, The American journal of cardiology.

[14]  J. Gibbs The heart and tuberous sclerosis. An echocardiographic and electrocardiographic study. , 1985, British heart journal.

[15]  N. Dahdah,et al.  Use of mTOR inhibitor everolimus in three neonates for treatment of tumors associated with tuberous sclerosis complex. , 2015, Pediatric neurology.

[16]  D. Gutmann,et al.  Tuberous Sclerosis Complex: Pathogenesis, Diagnosis, Strategies, Therapies, and Future Research Directions , 2004, Journal of child neurology.

[17]  H. Northrup,et al.  Germ-line mosaicism in tuberous sclerosis: how common? , 1999, American journal of human genetics.

[18]  P. Huttenlocher,et al.  Fine structure of cortical tubers in tuberous sclerosis: A Golgi study , 1984, Annals of neurology.

[19]  D. Laster,et al.  Diagnosis of Symptomatic and Asymptomatic Gene Carriers of Tuberous Sclerosis by CCT and MRI a , 1991, Annals of the New York Academy of Sciences.

[20]  J. Osborne,et al.  Tuberous sclerosis and polycystic kidney disease. , 1993, BMJ.

[21]  J. Odel,et al.  Hypopigmented iris spot. An early sign of tuberous sclerosis. , 1982, Ophthalmology.

[22]  Y. Fukuyama,et al.  High incidence of fundus hamartomas and clinical significance of a fundus score in tuberous sclerosis , 1986, Brain and Development.

[23]  R. Snell,et al.  Interaction between hamartin and tuberin, the TSC1 and TSC2 gene products. , 1998, Human molecular genetics.

[24]  A. Engel,et al.  Cortical Tuber Count: A Biomarker Indicating Neurologic Severity of Tuberous Sclerosis Complex , 1997, Journal of child neurology.

[25]  E. Ey,et al.  Congenital subependymal giant-cell astrocytoma: case report with prenatal ultrasonogram , 1999, Pediatric Radiology.

[26]  J. Sampson,et al.  Pitted enamel hypoplasia in tuberous sclerosis , 1992, Clinical genetics.

[27]  J. Lewis,et al.  Genotype and psychological phenotype in tuberous sclerosis , 2004, Journal of Medical Genetics.

[28]  B. Westmoreland,et al.  Tuberous sclerosis, early onset of seizures, and mental subnormality , 1982, Neurology.

[29]  I. Jambaqué,et al.  NEUROPSYCHOLOGICAL ASPECTS OF TUBEROUS SCLEROSIS IN RELATION TO EPILEPSY AND MRI FINDINGS , 1991, Developmental medicine and child neurology.

[30]  A. Green,et al.  Female germline mosaicism in tuberous sclerosis confirmed by molecular genetic analysis. , 1997, Human molecular genetics.

[31]  J. Maynard,et al.  Comprehensive mutation analysis of TSC1 and TSC2-and phenotypic correlations in 150 families with tuberous sclerosis. , 1999, American journal of human genetics.

[32]  D. Kwiatkowski,et al.  Tuberous sclerosis. , 1994, Archives of dermatology.

[33]  C. Crowson,et al.  Causes of death in patients with tuberous sclerosis. , 1991, Mayo Clinic proceedings.

[34]  J. Nyboer,et al.  Retinal lesions in tuberous sclerosis. , 1976, Archives of ophthalmology.

[35]  M. Goetting,et al.  Tuberous scllerosis with cardiogenic cerebral embolism , 1985, Neurology.

[36]  S. Povey,et al.  EVIDENCE THAT THE GENE FOR TUBEROUS SCLEROSIS IS ON CHROMOSOME 9 , 1987, The Lancet.

[37]  J. Weber,et al.  Linkage of an important gene locus for tuberous sclerosis to a chromosome 16 marker for polycystic kidney disease , 1992, Nature genetics.

[38]  J. Bissler,et al.  Tuberous Sclerosis Complex: Neurological, Renal and Pulmonary Manifestations , 2010, Neuropediatrics.

[39]  P. D. de Vries,et al.  Pilot validation of the tuberous sclerosis-associated neuropsychiatric disorders (TAND) checklist. , 2015, Pediatric neurology.

[40]  J. Osborne,et al.  Epidemiology of Tuberous Sclerosis , 1991, Annals of the New York Academy of Sciences.

[41]  D. Kwiatkowski,et al.  Mosaicism in tuberous sclerosis as a potential cause of the failure of molecular diagnosis. , 1999, The New England journal of medicine.

[42]  S. Steinberg,et al.  Multiple facial angiofibromas and collagenomas in patients with multiple endocrine neoplasia type 1. , 1997, Archives of dermatology.

[43]  O. Devinsky,et al.  MRI Characterization and Longitudinal Study of Focal Cerebellar Lesions in a Young Tuberous Sclerosis Cohort , 2013, American Journal of Neuroradiology.

[44]  A. Panigrahy,et al.  The diverse clinical manifestations of tuberous sclerosis complex: a review. , 2006, Seminars in pediatric neurology.

[45]  Vincent J Schmithorst,et al.  Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. , 2008, The New England journal of medicine.

[46]  W. H. Brummelkamp,et al.  Tuberous sclerosis and the relation with renal angiomyolipoma. A genetic study on the clinical aspects , 1989, Clinical genetics.

[47]  D. Kwiatkowski,et al.  Somatic mosaicism is rare in unaffected parents of patients with sporadic tuberous sclerosis , 2004, Journal of Medical Genetics.

[48]  I. Jambaqué,et al.  Neuropsychiatric Aspects of Tuberous Sclerosis , 1991, Annals of the New York Academy of Sciences.

[49]  A. Wilfong,et al.  Treating Epilepsy in Tuberous Sclerosis with Everolimus: Getting Closer , 2014, Epilepsy currents.

[50]  H Okazaki,et al.  Cerebral tuberous sclerosis: postmortem magnetic resonance imaging and pathologic anatomy. , 1989, Mayo Clinic proceedings.

[51]  J. Osborne,et al.  MORBIDITY ASSOCIATED WITH TUBEROUS SCLEROSIS: A POPULATION STUDY , 1996, Developmental medicine and child neurology.

[52]  J. Dennis,et al.  PSYCHIATRIC DISORDER AMONG CHILDREN WITH TUBEROUS SCLEROSIS , 1987, Developmental medicine and child neurology.

[53]  J. Declue,et al.  Identification of Tuberin, the Tuberous Sclerosis-2 Product. TUBERIN POSSESSES SPECIFIC Rap1GAP ACTIVITY (*) , 1995, The Journal of Biological Chemistry.

[54]  E. Henske,et al.  Lymphangioleiomyomatosis - a wolf in sheep's clothing. , 2012, The Journal of clinical investigation.

[55]  M. Delgado,et al.  Early Diagnosis of Subependymal Giant Cell Astrocytoma in Patients With Tuberous Sclerosis , 1998, Journal of child neurology.

[56]  R. Szczesniak,et al.  Lymphangioleiomyomatosis screening in women with tuberous sclerosis. , 2013, Chest.

[57]  M. Prokop,et al.  Radiological evidence of lymphangioleiomyomatosis in female and male patients with tuberous sclerosis complex. , 2011, Clinical radiology.

[58]  D. Krueger,et al.  Vigabatrin for childhood partial-onset epilepsies. , 2012, Pediatric neurology.

[59]  L. Chameides,et al.  Evolution of Cardiac Rhabdomyoma in Tuberous Sclerosis Complex , 1996, Clinical pediatrics.

[60]  P J Kelly,et al.  Surgical Treatment for Epilepsy in Cerebral Tuberous Sclerosis , 1993, Epilepsia.

[61]  B. King,et al.  Tuberous sclerosis associated neuropsychiatric disorders (TAND) and the TAND Checklist. , 2015, Pediatric neurology.

[62]  M. Delgado,et al.  Long-term outcome of transcatheter embolization of renal angiomyolipomas due to tuberous sclerosis complex. , 2005, The Journal of urology.

[63]  E. Thiele,et al.  Intracranial Arteriopathy in Tuberous Sclerosis Complex , 2014, Journal of child neurology.

[64]  S Povey,et al.  Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. , 1997, Science.

[65]  E. Thiele,et al.  Cognitive prognosis of patients with tuberous sclerosis complex , 2007, Neurology.

[66]  J. Rantanen,et al.  Hypopigmented skin alterations resembling tuberous sclerosis in normal skin. , 1996, Journal of medical genetics.

[67]  Arun D. Singh,et al.  Tuberous sclerosis complex: genotype/phenotype correlation of retinal findings. , 2012, Ophthalmology.

[68]  J. Osborne,et al.  Cranial magnetic resonance imaging in patients with tuberous sclerosis and normal intellect. , 1991, Archives of disease in childhood.

[69]  T. Hensle,et al.  The tuberous sclerosis complex: a comprehensive review. , 1998, Journal of the American College of Surgeons.

[70]  V. Whittemore,et al.  National Institutes of Health consensus conference: tuberous sclerosis complex. , 2000, Archives of neurology.

[71]  Hope Northrup,et al.  Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 Iinternational Tuberous Sclerosis Complex Consensus Conference. , 2013, Pediatric neurology.

[72]  R. Schwartz,et al.  Tuberous sclerosis complex: advances in diagnosis, genetics, and management. , 2007, Journal of the American Academy of Dermatology.

[73]  R. Hubbard,et al.  Survival and disease progression in UK patients with lymphangioleiomyomatosis , 2004, Thorax.

[74]  H. Chugani,et al.  α-[11C]-Methyl-l-tryptophan–PET in 191 patients with tuberous sclerosis complex , 2013, Neurology.

[75]  A. Vortmeyer,et al.  Cutaneous tumors in patients with multiple endocrine neoplasia type 1 show allelic deletion of the MEN1 gene. , 1998, The Journal of investigative dermatology.

[76]  D. Kwiatkowski,et al.  Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs. , 2001, American journal of human genetics.

[77]  E. Roach,et al.  Magnetic resonance imaging in tuberous sclerosis. , 1987, Archives of neurology.

[78]  J. Hahn,et al.  Neonatal subependymal giant cell astrocytoma associated with tuberous sclerosis , 1991, Neurology.

[79]  M. Delgado,et al.  Renal lesion growth in children with tuberous sclerosis complex. , 1998, The Journal of urology.

[80]  H. Weiner,et al.  Subependymal giant cell astrocytoma: diagnosis, screening, and treatment. Recommendations from the International Tuberous Sclerosis Complex Consensus Conference 2012. , 2013, Pediatric neurology.

[81]  S. Thomas,et al.  Identification and characterization of the tuberous sclerosis gene on chromosome 16 , 1993, Cell.

[82]  Christopher N Martyn,et al.  Prevalence of tuberous sclerosis estimated by capture-recapture analysis , 1998, The Lancet.

[83]  S. Weig,et al.  Carbamazepine‐induced heart block in a child with tuberous sclerosis and cardiac rhabdomyoma: Implications for evaluation and follow‐up , 1993, Annals of neurology.

[84]  J. Smallhorn,et al.  Natural history of cardiac rhabdomyoma in infancy and childhood. , 1990, The American journal of cardiology.

[85]  B. Edgar,et al.  Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins , 2003, Nature Cell Biology.

[86]  J B Stephenson,et al.  Genetic aspects of tuberous sclerosis in the west of Scotland. , 1989, Journal of medical genetics.

[87]  M. Delgado,et al.  Seizure remission and antiepileptic drug discontinuation in children with tuberous sclerosis complex. , 2003, Archives of neurology.

[88]  A. Byars,et al.  Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. , 2010, The New England journal of medicine.

[89]  G. Sethuraman,et al.  Rapamycin causes regression of astrocytomas in tuberous sclerosis complex , 2006, Annals of neurology.

[90]  P. Beighton,et al.  Evidence for genetic heterogeneity in tuberous sclerosis. , 1989, Journal of medical genetics.

[91]  R. Pagon,et al.  Prevalence of hypopigmented macules in a healthy population. , 1996, The Journal of pediatrics.

[92]  G. Mlynarczyk Enamel pitting: a common symptom of tuberous sclerosis. , 1991, Oral surgery, oral medicine, and oral pathology.

[93]  Eleonora Aronica,et al.  Cytoarchitectural alterations are widespread in cerebral cortex in tuberous sclerosis complex , 2012, Acta Neuropathologica.

[94]  D. Krueger,et al.  Tuberous Sclerosis Complex Surveillance and Management: Recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference , 2013, Pediatric neurology.