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Cited by 1,502Tuberous Sclerosis Complex ResearchGenetic and rare skin diseases.Vascular Malformations and Hemangiomas

Tuberous Sclerosis Complex Diagnostic Criteria Update: Recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference

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Northrup, Hope, Krueger, Darcy A., Northrup, Hope, Krueger, Darcy A., Roberds, Steven, Smith, Katie, Sampson, Julian, Korf, Bruce +76 more·2013·Pediatric Neurology
DOI 10.1016/j.pediatrneurol.2013.08.001PMC PMC4080684
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Abstract

BACKGROUND: Tuberous sclerosis complex is highly variable in clinical presentation and findings. Disease manifestations continue to develop over the lifetime of an affected individual. Accurate diagnosis is fundamental to implementation of appropriate medical surveillance and treatment. Although significant advances have been made in the past 15 years in the understanding and treatment of tuberous sclerosis complex, current clinical diagnostic criteria have not been critically evaluated or updated since the last clinical consensus conference in 1998. METHODS: The 2012 International Tuberous Sclerosis Complex Consensus Group, comprising 79 specialists from 14 countries, was organized into 12 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 diagnostic implications and was charged with reviewing prevalence and specificity of disease-associated clinical findings and their impact on suspecting and confirming the diagnosis of tuberous sclerosis complex. RESULTS: Clinical features of tuberous sclerosis complex continue to be a principal means of diagnosis. Key changes compared with 1998 criteria are the new inclusion of genetic testing results and reducing diagnostic classes from three (possible, probable, and definite) to two (possible, definite). Additional minor changes to specific criterion were made for additional clarification and simplification. CONCLUSIONS: The 2012 International Tuberous Sclerosis Complex Diagnostic Criteria provide current, updated means using best available evidence to establish diagnosis of tuberous sclerosis complex in affected individuals.

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  • TSC is a rare autosomal dominant neurodevelopmental disorder caused by loss-of-function mutations in TSC1 or TSC2, resulting in chronic hyperactivation of the mTOR pathway.

    “Tuberous sclerosis complex (TSC) is a rare autosomal dominant neurodevelopmental disorder caused by loss-of-function mutations in the TSC1 or TSC2 genes, which encode the proteins hamartin and tuberin (1).”

    From Amyloid-Independent Elevation of Plasma phosphorylated tau-217 Tracks Neurodegenerative Risk in Tuberous Sclerosis Complex: Implications for mTOR-Targeted Intervention (2026) · cites this paper as [1]

    The Introduction (page not provided) describes TSC as rare and identifies TSC1 and TSC2 as its two causative genes. Genetic diagnostic criteria (page not provided) describe pathogenic mutations that prevent protein synthesis or inactivate protein function. The cited passages do not establish the verbatim citing sentence’s autosomal-dominant classification or identify the proteins as hamartin and tuberin; the supplied paraphrase additionally mentions mTOR hyperactivation, which the retrieved passages do not address. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • TSC is a neurodevelopmental disorder arising primarily from mutations in TSC1 (hamartin) and TSC2 (tuberin).

    “Tuberous Sclerosis Complex (TSC) is a neurodevelopmental disorder arising primarily from mutations in TSC1 (hamartin) and TSC2 (tuberin) (TSC1/2) [8].”

    From Tuberous sclerosis complex is a novel, amyloid-independent tauopathy associated with elevated phosphorylated 3R/4R tau aggregation (2022) · cites this paper as [8]

    The Introduction identifies TSC1 and TSC2 as the two causative genes, and Genetic diagnostic criteria says a pathogenic mutation in either is sufficient for diagnosis. The copy does not identify their proteins as hamartin and tuberin. Its Introduction describes TSC as a disease affecting virtually any organ; the Central nervous system features section describes developmental brain abnormalities, but does not classify TSC as a neurodevelopmental disorder. No page numbers were provided for these passages. (LLM, conf=0.86)

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  1. [3]Stevenson A Fischer O Frequency of epiloia in Northern Ireland Br J Prev Soc Med 1956 10 134 135 13374272 PMC1058632
  2. [4]Nevin N Pearse W Diagnostic and genetical aspects of tuberous sclerosis J Med Genet 1968 5 273 280 5713638 PMC1468678
  3. [5]O’Callaghan F Shiell A Osborne J Martyn C Prevalence of tuberous sclerosis estimated by capture-recapture analysis Lancet 1998 352 318 319 9605811
  4. [6]Sampson J Scahill S Stephenson J Mann L Connor J Genetic aspects of tuberous sclerosis in the west of Scotland J Med Genet 1989 26 28 31 2918523 PMC1015532
  5. [8]European Chromosome 16 Tuberous Sclerosis Consortium Identification and characterization of the tuberous sclerosis gene on chromosome 16 Cell 1993 75 1305 1315 8269512
  6. [9]van Slegtenhorst M deHoogt R Hermans C Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34 Science 1997 277 805 808 9242607
  7. [10]Krueger DA Northrup H The International Tuberous Sclerosis Complex Consensus Group. Tuberous Sclerosis Complex Surveillance and Management: Recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference Pediatr Neurol 2013 49 255 265 24053983 PMC4058297
  8. [11]Roach E Gomez M Northrup H Tuberous sclerosis complex consensus conference: revised clinical diagnostic criteria J Child Neurol 1998 13 624 628 9881533
  9. [12]Roach ES Sparagana SP Diagnosis of tuberous sclerosis complex J Child Neurol 2004 19 643 649 15563009
  10. [13]Hoogeveen-Westerveld M Ekong R Povey S Functional assessment of TSC2 variants identified in individuals with tuberous sclerosis complex Hum Mutat 2013 34 167 175 22903760
  11. [14]Hoogeveen-Westerveld M Ekong R Povey S Functional assessment of TSC1 missense variants identified in individuals with tuberous sclerosis complex Hum Mutat 2012 33 476 479 22161988
  12. [15]Au K Williams A Roach E Genotype/phenotype correlation in 325 individuals referred for a diagnosis of tuberous sclerosis complex in the United States Genet Med 2007 9 88 1000 17304050
  13. [16]Dabora SL Jozwiak S Franz DN Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs Am J Hum Genet 2001 68 64 80 11112665 PMC1234935
  14. [17]Datta AN Hahn CD Sahin M Clinical presentation and diagnosis of tuberous sclerosis complex in infancy J Child Neurol 2008 23 268 273 18230839
  15. [18]Jozwiak S Schwartz RA Janniger CK Michalowicz R Chmielik J Skin lesions in children with tuberous sclerosis complex: their prevalence, natural course, and diagnostic significance Int J Dermatol 1998 37 911 917 9888331
  16. [19]Staley BA Vail EA Thiele EA Tuberous sclerosis complex: diagnostic challenges, presenting symptoms, and commonly missed signs Pediatrics 2011 127 e117 e125 21173003 PMC3010088
  17. [20]Yates JRW MacLean C Higgins JNP The tuberous sclerosis 2000 study: presentation initial assessments and implications for diagnosis and management Arch Dis Child 2011 96 1020 1025 21813552
  18. [21]Webb D Clarke A Fryer A Osborne J The cutaneous features of tuberous sclerosis: a population study Br J Dermatol 1996 135 1 5 8776349
  19. [22]Alper J Holmes L The incidence and significance of birthmarks in a cohort of 4,641 newborns Pediatr Dermatol 1983 1 58 68 6679890
  20. [23]Vanderhooft S Francis J Pagon R Smith L Sybert V Prevalence of hypopigmented macules in a healthy population J Pediatr 1996 129 355 361 8804323
  21. [24]Jozwiak S Schwartz RA Janniger CK Bielicka-Cymerman J Usefulness of diagnostic criteria of tuberous sclerosis complex in pediatric patients J Child Neurol 2000 15 652 659 11063078
  22. [25]Bansal C Stewart D Li A Cockerell C Histologic variants of fibrous papule J Cutan Pathol 2005 32 424 428 15953376
  23. [26]Darling TN Skarulis MC Steinberg SM Marx SJ Spiegel AM Turner M Multiple facial angiofibromas and collagenomas in patients with multiple endocrine neoplasia type 1 Arch Dermatol 1997 133 853 857 9236523
  24. [27]Toro J Glenn G Duray P BHD mutations, clinical and molecular genetic investigations of Birt-Hogg-Dubé syndrome: a new series of 50 families and a review of published reports J Med Genet 2008 45 321 333 18234728 PMC2564862
  25. [28]Aldrich CS Hong CH Groves L Olsen C Moss J Darling TN Acral lesions in tuberous sclerosis complex: insights into pathogenesis J Am Acad Dermatol 2010 63 244 251 20462663 PMC2947366
  26. [29]Zeller J Friedmann D Clerici T Revuz J The significance of a single periungual fibroma: report of seven cases Arch Dermatol 1995 131 1465 1466 7492148
  27. [30]Toro J Glenn G Duray P Birt-Hogg-Dubé syndrome: a novel marker of kidney neoplasia Arch Dermatol 1999 10 1195 1202 10522666
  28. [31]Darling T Moss J Mausner M Kwiatkowsi D Whittemore V Thiele E Dermatologic manifestations of tuberous sclerosis complex (TSC) Tuberous Sclerosis Complex: Genes, Clinical Features, and Therapeutics 2010 Weinheim Wiley-Blackwell
  29. [32]Mlynarczyk G Enamel pitting: a common symptom of tuberous sclerosis Oral Surg Oral Med Oral Pathol 1991 71 63 67 1994325
  30. [33]Lygidakis N Lindenbaum R Oral fibromatosis in tuberous sclerosis Oral Surg Oral Med Oral Pathol 1989 68 725 728 2594320
  31. [34]Sparling J Hong C Brahim J Moss J Darling T Oral findings in 58 adults with tuberous sclerosis complex J Am Acad Dermatol 2007 56 786 790 17239986 PMC2947382
  32. [35]Bataineh A Al-Dwairi N A survey of localized lesions of oral tissues: a clinicopathological study J Contemp Dent Pract 2005 6 30 39 16127470
  33. [36]Ono Y Takahashi H Inagi K Nakayama M Okamoto M Clinical study of benign lesions in the oral cavity Acta Otolaryngol Suppl 2002 547 79 84 12212602
  34. [37]Aronow M Nakagawa J Gupta A Traboulsi E Singh A Tuberous sclerosis complex: genotype/phenotype correlation of retinal findings Ophthalmology 2012 199 1917 1923 22608477
  35. [38]Rowley S O’Callaghan F Osborne J Ophthalmic manifestations of tuberous sclerosis: a population based study Br J Ophthalmol 2001 85 420 423 11264130 PMC1723924
  36. [39]Li L Li N Zhao J Findings of perinatal ocular examination performed on 3573, healthy full-term newborns Br J Ophthalmol 2013 97 588 591 23426739 PMC3632968
  37. [40]Franz D Non-neurologic manifestations of tuberous sclerosis complex J Child Neurol 2004 19 690 698 15563016
  38. [41]Northrup H Wheless J Bertin T Lewis R Variability in expression in tuberous sclerosis J Med Genet 1993 30 101 103 8423606 PMC1016232
  39. [42]Crino P Mehta R Vinters H Kwiatkowsi D Whittemore V Thiele E Pathogenesis of TSC in the brain Tuberous Sclerosis Complex: Genes, Clinical Features, and Therapeutics 2010 Weinheim Wiley-Blackwell 285 309
  40. [43]Black M Kadlez M Smallhorn J Freedom R Cardiac rhabdomyomas and obstructive left heart disease: histologically but not functionally benign Ann Thorac Surg 1998 65 1388 1390 9594871
  41. [44]Freedom RM Lee KJ MacDonald C Taylor G Selected aspects of cardiac tumors in infancy and childhood Pediatr Cardiol 2000 21 299 316 10865003
  42. [45]Tworetzky W McElhinney DB Margossian R Association between cardiac tumors and tuberous sclerosis in the fetus and neonate Am J Cardiol 2003 92 487 489 12914889
  43. [46]Beghetti M Gow R Haney I Mawson J Williams W Freedom R Pediatric primary benign cardiac tumors: a 15-year review Am Heart J 1997 134 1107 1114 9424072
  44. [47]Harding C Pagon R Incidence of tuberous sclerosis in patients with cardiac rhabdomyoma Am J Med Genet 1990 37 443 446 2260584
  45. [48]Holley D Martin G Brenner J Diagnosis and management of fetal cardiac tumors: a multicenter experience and review of published reports J Am Coll Cardiol 1995 26 516 520 7608458
  46. [49]Johnson SR Cordier JF Lazor R European Respiratory Society guidelines for the diagnosis and management of lymphangioleiomyomatosis Eur Respir J 2010 35 14 26 20044458
  47. [50]McCormack F Henske E Kwiatkowsi D Whittemore V Thiele E Lymphangioleiomyomatosis and pulmonary disease in TSC Tuberous Sclerosis Complex: Genes, Clinical Features, and Therapeutics 2010 Weinheim Wiley-Blackwell
  48. [51]Cudzilo C Szczesniak R Brody A Lymphangioleiomyomatosis screening in women with tuberous sclerosis Chest 2013 144 578 585 23539171
  49. [52]Adriaensen ME Schaefer-Prokop CM Duyndam DA Zonnenberg BA Prokop M Radiological evidence of lymphangioleiomyomatosis in female and male patients with tuberous sclerosis complex Clin Radiol 2011 66 625 628 21459371
  50. [53]Muzykewicz D Black M Muse V Multifocal micronodular pneumocyte hyperplasia: computed tomographic appearance and follow-up in tuberous sclerosis complex J Comput Assist Tomogr 2012 36 518 522 22992599
  51. [54]Henske E McCormack F Lymphangioleiomyomatosis—a wolf in sheep’s clothing J Clin Invest 2012 122 3807 3816 23114603 PMC3484429
  52. [55]Kobashi Y Sugiu T Mouri K Irei T Nakata M Oka M Clinicopathological analysis of multifocal micronodular pneumocyte hyperplasia associated with tuberous sclerosis in Japan Respirology 2008 13 1076 1081 18699800
  53. [56]Cancellieri A Poletti V Corrin B Respiratory failure due to micronodular type II pneumocyte hyperplasia Histopathology 2002 41 263 265 12207789
  54. [57]Franz D Brody A Meyer C Mutational and radiographic analysis of pulmonary disease consistent with lymphangioleiomyomatosis and micronodular pneumocyte hyperplasia in women with tuberous sclerosis Am J Respir Crit Care Med 2001 164 661 668 11520734
  55. [58]Muzykewicz DA Sharma A Muse V Numis AL Rajagopal J Thiele EA TSC1 and TSC2 mutations in patients with lymphangioleiomyomatosis and tuberous sclerosis complex J Med Genet 2009 46 465 468 19419980
  56. [59]Martignoni G Pea M Reghellin D Zamboni G Bonetti F PEComas: the past, the present and the future Virchows Arch 2008 452 119 132 18080139 PMC2234444
  57. [60]Fricke BL Donnelly LF Casper KA Bissler JJ Frequency and imaging appearance of hepatic angiomyolipomas in pediatric and adult patients with tuberous sclerosis AJR Am J Roentgenol 2004 182 1027 1030 15039181
  58. [61]Shepherd C Gomez M Lie J Crowson C Causes of death in patients with tuberous sclerosis Mayo Clin Proc 1991 66 792 796 1861550
  59. [62]Bissler J Henske E Kwiatkowsi D Whittemore V Thiele E Renal manifestations of tuberous sclerosis complex Tuberous Sclerosis Complex: Genes, Clinical Features, and Therapeutics 2010 Weinheim Wiley-Blackwell
  60. [63]Kozlowska J Okon K Renal tumors in postmortem material Pol J Pathol 2008 59 21 25 18655367
  61. [64]Bissler J Kingswood J Renal angiomyolipomata Kidney Int 2004 66 924 934 15327383
  62. [65]Pei Y Practical genetics for autosomal dominant polycystic kidney disease Nephron Clin Pract 2010 118 c19 c30 21071968
  63. [66]Brook-Carter P Peral B Ward C Deletion of the TSC2 and PKD1 genes associated with severe infantile polycystic kidney disease—a contiguous gene syndrome Nat Genet 1994 8 328 332 7894481
  64. [67]O’Callaghan F Osborne J Kwiatkowski D Whittemore V Thiele E Endocrine, gastrointestinal, hepatic, and lymphatic manifestations of tuberous sclerosis complex Tuberous Sclerosis Complex: Genes, Clinical Features, and Therapeutics 2010 Weinheim Wiley-Blackwell 369 385
  65. [68]Compton W Lester P Kyaw M Madsen J The abdominal angiographic spectrum of tuberous sclerosis AJR Am J Roentgenol 1976 126 807 813 179351
  66. [69]Bruneton J Drouillard J Rabin A Boedec R Broussin J Delorme G Angiomyolipomas (hamartomas) of the kidney. Radiology study apropos of 2 cases. Review of the literature J Can Assoc Radiol 1978 29 252 261 721884
  67. [70]Noldus J Ancker U Schafer H Conrad S Huland H Multilocular, giant angiomyolipoma of the kidney, adrenal gland, and para-aortic lymph nodes. Case report of a 9-year-old boy with tuberous sclerosis Der Urologe Ausg A 1994 33 353 356 7974936
  68. [71]Perou M Gray P Mesenchymal hamartomas of the kidney J Urol 1960 83 240 261 14431942
  69. [72]Verma B Tailor M Familial tuberous sclerosis: a review with report of three cases Indian Pediatr 1965 2 401 410 5865055
  70. [73]Dworakowska D Grossman AB Are neuroendocrine tumours a feature of tuberous sclerosis? A systematic review Endocr Relat Cancer 2009 16 45 58 18978035

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Authors
Northrup, H., Krueger, D. A., Northrup, H., Krueger, D. A., Roberds, S., Smith, K., Sampson, J., Korf, B., Kwiatkowski, D. J., Mowat, D., Nellist, M., Northrup, H., Povey, S., de Vries, P., Byars, A., Dunn, D., Ess, K., Hook, D., Jansen, A., King, B., Sahin, M., Whittemore, V., Thiele, E., Bebin, E. M., Chugani, H. T., Crino, P., Curatolo, P., Holmes, G., Nabbout, R., O'Callaghan, F., Wheless, J., Wu, J., Darling, T. N., Cowen, E. W., Gosnell, E., Hebert, A., Mlynarczyk, G., Soltani, K., Teng, J., Wataya-Kaneda, M., Witman, P. M., Kingswood, C., Bissler, J., Budde, K., Hulbert, J., Guay-Woodford, L., Sampson, J., Sauter, M., Zonneberg, B., Jóźwiak, S., Bartels, U., Berhouma, M., Franz, D. N., Koenig, M. K., Krueger, D. A., Roach, E. S., Roth, J., Wang, H., Weiner, H., McCormack, F. X., Almoosa, K., Brody, A., Burger, C., Cottin, V., Finlay, G., Glass, J., Henske, E. P., Johnson, S., Kotloff, R., Lynch, D., Moss, J., Smith, K., Rhu, J., Da Silva, A. T., Young, L. R., Knilans, T., Hinton, R., Prakash, A., Romp, R., Singh, A. D., DebRoy, A., Chen, P.-L., Sparagana, S., & Frost, M. D.
ORCID
Venue
Pediatric Neurology
Publisher
Elsevier BV
Published
2013-10
Volume
49
Issue
4
Pages
243-254
ISSN
0887-8994 (ISSN-L)
DOI
10.1016/j.pediatrneurol.2013.08.001
PMC
PMC4080684
OpenAlex
W2126467306
Cited by
1,502
References
3
Citations by year
2026: 56 · 2025: 85 · 2024: 91 · 2023: 92 · 2022: 127 · 2021: 201 · 2020: 181 · 2019: 136 · 2018: 143 · 2017: 127 · 2016: 116 · 2015: 92 · 2014: 40 · 2013: 11 · 2012: 1
FWCI
60.11
Type
journal article
Language
en
Open access
Licence
Locations
  • Pediatric Neurology (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • VUBIR (Vrije Universiteit Brussel) (submittedVersion)
Funders
Tuberous Sclerosis Alliance
Topics
  • Health Sciences › Medicine › Physiology › Tuberous Sclerosis Complex Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and rare skin diseases.
  • Health Sciences › Medicine › Surgery › Vascular Malformations and Hemangiomas
Keywords
tuberous sclerosis complex, diagnostic criteria, diagnosis, genetic testing, clinical features, diagnostic classification, consensus conference, medical surveillance
MeSH terms
Diagnosis, Differential, Genetic Testing, Humans, Tuberous Sclerosis, Practice Guidelines as Topic

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