FaCD Online Syndrome Fact Sheet

Last updated: 04 Aug 2011

Name: Tuberous Sclerosis

Synonym: TS, Tuberous Sclerosis Complex, TSC, Bourneville-Pringle disease

Mode of Inheritance: AD / de novo

Genes

TSC1, mapped to 9q34
TSC2, mapped to 16p13.3

Tumor features

angiomyelolipoma of the liver
angiomyolipoma of the liver
cardiac rhabdomyoma
colorectal adenomas
colorectal hamartomatous polyps
facial angiofibroma
gastrointestinal polyps, Peutz-Jeghers type
giant cell astrocytomas
gingival fibroma
nails, ungual fibroma
pancreatic endocrine tumor
pulmonary lymphangioleiomyomatosis
rectal cancer
renal angiomyolipomas
renal cell cancer, clear-cell (Grawitz tumor)
renal cell cancer, papillary
renal oncocytoma
retinal hamartomas
subependymal nodules

Tumor features (possible)

carcinoid of bronchus
optic glioma
parathyroid adenoma
pheochromocytoma
pituitary adenoma
retinal astrocytoma
testicular germ cell tumor
uterus, angiomyolipoma of the

Non-tumor features

bone cysts
dental pits
developmental delay/mental deficiency/mental retardation
epilepsy - West syndrome
facial (forehead) fibrous placque
hypomelanotic (ashleaf) macule
intracranial calcifications, periventricular
lung, honeycomb fibrosis of the
lymphangiomyomatosis
renal cysts
shagreen patch

Comment

In classical cases this order is characterized by mental retardation, seizures, facial angiofibromas, ashleaf shaped hypopigmented skin patches, shagreen patches of the skin, ungual fibromas, subependymal nodules and dental pits. However, only minimal signs of the disorder may be found in gene carriers.[1-4]

As shown in the diagnostic criteria below, a wide range of features can be found in TS. Familial Cylindromatosis may occasionally be confused with tuberous sclerosis[5]. Cardiac rhabdomyomas may be detected in more than 50% of young infants with TS and tend to regress in early childhood and again in adolescence[6]. An estimated 51-86% of cardiac rhabdomyomas are associated with TS[7]. Renal angiomyolipomas may be present in 40-80% of TS cases, often multiple and bilateral[8;9]. Some of these tumors show progression and may bleed[9]. Renal cell cancer, sometimes multiple and including mainly clear cell types, but also papillary types and oncocytomas may occur in this syndrome, possibly with a better prognosis than sporadic renal cell cancer[10-12]. Pea et al.[13] argued that some of these tumors have been misclassified and actually represent malignant epithelioid angiomyolipomas. Rakowski et al[23] observed renal lesions in 58% of their 167 TSC1 and 2 patients. Angiomyolipoma was seen in 85%, cysts in 45%, and renal cell carcinoma in 4% of cases. Both angiomyolipomas and cysts were significantly more common and more numerous in TSC2 than in TSC1. Angiomyolipomas were significantly more common in female than in male patients[23]. Leiomyomas of the kidney have been reported as well[12]. Torres et al.[12] stated that renal involvement is a major cause of morbidity in TS and second only to central nervous system complications as the cause of death. They suggested that the diagnosis of TS should be considered in a) patients with (multiple) renal angiomyolipomas, b) renal cysts without a family history of polycystic kidney disease (PKD) (a microdeletion may knock out both the TSC2 gene and its neighbor PKD1), c) in patients with familial and/or multiple (early-onset) renal cell cancer, and d) (rarely) in patients with chronic renal insufficiency, hyperechoic kidneys and moderate proteinuria. Angiomyolipomas of the liver may occur (16 % of patients with these tumors have TS)[14]. Hepatic angiomyelolipomas have been reported as well[15]. Angiomyolipoma of the uterus has been reported[24]. Pulmonary lymphangioleiomyomatosis is another typical feature of TS[19;20]. Subependymal giant cell astrocytomas occur in approximately 2-14% of TS patients[26].

Other tumors
Colonic and rectal hamartomas of the type typically seen in Peutz-Jeghers syndrome can occasionally be found in infants and adults with TS. Some TS patients have (early onset) colorectal adenomatous polyps[16;17] and probably only in rare cases (colo)rectal cancer (which has been diagnosed as early as 17 years[18]) develops. Benign or malignant islet cell tumors appear to be associated with TS; evidence for an association of TS with pituitary and parathyroid gland tumors, phaeochromocytoma and carcinoid is less strong[27]. Testicular cancer has been observed in 3 Norwegian TS patients, which was a much higher than expected frequency[25].

In a series of 150 unrelated TS patients and their families, germline mutations in either the TSC1 or TSC2 gene have been detected in 80%[21]. In approximately two thirds of cases, TS is sporadic and thought to be caused by a de novo mutation.

Diagnostic criteria for Tuberous Sclerosis[22]:
Definite TS: 2 major features ,or 1 major + 2 minor features
Probable TS: 1 major feature + 1 minor feature
Possible TS: 1 major feature or >1 minor features.

Major Features:

• facial angiofibromas or forehead plaque
• non-traumatic ungual or periungual fibroma
• >2 hypomelanotic macules
• shagreen patch (connective tissue nevus)
• multiple retinal nodular hamartomas
• cortical tuber (see below)
• subependymal nodule
• subependymal giant cell astrocytoma
• cardiac rhabdomyoma (single or multiple)
• lymphangiomyomatosis (see below)
• renal angiomyolipoma (see below)

• multiple randomly distributed dental enamel pits
• hamartomatous rectal polyps (histologic confirmation is suggested)
• bone cysts
• cerebral white-matter migration lines (radiological evidence) (see below)
• gingival fibromas
• nonrenal hamartomas (histologic confirmation is suggested)
• retinal achromatic patch
• 'confetti' skin lesions
• multiple renal cysts (histologic confirmation is suggested)

Links

Tuberous Sclerosis Alliance (TS Alliance) 24 1 08
Tuberous Sclerosis Association, UK 24 1 08

References

[1] Bundey S, Evans K. Tuberous sclerosis: a genetic study. J Neurol Neurosurg Psych 1969; 32:591-603.
[2] Pampiglione G, Moynahan EJ. The tuberous sclerosis syndrome: clinical and EEG studies in 100 children. J Neurol Neurosurg Psych 1976; 39:666-673.
[3] Osborne JP. Diagnosis of tuberous sclerosis. Arch Dis Child 1988; 63:1423-1425.
[4] Al-Gazali LI, Arthur RJ, Lamb JT, Hammer HM, Coker TP, Hirschmann PN, Gibbs J, Mueller RF. Diagnostic and counseling difficulties using a fully comprehensive screening protocol for families at risk for tuberous sclerosis. J Med Genet 1989; 26:694-703.
[5] Verhoef S, Schrander-Stumpel CTRM, Vuzevski VD, Tempelaars A, Jansen LAJ, Malfeyt GAM, Ceelen TL, Lindhout D, Halley DJJ, van den Ouweland AMW. Familial cylindromatosis mimicking tuberous sclerosis complex and confirmation of the cylindromatosis locus, CYLD1, in a large family. J Med Genet 1998; 35:841-845.
[6] Smith HC, Watson GH, Patel RG, Super M. Cardiac rhabdomyomata in tuberous sclerosis: their course and diagnostic value. Arch Dis Child 1989; 64:196-200.
[7] Harding CO, Pagon RA. Incidence of tuberous sclerosis in patients with cardiac rhabdomyoma. Am J Med Genet 1990; 37:443-446.
[8] Van Baal JG, Fleury P, Brummelkamp WH. Tuberous sclerosis and the relation with renal angiomyolipoma. A genetic study on the clinical aspects. Clin Genet 1989; 35:167-173.
[9] Van Baal JG, Smits NJ, Keeman JN, Lindhout D, Verhoef S. The evolution of renal angiomyolipomas in patients with tuberous sclerosis. J Urol 1994; 152:36-38.
[10] Sampson JR, Patel A, Mee AD. Multifocal renal cell carcinoma in sibs from a chromosome 9 linked (TSC1) tuberous sclerosis family. J Med Genet 1995; 32:848-850.
[11] Weinblatt ME, Kahn E, Kochen J. Renal cell carcinoma in patients with tuberous sclerosis. Pediatrics 1987; 80(6):898-902.
[12] Torres VE, Zincke H, King BK, Bjornsson J. Renal manifestations of tuberous sclerosis complex. In: Sessa A, Conte F, Meroni M, Battini G, editors. Hereditary Kidney Diseases. CH-4009 Basel: Karger, 1997: 64-75.
[13] Pea M, Bonetti F, Martignoni G, Henske EP, Manfrin E, Colato C, Bernstein J. Apparent renal cell carcinomas in tuberous sclerosis are heterogeneous: The identification of malignant epithelioid angiomyolipoma. Am J Surg Pathol 22[2], 180-187. 1998.
[14] Arblade S, Vilgrain V, Terris B, Zins M, Vullierme MP, Flejou JF, Belghiti J, Menu Y. Hepatic angiomyolipomas mimicking hepatic tumors. Report of 3 cases. Gastroenterol Clin Biol 20[11], 1022-1026. 1996.
[15] Yeo W, Leong A, Ward SC, Hui PK, Johnson PJ. Hepatic angiomyelolipoma and tuberous sclerosis. J Gastroenterol Hepatol 11[2], 196-198. 1996.
[16] Devroede G, Lemieux B, Masse S, Lamarche J, Herman PS. Colonic hamartomas in tuberous sclerosis. GASTROENTEROLOGY 1988; 94(1):182-188.
[17] Gould SR, Stewart JB, Temple LN. Rectal polyposis in tuberous sclerosis. J Ment Def Res 1990; 34:465-473.
[18] Digoy GP, Tibayan F, Young H, Edelstein P. Adenocarcinoma of the rectum with associated colorectal adenomatous polyps in tuberous sclerosis: a case report. J Pediatr Surg 2000; 35(3):526-527.
[19] Peccatori I, Pitingolo F, Battini G, Meroni M, Giordano G, Guarino M, Sessa A. Pulmonary lymphangioleiomyomatosis and tuberous sclerosis complex. In: Sessa A, Conte F, Meroni M, Battini G, editors. Hereditary Kidney Diseases. CH-4009 Basel: Karger, 1997: 98-101.
[20] Bonetti F, Chiodera P. Lymphangioleiomyomatosis and tuberous sclerosis: Where is the border? Eur.Resp.J. 9[3], 399-401. 1996.
[21] Jones AC, Shyamsundar MM, Thomas MW, Maynard J, Idziaszczyk S, Tomkins S, Sampson JR, Cheadle JP. Comprehensive mutation analysis of TSC1 and TSC2-and phenotypic correlations in 150 families with tuberous sclerosis. Am J Hum Genet 1999; 64(5):1305-1315.
[22] Roach ES, Sparagana SP. Diagnosis of tuberous sclerosis complex. Journal of child neurology 2004; 19(9):643-9.
[23] Rakowski SK, Winterkorn EB, Paul E, Steele DJ, Halpern EF, Thiele EA. Renal manifestations of tuberous sclerosis complex: Incidence, prognosis, and predictive factors. Kidney international 2006; 70(10):1777-82.
[24] Cil AP, Haberal A, Hucumenoglu S, Kovalak EE, Gunes M. Angiomyolipoma of the uterus associated with tuberous sclerosis: case report and review of the literature. Gynecologic oncology 2004; 94(2):593-6.
[25] Tandstad T, Indrebø G. Testicular cancer and the tuberous sclerosis complex. Acta Oncol. 2011 Jul 18. [Epub ahead of print]
[26] Grajkowska W, Kotulska K, Jurkiewicz E, Roszkowski M, Daszkiewicz P, Józwiak S, Matyja E. Subependymal giant cell astrocytomas with atypical histological features mimicking malignant gliomas. Folia Neuropathol. 2011;49(1):39-46.
[27] Dworakowska D, Grossman AB. Are neuroendocrine tumours a feature of tuberous sclerosis? A systematic review. Endocr Relat Cancer. 2009 Mar;16(1):45-58.