2003-08-14-12 Tuberous sclerosis © Jeanty www.thefetus.net/
Updated 8/13/2003 by Pedroli Gianluca MD
Original text 1999-05-27 Philippe Jeanty, MD, PhD & Sandra R Silva, MD
Definition: Tuberous Sclerosis is an autosomal dominant neurocutaneous syndrome affecting multiple organ systems and demonstrating highly variable clinical manifestations(a).This syndromes associates facial angiofibroma (often incorrectly called adenoma sebaceum), epilepsy, mental retardation, renal cysts, multiple and bilateral angiofibroma of the kidney and rhabdomyoma of the heart. Diverse cutaneous manifestation such as hypochromic patches (visible under Wood light) and “café au lait” patches (fig. 1) (light brown areas) are also typical of the syndrome. Brain tumors such as ependymoma of the third ventricle and astrocytoma may also be present.
Figure 1: The typical café au lait spot of Tuberous sclerosis
Synonyms: Bournevilles sclerosis and Brissaud.
Age of onset: first decade.
Risk factors: Low in case of de novo mutation, if two or more siblings with Tuberous Sclerosis then one parent always has at least one skin manifestation of Tuberous Sclerosis . If both parents are normal the Tuberous Sclerosis in the child is probably a new mutation. Higher in cases of gonadal mosaicism, 50% in case of parental involvement.
Genetic anomaly, etiology and pathogenesis: Autosomal dominant inheritance with a large proportion of fresh mutations (sporadic cases). The expression is highly variable. Tuberous Sclerosis C is caused by defects or mutations on two genes, Tuberous Sclerosis C1 and Tuberous Sclerosis C2. Only one of the genes needs to be affected for Tuberous Sclerosis C to be present. The Tuberous Sclerosis C1 gene, discovered in 1997, is on chromosome 9 and produce a protein called hamartin. The Tuberous Sclerosis C2 gene, discovered in 1993, is on chromosome 16 and produce a protein called tuberin. These proteins act as tumor suppressors, agents that regulate cell proliferation and differentiation.
(Henske et al. 1996)
Many scientists tried to identify more elements to understand the origin of this genetic deregulation. For instance (b) Tuberous Sclerosis C2 gene product, tuberin, encodes a GTPase activating protein (GAP) domain, which regulates the activity of RAP1 (repressor-activator protein 1) in vitro. In order to understand if RAP1 deregulation leads to an increased astrocyte proliferation in vivo, it was generated a transgenic mice expressing activated RAP1, proper of the astrocytes. The result was that the tumor suppressor properties of tuberin are unlikely to be related to RAP1 inactivation and the RAP1 inhibits mitogenic oncogene RAS pathway signaling in astrocytes. In addiction it is necessary to underline the great spectrum of mutations across Tuberous Sclerosis C and Tuberous Sclerosis C2 loci that are responsible of the difference in severity of Tuberous Sclerosis C1 and Tuberous Sclerosis C2 associated diseases (c).
Many studies in animals demonstrated that Tuberous Sclerosis C2+/- loss or inhibition is associated with up-regulation of a peptide named cyclin D1, regulated by a beta-catenin and the results were that the cell proliferation effects of hamartin and tuberin are mediated through beta-catenin protein and the high levels of beta-catenin were linked to renal tumors as angiomyolipoms in Tuberous Sclerosis C2 mutations. So the hypothesis is that hamartin and tuberin regulates negatively the beta-catenin stability and activity by the deregulation of the beta-catenin complex. The localization and the distribution of hamartin and tuberin are different in different tissues. In general, hamartin and tuberin are expressed in epithelium cells, myocites and neuro tissues. Besides seems that the co-expressing hamartin and tuberin tissues are prone to a higher incidence of hamartomas than those expressing only one protein but in different patterns of cellular localization (d).
Physiopatology: Tubers are the expression of an early disorder of the embryogenesis. Greater are the number of tubers and greater are the neurological impairments. They can be found everywhere within the cerebral hemispheres as subependymal region located in the walls of lateral ventricles and on the surface of the basal ganglia and may extend into the ventricles, in the foramen of Monro area and they can cause obstruction and hydrocephalus and in the end in the cortical gyri and sulcus terminalis. Tuberous Sclerosis induce a reduction of the number of neurons that are substituted by “monster” giant neurons multinucleated. Besides the overgrowth of the fibrillary astrocytes can determinate malignant astrocytomas. The sclerosis induces a demyelization, calcium deposition in the glia and the blood vessels go through a hyaline degeneration.
Clinical findings: they can show a wide variety of sign that involve many organs as consequence of the multifactorial origin of this genetic disorder.
Adenoma Sebaceum (80%):
· Rare at birth, they are present in 12% at 1 year, 33% at 2 years and 40% at 3 years
· Histologically they are angiofibromas
Ash-leaf Spots (90%):
· Localized on the trunk and limbs. Vary in number and size appearing as hypopigmented oval or leaf-shaped spots. The Wood’s light let to visualize them.
Shagreen Patches (35%):
· Isolated raised and thickened plaques with orange-peel consistency, localized in the lumbosacral area. Develop in late infancy
Café-au-lait spots (7-16%)
· First and most common symptom of Tuberous Sclerosis C. It shows itself as spasms at the beginning and later develops as generalized seizures (tonic, clonic, akinetic, myoclonic) until epileptogenic foci.
Mental Retardation (60-70%).
Hydrocephalus if tubers obstruct the foramen of Monro or the aqueductus.
· Rhabdomyomas occur solitary or multiple. Can infiltrate or diffuse the heart walls, valves and septi. Can cause congestive heart failure or arrhythmias such as Wolf-Parkinson-White. They can cause in utero deaths or before skin manifestation.
· Koenen’s tumors as subungual fibromas localized often on toes.
· Astrocytomas localized on the lateral ventricles or anterior portion of the 3rd ventricle. They can cause vomiting, papilledema and nausea as hemianopsia and hemiparesis.
Diagnosis: The diagnosis is usually suggested by the discovery of cardiac tumors (fig. 2), that resemble small uterine fibroids (round usually well delineated homogeneous masses). Between 51 and 86% of cardiac rhabdomyomas are associated with tuberous sclerosis. Occasionally the finding of a rhabdo during routine second trimester ultrasound examination may lead to the recognition that the mother is affected (this was the case in the patient in fig. 1 when the lesion in fig 2 was recognized). Cardiac rhabdomyomata increase prenatally, may regress in early infancy, remain unchanged during childhood, and then again regress in adolescence. The rhabdos may cause rhythm disruptions (Wolff-Parkinson-White, supraventricular tachycardia, paroxysmal arrhythmias) as well as obstructions or regurgitation. Renal angiofibroma have not been recognized prenatally, although this may simply be a matter of time. Some recent unpublished reports have demonstrated that the periventricular subependymal nodules could also be detected. The MRI help in this case to reveal intracranial calcifications as subependymal tubers, in foramen of Monro or periventricular regions or at the level of the 3rd ventricle that appear as candle drippings.
Figure 2: A large rhabdomyomas
Associated anomalies: See definition.
Differential diagnosis: The predominant prenatal finding is that of the rhabdos. Other cardiac tumors such as fibroma should also be considered.
Prognosis: When no hydrops result from the presence of the rhabdos, the prognosis depends on the other complications of the disorder. Because of the great variability of expression, an accurate prediction of the status of the child is difficult to infer from the status of the parent. Further, new genetic evidence seems to indicate that the mental prognosis varies with the locus of the defective gene, thus this may influence the decision about the pregnancy in the future.
Management: Termination of the pregnancy may be offered before viability but a multidisciplinary approach is a must.
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[a] Lendvay T.S., Marshall F.F. : The tuberous sclerosis complex and its highly variable manifestations. J. Urol. 2003 May; 169 (5): 1635-42.
[b] Apicelli A.J., Uhlmann E.J., Baldwin R.L., Ding H., Nagy A., Guha A., Gutmann D.H. : Role of the Rap1 GTPase in astrocyte growth regulation. Glia 2003 May; 42 (3): 225-34.
[c] Jones A.C., Shyamsundar M.M., Thimas M.W., Maynard J., Idziaszczyk S., Tomkins S., Sampson J.R., Cheadle J.P. : Comprehensive mutation analysis of Tuberous Sclerosis C1 and Tuberous Sclerosis C2 and phenotypic correlations in 150 families with tuberous sclerosis. Am. J. Hum. Genet. 1999 May; 64 (5): 1305-15.
[d] Wei J., Li P., Chiriboga L., Mizuguchi M., Yee H., Miller D.C., Greco M.A. : Tuberous sclerosis in a 19-week fetus: immunohistochemical and molecular study of hamartin and tuberin. Pediatr. Dev. Pathol. 2002 Sep-Oct; 5(5) : 448-64.