Tuberous sclerosis, otherwise referred to as Bourneville's disease or tuberous sclerosis complex, is an inherited disease that affects multiple systems. It is an uncommon condition, which leads to the formation of many tumors in various locations of the body, which are non-malignant.
Tuberin and hamartin, the two proteins related to the inhibition of cellular growth and differentiation are responsible for mediating these processes in the entire body. Their failure to serve their purpose practically implies that tumors, benign in nature, are allowed to develop nearly everywhere throughout the body. A defined set of diagnostic criteria have been established by the Diagnostic Criteria Committee of the National Tuberous Sclerosis Association (USA) .
Patients affected by tuberous sclerosis may present with the following tumors and symptoms:
Patients with tuberous sclerosis present with fluctuating clinical pictures, due to the multiplicity of the locations where the tumors may form.
In order to diagnose tuberous sclerosis, either of the two diagnostic criteria must be met:
Under the category of major features fall the following abnormal findings:
Depending on the pathological findings, various other laboratory or imaging tests can be performed. Renal hamartomas can be monitored with urinalysis and an electrolyte test. Cortical tubers, SENs and SEGAs can be illustrated and followed-up with the use of a magnetic resonance imaging scan (MRI)  or a computerized tomography scan (CT).
Renal abnormalities are best pictured with the use of ultrasonography. CT and MRI scans can further be used to monitor patients with renal dysfunction due to lesions every six to twelve months; CT scans should be conducted as less frequently as possible, due to the radiation the patient is exposed to. Cardiac rhabdomyomas usually subside as the disease progresses and can be revealed and monitored with the use of echocardiography; an electrocardiogram is also useful in order to perform an adequate follow up. Pulmonary lesions are visible on an x-ray or a CT scan.
With reference to additional affected systems, fundoscopy is the examination of choice in order to detect and closely monitor patients with tuberous sclerosis and ocular irregularities. Up to 80% of retinal hamartomas are visible via fundoscopy.
The most challenging and potentially life-threatening symptom related to tuberous sclerosis is epilepsy. Epilepsy should be treated in the same way a non-TSC epilepsy is managed: a single medication is administered in the minimum dosage, which is progressively increased until a therapeutic effect is attained. In cases of drug inefficacy, the antiepileptic drug is changed. A double-drug regime is followed only if the monotherapy does not produce the necessary control. In cases of patients with brain lesions, the administration of anticonvulsive medications should be initiated before seizures start to occur   .
Should a patient present with lymphangioleiomyomatosis, hormonotherapy may be chosen to treat the symptom. Progesterone in combination with an oophorectomy is the treatment of choice. Hypertension occurring as a result of renal dysfunction can be managed with antihypertensive medications and inotropic agents can help to improve the heart's contractility, if the patient suffers from cardiac disease.
The two drugs exclusively used for the management of tuberous sclerosis are everolimus and sirolimus. Given that the products of the TSC1 and TSC2 genes, tuberin and hamartin, actually inhibit the mammalian target of rapamycin complex 1 and tuberous sclerosis patients posses mutated genes, these drugs aim at the compensation of this inadequacy. They act in replacement of the dysfunctional proteins and hinder cellular growth, in order to prevent tumors from forming.
Tuberous sclerosis leads to the formation of benign hamartomas in various locations of the body. Even though the tumors may be quite extensively dispersed, the absence of malignancy renders their prognosis better than it was originally believed. Naturally, the location of the tumor stipulates the rates of morbidity and mortality.
Patients with tuberous sclerosis may have a relatively low quality of living, given that even benign hamartomas can disrupt the functionality of the organs. Death or serious complications, however, are a result of tumors located in the brain and is usually brought on by epileptic seizures or falls and traumatizations that occur as a result of epileptic phenomena. Brain tumors can also lead to an elevated intracranial pressure (hydrocephalus) and antiepileptica can also lead to fatal complications when administered for a long period of time or in an excessive manner. Additionally, hamartomas located on the heart can cause life-threatening arrhythmia, even though they are usually self-restricting.
Another factor that considerably contributes to the elevated morbidity and/or mortality that accompanies tuberous sclerosis is the difficulty to diagnose and effectively manage cases of the disease. A significant number of patients remain undiagnosed or undergo unnecessary and/or possibly risky surgical operations in order to excise a tumor that could also be monitored.
The genetic abnormality that leads to such a clinical picture has been identified as a mutation in the TSC1 or TSC2 gene: they encode for tuberin and hamartin, proteins that inhibit the mammalian target of rapamycin complex 1 (mTORC1). The latter controls the process of cellular growth and metabolic process and without the inhibitory effect of hamartin and tuberin, hyperplasias and benign tumors can form in virtually every part of the body. It has been calculated that the most common mutations affect the TSC2 gene.
Tuberous sclerosis is not commonly encountered in the daily clinical practice, as it affects 40,000 people in the USA. The prevalence has been exhibiting a steady increase during the past years, which has been attributed to the establishment of different criteria and the improvement of diagnostic efficacy.
At an international level, tuberous sclerosis seems to affect approximately 2,000,000 people in the whole world. The type of gene affected by the mutation seems to be dependent upon ethnicity, with some populations presenting with a higher ratio of TSC1/TSC2 mutations when compared to others.
The pathophysiological background of tuberous sclerosis has been mapped since approximately 1993, mutations in the genes TSC1 and TSC2 are responsible for the occurrence of tuberous sclerosis. They are located on chromosomes 9 and 16 respectively and, although their role has yet to be fully illustrated, they are known to play an inhibitory role in the process of cellular growth and differentiation through an interaction with beta-catenin.
Both genes exert an inhibitory effect on the process of cellular growth; they are therefore responsible for controlling the expansion of tumors and preventing tumorigenesis throughout the entire organism. Mutations in those two genes result in an unregulated proliferation of cells and hamartomas. The exact pathway seems to require a second-hit mutation and a LOH (loss of heterozygosity) for a hamartoma to occur, with the exception of brain tumors comprising giant cells.
TSC1 and TSC2 constitute the standard genes that are subject to mutations and induce the condition known as tuberous sclerosis. The types of mutations responsible for the disease vary, with more than 1,800 distinct mutations recognized.
Tuberous sclerosis complex (TSC) or, simply, tuberous sclerosis, is a genetic disease which induces multiple tumors to form in diverse regions of the body. These tumors have no malignant characteristics but nevertheless interfere with each organ's function. The organs that are primarily affected are the lungs, brain, heart and kidneys.
Depending on the location of the tumors, the functionality of the organs may be severely compromised and life-threatening sequelae may be caused, such as hydrocephalus and epilepsy. Disfigurement due to skin tumors may lower the quality of life for a patient and the multitude of the symptoms that can arise definitely renders the individuals affected by the disease considerably disabled. Various degrees of mental disability accompany the clinical picture almost in 80% of the cases and developmental disorders may also be present   .
The condition is a result of a mutation on two specific genes, TSC1 and TSC2. These genes produce two proteins, which prevent the formation of tumors because they prevent cells from growing excessively. The mutations produce faulty proteins, which cannot stop the rapid reproduction of cells and, therefore, tumors are allowed to develop.
Since patients with tuberous sclerosis can have lesion in many organs, the symptoms they experience are multiple and depend on the organ that is affected. The most severe and possibly life-threatening symptom is epilepsy, caused by brain tumors.
Tuberous sclerosis is diagnosed based on a set of criteria, depending on the symptoms. Treatment follows a symptomatic plan, which means that each patient is treated accordingly, depending on the clinical picture they present with. Two drugs, everolimus and sirolimus, are currently studied for their potential contribution to the management of tuberous sclerosis patients in general.