The tuberous sclerosis ( ET ) or Bourneville ‘s disease is a disease of genetic origin that produces the growth of beningnos tumors (hamartomas) and various anatomical malformations in one or more organs: skin, brain, eyes, lungs, heart, kidneys, etc … (Sáinz Herández and Vallverú Torón, 2016).
At the neurological level, it generally affects significantly the central nervous system (CNS) and peripheral (SNP) and, in addition, can result in a combination of symptoms including seizures, generalized developmental delay, behavioral changes, skin malformations and renal pathologies (National Institute of Neurological Disorders and Stroke, 2016).
The incidence and severity of symptoms vary considerably among those affected. Many people with tuberous sclerosis have a good quality of life (National Tuberose Sclerosis Association, 2016).
The pathology that puts the affected person’s life at greater risk is kidney involvement. Many of the patients die as a result of kidney problems and not by neurological or cardiac problems (Curatolo, 2003).
Tuberous Sclerosis Treatment
The tuberous sclerosis is a medical condition which is typically detected in the early stages of life, usually during infancy. However, in some cases the absence of a significant clinical course delays diagnosis until adulthood (Mayo Clinic, 2014).
Currently, there is no specific curative treatment for tuberous sclerosis. All the medical interventions will be conditioned to the pathologies and specific clinical manifestations in each case (Sáinz Herández and Vallverú Torón, 2016).
Characteristics of tuberous sclerosis
Tuberous sclerosis (TS) is a medical condition described more than 100 years ago (Argüelles and Álvarez-Valiente, 1999).
In the year 1862, Von Recklinghausen published a clinical report describing a case of a newborn whose death was due to the presence of cardiac tumors and numerous cerebral sclerosis (Gerogescou et al., 2015)
Although the French neurologist Bourneville, in 1880, described for the first time the brain lesions characteristic of this pathology, it was not until 1908 when Vogt, defined precisely the clinical course characterized by the presentation of the classic triad: sebaceous adenoma, delay mental and convulsive episodes (Argüelles and Álvarez-Valiente, 1999).
In addition, in 1913 it was Berg who demonstrated the hereditary character of the transmission of this pathology (Gerogescou et al., 2015).
The term that gives its name to this disease, tuberous sclerosis, refers to the appearance of the tumor lesions (calcified, with a shape similar to a tubercle ) (Sáinz Herández and Vallverú Torón, 2016).
However, in the medical literature we can also find other names such as Bourneville disease, tuberous sclerosis complex, tuberous sclerosis phacomatosis, among others.
Tuberous sclerosis (TS) is a genetic disease that is expressed in a variable manner, characterized by the presence of hamartomas or benign tumors in various organs, especially in the heart, brain and foot (Arango et al., 2015).
Tuberous sclerosis is a disease that affects both men and women and all ethnic groups (Gerogescou et al., 2015).
In addition, it presents a frequency of 1 case per 6,000 people (Curatolo, 2003).
However, other statistical studies estimate the prevalence of this pathology in one case per 12,000-14,000 people under ten years of age. While the incidence is estimated at 1 case per 6,000 births (Gerogescou et al., 2015).
It is estimated that around one million people worldwide suffer from tuberous sclerosis (Tubeorus Sclerosis Association, 2016).
In the case of the United States, it is considered that tuberous sclerosis can affect approximately 25,000-40,000 citizens (National Institute of Neurological Disorders and Stroke, 2016).
It has an autosomal dominant genetic origin in 50% of the cases, while the other 50%, this pathology is due to a de novo genetic mutation (Curatolo, 2003).
Signs and symptoms
The clinical characteristics of tuberous sclerosis are based mainly on the presence of non-cancerous tumors or other types of growths that grow in different parts of the body, being more common in the skin, heart, lungs, kidneys and brain (Mayo Clinic, 2014).
In the case of skin lesions, some of the most frequent manifestations are (Sáinz Herández and Vallverú Torón, 2016, National Association of Tuberous Sclerosis, 2016):
- Facial angiofibromas: Small tumors of benign type constituted by connective and vascular tissue. They usually appear on the nose and on the cheeks, and, at the beginning, they usually appear as small reddish bulges that tend to increase in size over time. They usually appear in 70-80% of cases.
- Ungual Fibroids or Köenen tumors : fleshy formations that develop under or around the nails.
- Fibrous plates : Pink spots or formations located on the face, especially on the forehead or cheeks.
- Hypochromic spots (lighter color than skin) or acromic (total absence of skin pigment): This type of skin involvement occurs in approximately 90% of cases of tuberous sclerosis.
In the case of the kidneys, some of the most frequent manifestations are (Sáinz Herández and Vallverú Torón, 2016, National Association of Tuberous Sclerosis , 2016):
- Renal angiomyolipomas (AMLs) : These are benign tumor formations. It usually appears and childhood and develop slowly, so they usually do not cause major medical problems until adulthood. It is a common clinical manifestation, it appears in 70-80% of cases. Some of the symptoms that will cause are: hypertension, kidney failure, or blood in the urine, among others.
- Kidney cysts: Kidney cysts are sacs or bags of fluids that form in different areas of the kidneys. Although in many cases they do not usually have great clinical relevance, in other cases they may be due to renal carcinoma (a type of kidney cancer).
Cardiac lesions, if present, usually present a larger size, in addition to more serious in the early stages of life and have to be reduced with the normal development of the organism (Mayo Clinic, 2014).
- Cardiac rhabdomyomas : It is the most frequent cardiac involvement, usually occurring in approximately 70% of cases. They are benign tumor formations that usually reduce their size or disappear with increasing age. It is possible that, as a consequence, other cardiac symptoms such as arrhythmias or tachycardias appear (Sáinz Herández and Vallverú Torón, 2016, National Association of Tuberous Sclerosis, 2016)
Lung signs and symptoms are more frequent in women than in men. In addition, it is usually associated with the presence of lymphangioleiomyomatosis (LAM), a type of degenerative pathology that affects the lungs (Sáinz Herández and Vallverú Torón, 2016).
The clinical consequences of pulmonary involvement usually consist of respiratory failure, spontaneous pneumothorax, pulmonary collapse, among others (Sáinz Herández and Vallverú Torón, 2016).
Tuberous sclerosis is a pathology that affects a wide variety of structures of our body, however, the most remarkable and the main area affected is the nervous system. Neurological involvement usually occurs between 80% and 90% of cases (Curatolo, 2003).
Some of the medical conditions that usually affect the neurological sphere are (Sáinz Herández and Vallverú Torón, 2016, National Association of Tuberous Sclerosis, 2016):
- Cortical tunnels: The tubers or cortical tuberosities are small tumor formations that are usually located in frontal and parietal areas. In addition, they are usually formed by abnormal or disorganized cells.
- Subependymal glial nodes: This type of involvement is constituted by an abnormal accumulation of cells in different areas of the cerebral ventricles. They usually present an asymptomatic clinical course.
- Subpendimary giant cell astrocytomas: These are tumor formations derived from subependymal glial nodules. When they reach a high size they can block the drainage of cerebrospinal fluid and consequently, lead to the development of intracranial hypertension.
The affectation of each one of these areas, will produce a series of medical complications or secondary symptoms, among which are:
- Convulsive episodes : The presence of tumor formations at the neurological level can lead to epileptic discharges in approximately 92% of cases. When this type of crisis is not controlled effectively, cumulative brain damage may appear.
- Motor symptoms : Similarly, tumor formations at the brain level can lead to the development of hemiplegia, motor uncoordination, presence of involuntary movements, among others.
- Intellectual disability : The cerebral alterations and the persistence of the convulsive episodes can have a strong impact so much in the general intellectual functioning, as in the different cognitive domains in particular.
- Behavioral alterations : In many cases of tuberous sclerosis has been observed the presence of autistic features, hyperactivity, aggressive behavior, obsessive-compulsive features, lack or absence of verbal communication, irritability, lability, lack of initiative, among others.
The origin of tuberous sclerosis is genetic. Clinical and experimental studies have managed to identify that this pathology is due to the presence of defects or mutations in two genes, TSC1 and TSC2 (National Institute of Neurological Disorders and Stroke, 2016).
- The TSC1 gene was discovered in the 1990s. It is present on chromosome 9 and is responsible for the production of a protein called hamartin (National Institute of Neurological Disorders and Stroke, 2016).
- The TSC2 gene, present on chromosome 16, is responsible for the production of the tuberin protein (National Institute of Neurological Disorders and Stroke, 2016).
The diagnosis of tuberous sclerosis is usually based on the clinical signs characteristic of this disease: mental retardation, seizures, tumor formations (Argüelles and Álvarez-Valiente, 1999).
At a conference in 1998, a series of consensus diagnostic criteria for tuberous sclerosis were established (Gerogescou et al., 2015)
Currently, the diagnosis can be probable or possible and in addition a genetic test must be included (Gerogescou et al., 2015).
The results of the genetic tests must show the presence of a mutation or pathogenic alteration in one of the genes TSC1 or TSC2.
Generally, a positive result is usually sufficient for the diagnosis, however, a negative result does not exclude the presence. Approximately between 10% and 15% of diagnosed cases have not been able to identify a specific genetic mutation.
Major and minor clinical criteria
Major clinical criteria
The major clinical criteria include a wide variety of medical conditions among which are: hypopigmented macules, angiofibromas, nail fibroids, skin patches, retinal hamartomas, cortical dysplasias, subependymal nodules, cardiac rhabdomyoma, renal angiomyolopymas and lifangioleimiomatosis.
Minor clinical criteria
Less clinical criteria include: dental depressions, skin lesions, intraoral fibroids, retinal macules, multiple renal cysts and extrarenal hamartomas.
Thus, depending on the presence of the major and / or minor criteria, the diagnosis of tuberous sclerosis can be (Gerogescou et al., 2015):
- Definitive diagnosis : presence of two major criteria or a greater increase and 2 or more minor ones.
- Possible diagnosis : presence of a major criterion or two or more minor criteria.
- Probable diagnosis : presence of a major criterion and a minor criterion.
Currently, there is no cure for tuberous sclerosis. Despite this, there is a wide variety of treatment available for symptom control.
In this way, the therapeutic interventions will depend fundamentally on the areas that are affected and the medical signs and symptoms that are present.
At the pharmacological level, one of the most used treatments are antiepileptic drugs. The basic objective of these is the control of seizure episodes to prevent the development of secondary brain damage.
On the other hand, it is also possible to use surgical procedures for the elimination of tumor formations. Normally, it is used to eliminate tumors that have easy access.
In addition, important advances are being made at experimental level for the identification of curative treatments.
On the other hand, psychological intervention is also fundamental in cases of intellectual affectation.