Tuberous sclerosis symptoms, causes and treatment

The tuberous sclerosis (ET) or Bourneville disease It is a pathology of genetic origin that produces the growth of benign tumors (hamartomas) and various anatomical malformations in one or more organs: skin, brain, eyes, lungs, heart, kidneys, etc..

At the neurological level, it usually significantly affects the central (CNS) and peripheral (PNS) nervous systems and, in addition, can result in a combination of symptoms including seizures, generalized delay in development, behavioral disturbances, skin malformations and kidney pathologies.

The incidence and severity of symptoms vary considerably among those affected. Many of the people with tuberous sclerosis have a good quality of life.

The pathology that puts the life of the affected person at greatest risk is kidney involvement. A good part of the patients die as a consequence of kidney problems and not due to neurological or cardiac problems..

Tuberous sclerosis is a medical condition that is usually detected early in life, usually during childhood. However, in some cases the absence of a significant clinical course delays the diagnosis until adulthood..

There is currently no specific curative treatment for tuberous sclerosis. All medical interventions will be conditioned to the specific pathologies and clinical manifestations in each case..

Article index

• 1 Characteristics of tuberous sclerosis
• 2 Frequency
• 3 Signs and symptoms
  • 3.1 -Skin involvement
  • 3.2 -Renal involvement
  • 3.3 -Cardiac involvement
  • 3.4 -Lung involvement
  • 3.5 -Neurological involvement
• 4 Causes
• 5 Diagnosis
• 6 Genetic test
• 7 Major and minor clinical criteria
  • 7.1 -Major clinical criteria
  • 7.2 -Minor clinical criteria
• 8 Treatment
• 9 References

Characteristics of tuberous sclerosis

Tuberous sclerosis (TS) is a medical condition that has been described more than 100 years ago. In 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 brain sclerosis.

Although the French neurologist Bourneville, in 1880, first described the characteristic brain lesions of this pathology, it was not until 1908 when Vogt precisely defined the clinical course characterized by the presentation of the classic triad: sebaceous adenoma, delayed mental and seizure episodes.

In addition, in 1913 it was Berg, who demonstrated the hereditary nature of the transmission of this pathology.

The term that gives its name to this disease, tuberous sclerosis, refers to the appearance of tumor lesions (calcified, with a shape similar to a tuber).

However, in the medical literature we can also find other names such as Bourneville's disease, tuberous sclerosis complex, tuberous sclerosis phakomatosis, among others..

Tuberous sclerosis (TS) is a genetic disease that is expressed in a variable way, it is characterized by the presence of hamartomas or benign tumors in various organs, especially in the heart, brain and skin.

Frequency

Tuberous sclerosis is a disease that affects both men and women and all ethnic groups. In addition, it presents a frequency of 1 case per 6,000 people.

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.

It is estimated that around one million people worldwide suffer from tuberous sclerosis. In the case of the United States, it is considered that tuberous sclerosis can affect approximately 25,000-40,000 citizens.

It has an autosomal dominant genetic origin in 50% of cases, while the other 50%, this pathology is due to a de novo genetic mutation.

Signs and symptoms

The clinical characteristics of tuberous sclerosis are fundamentally based on the presence of non-cancerous tumors or other types of formations that grow in various parts of the body, being more common in the skin, heart, lungs, kidneys and brain..

-Skin involvement

In the case of skin lesions, some of the most frequent manifestations are:

• Facial angiofibromas: small benign tumors made up of connective and vascular tissue. They usually appear on the nose and cheeks, and, in addition, at the beginning they usually appear as small reddish bumps that tend to increase in size with the passage of time. They usually appear in 70-80% of cases.
• Nail fibromas 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 (color lighter than the skin) or achromic (total absence of skin pigment): this type of skin involvement appears in approximately 90% of cases of tuberous sclerosis.

-Kidney involvement

In the case of the kidneys, some of the most frequent manifestations are:

• Renal angiomyolipomas (AMLs): they are benign tumor formations. It usually appears in childhood and develops slowly, so they do not usually 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 fluid sacs or pockets that form in different areas of the kidneys. Although in many cases they are not usually of great clinical relevance, in other cases they may be due to renal carcinoma (a type of kidney cancer).

-Cardiac involvement

Cardiac lesions, if present, tend to be larger in size, as well as more severe in the early stages of life and tend to decrease with normal body development.

• Cardiac rhabdomyomas: it is the most frequent cardiac affectation, it usually appears in approximately 70% of cases. They are benign tumor formations that usually reduce their size or disappear with increasing age. As a consequence, other cardiac symptoms such as arrhythmias or tachycardias may appear..

-Lung involvement

Pulmonary signs and symptoms are usually more common 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.

The clinical consequences of lung involvement usually consist of respiratory failure, spontaneous pneumothorax, lung collapse, among others..

-Neurological involvement

Tuberous sclerosis is a pathology that affects a wide diversity of structures in our body, however, the most notable and the main affected area is the nervous system. Neurological involvement usually appears between 80% and 90% of cases.

Some of the medical conditions that usually affect the neurological sphere are:

• Cortical tubers: the tubers or cortical tuberosities are small tumor formations that are usually located in the frontal and parietal areas. In addition, they are usually made up of abnormal or disorganized cells..
• Subependymal glial nodules: This type of affectation is constituted by an abnormal accumulation of cells in different areas of the cerebral ventricles. They usually present an asymptomatic clinical course.
• Subpendymal giant cell astrocytomas: They are tumor formations derived from subependymal glial nodules. When they reach a large size, they can block the drainage of cerebrospinal fluid and consequently, lead to the development of intracranial hypertension.. 

The affectation of each 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 these types of seizures are not controlled effectively, cumulative brain damage may develop..
• Motor symptoms: Likewise, tumor formations at the brain level can lead to the development of hemiplegia, motor incoordination, presence of involuntary movements, among others.
• Intellectual disability: brain alterations and the persistence of seizures can have a strong impact both on general intellectual functioning, as well as on different cognitive domains in particular.
• Behavioral disturbances: in many cases of tuberous sclerosis the presence of autistic features, hyperactivity, aggressive behavior, obsessive-compulsive features, lack or absence of verbal communication, irritability, mood lability, lack of initiative, among others have been observed.

Causes

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..

• The TSC1 gene was discovered in the 90s. It is present on chromosome 9 and is responsible for the production of a protein called hamartin.
• The TSC2 gene, present on chromosome 16, is responsible for the production of the tuberin protein.

Diagnosis

The diagnosis of tuberous sclerosis is usually based on the characteristic clinical signs of this disease: mental retardation, seizures, tumor formations.

At a conference in 1998, a set of consensus diagnostic criteria for tuberous sclerosis was established. Currently, the diagnosis may be probable or possible and a genetic test must also be included..

Genetic testing

Genetic test results must show the presence of a pathogenic mutation or alteration in one of the TSC1 or TSC2 genes.

Generally, a positive result is usually sufficient for the diagnosis, however, a negative result does not exclude the presence. Approximately 10-15% of diagnosed cases have failed to identify a specific genetic mutation.

Major and minor clinical criteria

-Major clinical criteria

Major clinical criteria include a wide variety of medical conditions, including: hypopigmented macules, angiofibromas, nail fibromas, skin plaques, retinal hamartomas, cortical dysplasias, subependymal nodules, cardiac rhabdomyoma, renal angiomyolopima, 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:

• Definitive diagnosis: presence of two major criteria or one major increment and 2 or more minor ones.
• Possible diagnosis: presence of one major criterion or two or more minor criteria.
• Probable diagnosis: presence of a major criterion and a minor criterion.

Treatment

Currently, there is no cure for tuberous sclerosis. Despite this, there is a wide variety of treatments available for symptom control..

In this way, therapeutic interventions will depend fundamentally on the areas that are affected and the medical signs and symptoms that are present..

On a pharmacological level, one of the most used treatments is antiepileptic drugs. The basic objective of these is the control of seizures to avoid the development of secondary brain damage.

On the other hand, it is also possible to use surgical procedures to remove tumor formations. Typically used to remove easily accessible tumors.

In addition, important advances are being made at the experimental level for the identification of curative treatments. On the other hand, psychological intervention is also essential in cases of intellectual impairment.

References

1. Argüelles, M., & Álvarez-Valiente, H. (1999). Clinical Study of Tuberous Sclerosis. Rev Neurol.
2. Clinic, M. (2014). Tuberous Sclerosis. Obtained from Mayo Clinic.
3. Curatolo, P. (2004). Tuberous sclerosis complex. Rev Neurol.
4. Georgescou, G., de la Vaissière, S., Castelnau, P., Halimi, J., & Toutain, A. (2015). Bourneville tuberous sclerosis. EMC-Dermatology.
5. NIH. (2014). Tuberous sclerosis. Retrieved from MedlinePlus.
6. NIH. (2016). Tuberous Sclerosis. Obtained from National Institute of Neurological Disorders ans Stroke.
7. Sáinz Hernández, M., & Vallverdú Torón, H. (2016). Chapter XII. Tuberous sclerosis.
8. Tuberosa, A. N. (s.f.). Tuberous sclerosis. Obtained from Tuberous Sclerosis.og.
9. Tuberous Sclerosis Alliance. (2016). What is TSC? Obtained from Tuberous Sclerosis Alliance.