Tuberous sclerosis

Generality

Tuberous sclerosis is a genetic disease that affects several organs and tissues of the human body. For this reason, it presents a wide spectrum of symptoms, some typical of early childhood, others of adulthood. Tuberous sclerosis can be transmitted from parents to children, but it can also arise due to a spontaneous DNA mutation.

What is tuberous sclerosis

Tuberous sclerosis is a genetic disorder characterized by the formation of hamartomas in different organs or tissues.

The hamartoma identifies an area of ​​tissue in which the cells have multiplied quite intensely, forming an evident mass, similar to a nodule or a tuber . Hamartomas remember tumors, but should not be confused with them: in fact, the cells of the hamartoma are identical to those of the tissue in which they proliferate; those of a tumor, on the other hand, have different characteristics. It should be remembered, however, how these cells can evolve and give rise to benign neoplasms, fibroids and angiofibromas .

Brain, skin, kidneys, eyes, heart and lungs are the most affected districts, but they are not the only sites. Due to the multiplicity of organs and tissues involved, tuberous sclerosis is also called a multisystem genetic disease .

Later on you will understand why hamartomas appear only in certain areas.

Epidemiology

The incidence and number of cases in the world are uncertain. The uncertainty is due to the fact that many patients do not show symptoms and lead a normal life.

However, it is estimated that the incidence of tuberous sclerosis is one in every 5, 000-10, 000 newborns. There are about two million cases worldwide.

Cause

Tuberous sclerosis is a genetic disease; this means that a gene, present in the DNA of the affected subject, has changed.

There are two genes that cause tuberous sclerosis when affected by their mutations:

• TSC1 .
• TSC2 .

The cases of tuberous sclerosis so far observed have only one of these genes mutated. Therefore, the single mutation of TSC1, or TSC2, is sufficient to determine tuberous sclerosis.

Studies conducted in Europe and the United States report that the mutation in TSC2 (80% of cases) is much more frequent than in TSC1 (the remaining 20%).

TSC1 and TSC2

The TSC1 gene resides on chromosome 9 and produces a protein called amartina .

The TSC2 gene resides on chromosome 19 and produces a protein called tuberin .

The proteins produced, amartina and tuberina, unite and work together. This explains why the mutation of one or the other determines the same pathology.

FUNCTION OF TSC1 AND TSC2

They are considered tumor suppressor genes and have a fundamental role in the processes of:

• Growth and differentiation of cells, during embryogenesis.
• Protein synthesis.
• Autophagy.

When TSC1 and TSC2 are mutated, the proteins produced are defective and these physiological processes no longer take place regularly.

INSURANCE OF THE AMARTOMI

Hamartomas can arise when a mutation occurs in a gene that controls cell growth and differentiation, such as TSC1 or TSC2. Consequently, the cells grow in number, generating obvious masses; thus, plaques with a shape similar to a nodule or a tuber are formed. In histology, this process is defined as hyperplasia .

GENETICS

Two premises:

• Each human DNA gene is present in two copies. These copies are called alleles .
• Human beings have 23 pairs of chromosomes. Of these, only one couple determines sex (sex chromosomes); all the others are called autosomal chromosomes .

Tuberous sclerosis is an autosomal dominant genetic disorder . For this reason, it is sufficient for an allele to be changed so that the whole gene does not work properly. In fact, the mutated allele has more power than the healthy one ( dominance ).

In fact, tuberous sclerosis disorders worsen when both alleles of TSC1, or TSC2, are mutated. In other words, only one allele, albeit dominant on the other, does not cause obvious symptoms. In these cases we speak of incomplete dominance alleles.

INHERITANCE? OR SPONTANEOUS MUTATION?

The mutation of TSC1, or TSC2, may arise due to:

• Inherited transmission (ie from one of the two parents) of a mutated allele.
• Spontaneous mutation of an allele in embryonic phase (or embryogenesis).

One third of the cases of tuberous sclerosis are due to hereditary transmission. In these cases, it is sufficient for a parent to have a mutation of the TSC1 or TSC2 genes in order for the offspring to be affected by the disease (we have indeed seen that tuberous sclerosis is an autosomal dominant inherited disease).

The remaining 2/3 of the cases is due to a spontaneous mutation during the embryonic phase.

WHY ARE THEY ONLY AFFECTED BY ORGANS?

Premise: during the early stages of its development, the embryo presents three layers of cells:

• Ectoderma, the most external.
• Mesoderma, the central.
• Endoderm, the innermost.

Specific organs and tissues derive from each layer.

We are now in possession of all the elements to understand why hamartomas arise only in certain districts of the body.

TSC1 or TSC2 mutations occur in the embryonic phase of ectoderm and mesoderm cells. Therefore, the tissues, which will be born from these cellular layers, will present hamartomas.

Symptoms

To learn more: Tuberous Sclerosis - Causes and Symptoms

There are numerous organs and tissues affected by tuberous sclerosis. The districts most affected are:

• Brain, Skin, Kidneys, Heart, Eyes

But we must not forget other, more rare, disorders:

• Lungs, Intestine, Liver, Teeth, Endocrine System, Bones

Some symptoms appear at a young age, others in adulthood.

INCOMPLETE DOMINANCE

It has already been mentioned above that the dominance of the mutated allele of the TSC1 or TSC2 genes is incomplete. This means that the healthy allele is still able to produce a "healthy" protein (amartina or tuberina), albeit in lower quantities. The presence of the "healthy" protein makes up for the damage caused by the mutated protein. Under these conditions, hamartomas do not yet cause dramatic manifestations.

At the moment when the other allele changes (it is a rare but possible event), hamartomas grow in an uncontrolled way.

SKIN MANIFESTATIONS

About 90% of patients have skin changes. The events are numerous and varied. The typical ones are depigmented spots, Pringle sebaceous adenomas and Koenen's nail tumors.

The depigmented spots are hypomelanotic spots, ie with a lower melanin content

Pringle sebaceous adenomas are benign tumors also called facial angiofibromas . Hamartomas appear as small, globular-shaped masses of bright red color. Koenen's nail tumors are fibroids and derive from hamartomas of a few millimeters.

Photo on cutaneous manifestations of tuberous sclerosis

The table shows the numerous cutaneous manifestations due to tuberous sclerosis:

NEUROLOGICAL SYMPTOMS

The sites of the brain affected by tuberous sclerosis are:

• The cerebral cortex
• The white substance
• The ventricles
• The basal ganglia

The two figures help the reader understand the areas involved.

Depending on the location and shape of the hamartomas, different disorders may occur, such as:

• Epilepsy
• Subependymal nodules
• Brain tumors of the astrocytoma type
• Mental, behavioral and learning deficits.

KIDNEY LESIONS

They are very frequent. In fact, they appear in 60-80% of cases. Consist of:

• Hamartomas similar to benign tumors.
• Malformations of the renal structure.

CARDIOVASCULAR LESIONS

Also in this case, they are due to hamartomas similar to benign tumors, called rhabdomyomas.

PULMONARY INJURIES

They are mainly due to pulmonary lymphangioleiomyomatosis ( LAM ) and, to a lesser extent, to micronodular multifocal hyperplasia . They are typical manifestations of adulthood.

OTHER INJURIES

Diagnosis

The diagnosis consists of:

• history
• Clinical analysis of the aforementioned signs
• Instrumental examinations

HISTORY

The doctor makes an investigation into the patient's family history to see if tuberous sclerosis is inherited or due to a spontaneous mutation.

CLINICAL ANALYSIS OF SIGNS

In 1998, a group of international doctors established a diagnostic criterion based on the aforementioned clinical manifestations. They have been divided into:

• Major signs (or criteria)
• Minor signs (or criteria)

The classification of the signs is as follows:

INSTRUMENTAL EXAMINATIONS

GENETIC TEST

This is a long survey, which takes a couple of months. It is therefore not useful for early diagnosis. Rather, it serves to confirm the diagnosis based on clinical signs.

Therapy

There is no specific and effective cure, as tuberous sclerosis is one:

• Genetic disease.
• Multisystem disease.

However, some symptoms can be contained to avoid complications and improve the quality of life of patients.

PHARMACOLOGICAL TREATMENT

The clinical manifestations that can be treated with drug administration are:

• Infantile epilepsy
• Pulmonary lymphangioleiomyomatosis (LAM)
• Renal disorders

Infantile epilepsy . The small patient receives anti-convulsant drugs:

• ACTH (adrenocorticotropic hormone)
• Vigabatrin

Pulmonary lymphangioleiomyomatosis . Bronchodilators, beta-2 agonists such as salbutamol are useful. The efficacy of hormone therapy based on progesterone or buserelin is uncertain

Renal disorders . Antihypertensives such as ACE inhibitors and diuretics are used.

PHYSICAL-SURGICAL TREATMENTS

They consist of interventions aimed at removing:

• Facial angiofibromas
• Nail fibers
• Skin plates
• The knurled spots
• Subependymal astrocytomas in giant cells (SEGA)
• Renal angiomyolipomas
• Lung lesions
• The tubers of the cerebral cortex, which cause epilepsy

The following table summarizes the main therapeutic treatments and their characteristics.

Follow-up and prognosis

Premise: the medical follow-up term refers to the patient who, suffering from cancer, has undergone a surgical operation.

Periodic checks are recommended for follow-up . Ophthalmoscopy, ie the examination of the ocular fundus, can also be performed once a year. Conversely, neurological, cardiac and renal conditions require more frequent monitoring.

PROGNOSIS

The evolution of tuberous sclerosis is variable and depends on each case.

Some patients show mild, almost imperceptible symptoms. For these, the quality of life is not affected by the disease and the prognosis is excellent.

Conversely, other patients show a much more dramatic and obvious symptomatology. Death comes mainly due to neurological lesions, therefore the prognosis becomes very unfavorable.

GENETIC CONSULTING

If one parent has tuberous sclerosis, the likelihood of a child inheriting the same condition is 50%.

If, on the other hand, a child of healthy parents is affected, the likelihood of a second child falling ill is very low. In these cases, a genetic test clarifies whether the parents are carriers of tuberous sclerosis, or whether, instead, a spontaneous mutation has occurred.