Tuberous sclerosis: signs and symptoms, etiology, epidemiology, diagnosis, and treatment

Tuberous sclerosis complex (TSC), also known as Bourneville disease, is an autosomal dominant neurodermal syndrome, there are sporadic cases, mostly by the organ development of ectodermal tissue, can appear brain, skin, peripheral nerves, kidneys and other organs involved, clinical features are facial sebaceous adenoma, seizures and intellectual decline

First, the general overview

Tuberous sclerosis is a rare inherited multisystem disease that usually appears

2.

Tuberous sclerosis is a highly variable disease

Due to the highly variable nature of the disease, it is important to note that affected individuals may not have all the symptoms discussed below, and that the manifestations and progression of

Almost all patients with tuberous sclerosis develop skin abnormalities

Small lumps or red dots called hemangiofibromas may appear between the ages of 3 and 5 years, appear mainly on the face, and are usually butterfly-shaped

Bulging, thickened areas of the skin called fibrous plaques may form on the forehead and less commonly on the scalp or cheeks

Patients with tuberous sclerosis are often involved in the central nervous system

Affected individuals may have normal developmental and cognitive functions, but most people experience delays when they reach developmental milestones (developmental delays) and have some degree of intellectual disability

Tuberous sclerosis is a highly variable disease

Due to the highly variable nature of the disease, it is important to note that affected individuals may not have all the symptoms discussed below, and that the manifestations and progression of

Almost all patients with tuberous sclerosis develop skin abnormalities

Small lumps or red dots called hemangiofibromas may appear between the ages of 3 and 5 years, appear mainly on the face, and are usually butterfly-shaped

Bulging, thickened areas of the skin called fibrous plaques may form on the forehead and less commonly on the scalp or cheeks

Patients with tuberous sclerosis are often involved in the central nervous system

Affected individuals may have normal developmental and cognitive functions, but most people experience delays when they reach developmental milestones (developmental delays) and have some degree of intellectual disability
.
Individuals may develop a range of neuropsychiatric disorders, including autism spectrum disorder, attention deficit hyperactivity disorder (ADHD), sleep disorders or disorders, learning and cognitive impairments, or behavioral problems including disruptive and emotional behaviors or problems
.
The term TSC-associated neuropsychiatric disorders (TANDs) can be used to describe collective behavioral, psychiatric, intellectual, academic, neuropsychological, and psychosocial abnormalities
that may be associated with the disorder.

3.
Causes

Tuberous sclerosis is caused
by a change (mutation) in one of two different genes (TSC1 gene or TSC2 gene).
Genes provide guidance
for the creation of proteins that play a key role in many functions of the body.
When a gene is mutated, protein products may be defective, inefficient, or missing
.
Depending on the function of a particular protein, this affects many organ systems of the body, including the brain
.
Often, alterations in the TSC2 gene lead to more severe disease expression
.

In many cases, the changes that lead to tuberous sclerosis occur in the form of new (sporadic or de novo) mutations, meaning that the genetic changes occur only when the child's eggs or sperm are formed, and no other family members are affected
.
The disease is not inherited or "carried" from healthy parents
.
However, this alteration can also be transmitted through dominant inheritance (one of the traits passed on to their children from the affected mother or father
).

Most genetic disorders are determined by the state of two copies of a gene, one from the father and one from the mother
.
Dominant genetic disease occurs when only one copy of an abnormal gene is needed to cause a specific disease
.
Abnormal genes can be inherited from either parent or as a result of new mutations (genetic alterations) in affected individuals
.
There is a 50%
risk of passing the abnormal gene from the affected parents to the offspring per pregnancy.
Men and women are at the same
risk.

The TSC1 gene is located on the long arm (q) of chromosome 9 (9q34); TSC2 is located on
the short arm (p) of chromosome 16 (16p13.
3).
Chromosomes are present in the nuclei of all somatic cells
.
They carry the genetic characteristics
of each individual.
Human pairs are numbered from 1 to 22, with the 23rd pair of X and Y chromosomes not equal in males and two X chromosomes in females
.
Each chromosome has a short arm, called a "p", and a long arm is identified
by the letter "q".
Chromosomes are further subdivided into numbered bands
.

The TSC1 gene regulates (encodes) the production of a protein called hamartin, which is thought to be a tumor suppressor
.
The TSC2 gene encodes a different tumor suppressor protein called a tuber protein
.
Tumor suppressor genes are genes that slow cell division, repair cell DNA damage, and/or tell cells when they die, a normal process
called apoptosis.
Hamartin and tuberin are thought to inhibit the activity
of mammalian targets called rapamycin in vivo, or chemical pathways of the mTOR pathway.
This chemical pathway involves many complex interactions that are essential for normal human development; The mTOR pathway regulates the production (synthesis) of proteins involved in many cellular functions, including cell growth, proliferation, and survival
.
Alterations in the TSC1 and TSC2 genes eventually lead to uncontrolled activity or "over-activation" of the mTOR pathway, leading to the development
of tumors characterized by tuberous sclerosis.

4.
Epidemiology

Tuberous sclerosis is a rare genetic disorder that affects 1 in 6,000 newborns
in the United States.
In the United States, approximately 40,000 to 80,000 people suffer from tuberous sclerosis
.
The prevalence in Europe is estimated to be between one in 25,000 and one in 11,300
.
It is believed that as many as 2 million people worldwide suffer from this disease
.
Men and women are affected in the same amount, and the disease occurs in
all racial and ethnic groups.

TSC is the most common genetic disorder
associated with epilepsy and autism.
It can occur in all races and ethnicities, with no difference in incidence between males and females, with TSC
in 1 in every 6 000 to 10 000 newborns.
About two-thirds of patients with TSC have no family history, and one-third of patients' parents also have TSC
.
If one of the parents is diagnosed with TSC, the probability of the child being sick is 50%.

5.
Differential diagnosis

Symptoms of the following disorders may be similar
to those of tuberous sclerosis.
Comparison may be helpful in the differential diagnosis:

The various symptoms of tuberous sclerosis are nonspecific, and many symptoms can appear
as isolated findings or as part of another syndrome or disease.
Examples of such disorders include Ito hypopigmentation, Sturge-Weber syndrome, epidermal nevi syndrome, Birt-Hogg-Dube syndrome, multiple endocrine tumors, and various epilepsy disorders
.
Isolated brain tumors and cardiac myxomas, as well as other tumors, may need to be distinguished from
tuberous sclerosis.
(For more information about these diseases, select the specific disease name as your search term in the Rare Diseases Database.

) ）

Some people with tuberous sclerosis syndrome also develop symptoms of autosomal dominant polycystic kidney disease (ADPKD), a rare kidney disease
.
This is due to the loss (deletion) of genetic material on chromosome 16, which contains the TSC2 and PKD1 genes that cause ADPKD
.
This is called a continuous genetic syndrome
.

6.
Diagnosis

Diagnosis of tuberous sclerosis is based on identification of characteristic symptoms, detailed patient and family history, comprehensive clinical evaluation, and various specialized tests
.
For example, hypopigmented spots of the skin that appear with seizures or autism are diagnostic cues
of tuberous sclerosis.
Clinical diagnostic criteria for tuberous sclerosis have been established and updated (Northrup et al.
, 2018
).

In general, in individuals with two or more primary features or one primary feature and two or more minor features, the diagnosis is considered definitive
.
A possible diagnosis is suspected when one primary feature or two or more minor features
are present.

In some cases, cardiac rhabdomyomas
can be detected before birth (prenatal).

Clinical testing and examination

Molecular genetic tests can confirm the diagnosis
of tuberous sclerosis.
Molecular genetic testing can detect changes in one of the two genes known to cause disease and can be used
as a diagnostic service in specialized laboratories.

A variety of tests can be used to help obtain a diagnosis of tuberous sclerosis or to assess or determine the extent of
an individual's disease.
Such tests include computed tomography (CT) scans and magnetic resonance imaging (MRI) to assess the brain for tumors or other brain involvement
.
MRI may also be used to evaluate the kidney or liver for tumors
.
High-resolution CT scans can be used to evaluate the lungs
.
During CT scans, computers and X-rays are used to make film showing cross-sectional images of certain tissue structures
.
MRI uses magnetic and radio waves to produce cross-sectional images of specific organs and body tissues
.

Echocardiography and electrocardiogram (EKG) can be used to evaluate the heart for rhabdomids
.
In echocardiography, sound waves are directed at the heart, enabling doctors to study heart function and movement
.
An electrocardiogram records the electrical impulses of the heart and may show abnormal electrical patterns
.

Diagnostic criteria for tuberous sclerosis, see table 114-1
.

7.
Treatment

Treatment may require a coordinated effort by a team of specialists
.
Pediatricians and general physicians, neurologists, dermatologists, cardiologists, dental specialists, ophthalmologists, psychiatrists, and other healthcare professionals may need to plan the treatment
of affected children systematically and comprehensively.
Genetic counseling will be beneficial to affected individuals and their families
.

Treatment of tuberous sclerosis is supportive and symptomatic
.
Early developmental interventions are important
to ensure that affected children reach their potential.
Most affected children will benefit from occupational, physical and speech therapy
.
Various rehabilitation and behavioral treatments can be beneficial
.
Treatment must be continued throughout the year to promote the development of new skills and prevent degradation
.
Additional medical, social and/or vocational services, including special remediation education, may be required
.
Psychosocial support for the whole family is also important
.

Antiepileptic drugs (anticonvulsants) may be prescribed to control seizures
.
The specific medication used depends on several factors, including the specific type of seizure, the age of the affected individual, other organ systems affected, and the severity
of the symptoms 。 Conventional anticonvulsants that can be used include phenobarbital, dilantin (phenytoin), clonopine (clonazepam), depacconiate/depacater (valproic acid/sodium dipropionate), ticagreto (carbamazepine), traleto (oxcarbazepine), topame (topiramate), lamotrigine (lamotrigine), Zonegran (zonisemide), Vimpat (lacosamide), Banzel (rufinamide), Onfi ( clobazam) and so on
.
All of these anticonvulsants have potential side effects that require careful monitoring
by a doctor.

The U.
S.
Food and Drug Administration (FDA) has approved two drugs specifically for the treatment of seizures
associated with tuberous sclerosis.
The FDA approved Afinirter (everolimus) for the treatment of seizures in adults and children with tuberous sclerosis 2 years of age and older in 2018 and Epidiolex (cannabidiol) for the treatment of patients
1 year of age and older in 2020.

Sabril (vigabatrin) was approved by the FDA in 2009 for the treatment of infantile spasms
in children aged 1 month to 2 years.
The treatment of children with tuberous sclerosis and infantile spasms has been found to be effective
with vigabatene.
Loss of vision is an important safety issue
in the use of this drug.
The FDA has also approved adrenocorticotropic hormones or ACTH (Acthar gel) for the treatment of infantile spasms
.
This drug is also used to treat babies
with tuberous sclerosis.
Due to their side effects, these drugs are used
with caution.

There are no specific anti-epileptic drugs available to all affected individuals
.
Often, a combination of different drugs may be required to treat certain individuals
.
Alternative treatments include a ketogenic diet or a glycemic diet
.
Sometimes, seizures can be difficult to treat, and drugs or diets that are initially effective will no longer provide benefit (refractory seizures
).
In some cases, epilepsy surgery may be required to remove areas of brain dysplasia to help control seizures
that do not respond to drugs or stop responding.
Less invasive surgical options for controlling seizures include the implantation of a vagus nerve stimulator (VNS device
).
This is a small electrical stimulator that is placed under the upper chest skin and connected to a vagus nerve to provide intermittent electrical stimulation, like a pacemaker for the brain
.

If the normal function of a particular organ is impaired by the presence of a tumor, surgery
on other organs may be required.
For example, cerebrospinal fluid (CSF) circulation obstruction (intracranial hypertension) due to benign tumors may require shunt surgery to drain fluid or surgery to remove the tumor
.

In 2012, the FDA approved the use of Afinitor for the treatment of children and adults
with subependymal giant cell astrocytoma that cannot be resected or can only be partially removed by surgery.
The FDA has also approved everolimus for the treatment of tuberous sclerosis
in adults with renal angiomyolioma that does not require immediate surgery.
In some cases, angiomyolioma requires surgery or embolization
.
Cutting off the blood supply to kidney tumors (arterial embolism) can be used to shrink the size of the
tumor.
After embolization, tumors that retain the kidney or destroy (ablate) tumors that are preserved in the kidneys are usually treated with corticosteroids and surgery
.
Large cystic lesions of the kidneys may also require surgical decompression or removal
.

Benign tumors within the heart (rhabdomyomas) may not cause symptoms and usually do not require treatment because they usually resolve
on their own within the first few years of life.
However, if there are symptoms, surgical excision (excision)
may be required.
Reports in the medical literature detail the off-label use of mTOR inhibitors when treating these tumors and achieve positive results
.
Some affected people may take certain medications to treat arrhythmias (arrhythmias
).

Individuals who take mTOR inhibitors for internal tumors, such as SEGA or angiomyolitomyoma, may see improvement
in skin damage.
Topical formulations of mTOR inhibitors have shown promise for
the treatment of facial angiofibromas.
Individuals who are not immediately indicated for mTOR inhibitor therapy may undergo certain procedures to improve the appearance of skin lesions, including microdermabrasion, laser treatment, or surgical resection (resection) of the injury
.

In 2015, the FDA approved the use of mTOR inhibitors for the treatment of lung complications such as LAM in patients with tuberous
sclerosis.
Since LAM most often occurs in young women of childbearing age, researchers speculate that female hormones such as estrogen play a role
in the development of the disease.
The link between LAM and estrogen has not been confirmed
.
However, many doctors have explored the use of drugs
that reduce the production or effect of estrogen in the body.
Results vary from person to person
.
Such agents may include medroxyprogesterone
acetate.
Patients with LAM should discontinue estrogen-containing medications and dietary supplements
.

Some people with impaired lung function may require supplemental oxygen therapy
.
In individuals with severe lung disease who are resistant to treatment, lung transplantation
may eventually be required.

8.
Rare disease information registration

If you are willing to seek constantly updated information, it is recommended that you register the patient's information here, even if you are not fully diagnosed, you can register, click to enter:

Patient Information Registry System for Rare Diseases

Resources:

#/knowledge/jbzsk/detail/148

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