2Department of Medical Biology and Genetics, İstanbul Arel University Faculty of Medicine, İstanbul-Türkiye DOI : 10.5505/tjo.2023.3986
Summary
Tuberous sclerosis complex (TSC) is a neurocutaneous syndrome that can affect multiple organ systems such as the brain, heart, and lung, and neurological disorders such as autism spectrum disorder and mental retardation can be observed along with epileptic seizures in affected individuals. The disease can occur at any age. A genetic disease of TSC develops due to the mutations in TSC1 and TSC2 genes that cause dysfunction in Tuberin and/or Hamartin proteins. Although the disease has a highly variable penetrance, the cellular signal transduction mechanisms of TSC-related genes have largely been elucidated. The diagnostic criteria created by International TSC Consensus Group in 2012 are used in the diagnosis of the syndrome in addition to the genetic tests. At present, it is estimated that there are approximately 2 million people with TSC worldwide and 50,000 people are affected by the disease in the USA alone. It is important to know about the molecular genetics and clinical features of the disease for targeted therapies and well-managed surveillance. In the present study, we aimed to examine the genetic, biological, and clinical features of TSC and to discuss the genetic counseling approach that should be applied to patients with TSC.Introduction
Tuberous sclerosis is a neurocutaneous disease; which was reported by Desire-Magloire Bourneville in 1880 when he named and reported the neuropathological findings as "tuberosclerosis" detected in a young patient with mental abnormality, seizures, hemiplegia, and kidney tumors.[1] The involvement of the hamartomatous or benign lesions in brain, heart, lungs, and kidneys is generally detected in the presence of the disease. In addition, tuberous sclerosis epileptic seizures and neuropsychiatric disorders such as autism spectrum disorder (ASD) and mental retardation are commonly encountered. The disease is often named as tuberous sclerosis complex (TSC) as the disease simultaneously affects various organ systems.[2] The TSC1 and TSC2 genes are responsible for TSC pathology, and the penetrance of these genes varies widely from patient to patient. Although it is known that there are approximately 2 million people with TSC worldwide and 50,000 people are affected by this disease in the USA alone, currently the incidence of the disease is approximately 1 in every 6,000?10,000 live births; and the prevalence is estimated as 1 in 20,000. The disease can occur in all races and ethnic groups and there is no difference between the sexes.[3,4] In terms of clinical features, individuals with TSC can vary widely, even within the same family. In the diagnosis, the diagnostic criteria created by the International TSC Consensus Group in 2012 are used in addition to the genetic tests.[5] Treatment options are organized in accordance with the affected organ(s), and after diagnosis, the patients are followed up for symptoms at frequent intervals throughout their lives. Although inhibitors targeting TSC-related cell signaling pathway as a treatment option are very new, the number of studies on the efficacy of the epidemiological studies is scarce. In the present review, we have discussed the association of TSC with cancer in addition to its genetic, biological, and clinical features.
THE GENETICS OF THE TSC
The genes associated with TSC disease were discovered
as a result of multicentered, and genetic linkage
analysis studies conducted with the inclusion of families
with large number of TSC disease toward the end
of the 1900s. Approximately 10 years after the first linkage
analysis study, the TSC1 gene encoding the 8.6 kb
transcript, consisting of 23 exons and localized in the 55
kb area of 9q34.3; and in later studies, the TSC2 gene,
which is localized in the 40 kb area of 16p13.3, consists
of 41 exons and encodes a 5.5 kb transcript, were found
responsible for the disease.[6,7] At present, it is known
that approximately 2/3 of individuals with TSC have de
novo advanced germline mutations in TSC1 or TSC2 tumor
suppressor genes; and 1 in 3 patients has hereditary
TSC1 or TSC2 mutations and TSC shows an automosal
dominant inheritance pattern.[6] While there may be a
mutation in only one of the genes responsible for the
disease in patients with TSC, the detection of the mutations
in both genes is quite rare; however, there are cases
where mutations are detected in both genes. At present,
1135 unique variants for TSC1 and 3261 unique variants
for TSC2 have been reported in the Leiden Open Variation
database as of July 2020.[8] Mutations in TSC1
are usually in the form of small insertion and deletion
(indel) mutations that produce a premature stop codon
leading to shortening of the protein (truncated gene
product). However, large deletions, duplications, insertions
and stop codon mutations (nonsense) and missense
mutations are encountered in the TSC2 gene.[7,9]
These mutations are found to have spread through the
encoding regions of the genes except for the exon 23 of
TSC1 and alternative spliced exons 25 and 31 of TSC2.
TSC cases associated with TSC1 gene mutations show a
better phenotype than the phenotypes of the cases associated
with TSC2 gene mutations. It is also reported that
TSC1 is more commonly associated with familial TSC.
In addition, some studies showed that there are differences in the severity of the disease phenotype, especially
in terms of neuropsychiatric findings, related to the localization
of mutations in TSC1 and TSC2 mutations.[4]
The small mutational changes commonly detected in TSC1 and TSC2 genes[6] are given in Tables 1 and 2. TSC2 mutations have been shown to be present in approximately 70%, and TSC1 gene mutations in 20% of TSC patients. Although TSC findings were detected in the remaining 10% of individuals, mutations in TSC1 and TSC2 genes have not been reported, and there may be other genes responsible for TSC in individuals in this group.[4,9] It was suggested that the possible genes might be the other genes that play a role in the signaling pathway where the TSC1 and TSC2 were associated with, however, no evidence was found to support this idea in the studies.[9] In the studies using the nextgeneration sequencing (NGS) technologies and RNAbased approaches, it was observed that TSC patients who were suggested to have no mutations in TSC1 and TSC2 genes actually carried low-level somatic mosaicism and intronic splicing variants affecting TSC1 and TSC2 genes.[10,11] After this information, researchers reached to a consensus that there is no third gene which is directly responsible for the development of TSC. As an exception, although not directly responsible for the development of TSC, the Polycystin 1 (PKD1) gene is adjacent to TSC2 on chromosome 16, and polycystic kidney disease (PKD) was reported to have been detected as a different phenotype in TSC when the large deletions detected in TSC2 also affect PKD1.[12]
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Knudson's "two hit" hypothesis is of great importance in understanding the variable clinical manifestations as well as development of lesion in TSC syndrome. Individuals with TSC who are born with defect in one of the alleles of the tumor suppressor TSC1 or TSC2 genes sporadically or with a germline, show TSC findings in their phenotype and develop tumors localized in different organs due to the biallelic inactivation when they lose the function of the non-defective copy of the TSC1 or TSC2 genes due to the second hit mutation to develop later.[13,14] Figure 1 summarizes the localization of TSC1 and TSC2 genes on the relevant chromosomes, the physical features of the genes and the development of Loss of Heterozygosity (LOH) with the two hit hypothesis.
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THE CELL SIGNAL PATHWAY IN TSC
The TSC1 gene encodes the 130 kDa Hamartin protein
consisting of 1164 amino acids, and the TSC2 gene encodes
the 198 kDa Tuberin protein consisting of 1807 amino acids. The complex formed by these two tumor
suppressor proteins are known to play a suppressive
role in the regulation of the mamalian/mechanistic
target of rapamycin (mTOR) signaling pathway.
[15] Hamartin and Tuberin proteins form a heterotrimeric
protein complex with TBC1 domain family
member 7 in the cell. This heterotrimeric complex
dephosphorylates Rheb (RAS Homologous Enriched
in Brain) through its GTPase activating domain and
inactivates Tuberin. Rheb is in active form when it is
bound to GTP. The active Rheb mTOR activates the
mTORC1 complex consisting of mLST8 (Mammalian
Lethal with SEC13 Protein 8), PRAS40 (Proline-Rich
Akt Substrate, 40 kDa), Raptor and Deptor.[16,17]
The activated mTORC1 complex becomes the driving
force for the cellular events such as cell growth,
ribosome biogenesis, protein synthesis, nucleotide
synthesis, lipid synthesis, proliferation, cellular survival, invasion, and metastasis through activation of
S6K (Ribosomal Protein S6 Kinase 1) and suppression
of 4E-BP1 (Eukaryotic Translation Initiator Protein
4E-Linking Protein 1). In response to all these events,
while the activated mTORC1 complex suppresses autophagy,
on the other hand, it may show to have an
anti-apoptotic effect by suppressing Bcl-2 and Bad, by
increasing the p53 activation.[18-21] In TSC patients,
an active heterotrimeric protein complex cannot be
formed due to the inability to express Hamartin or
Tuberin proteins as a result of mutations in the TSC1
or TSC2 tumor suppressor genes or due to the formation
of a shortened gene product. Therefore, the Rheb
and indirectly the mTORC1 protein complex remain
constantly activated. This mechanism is suggested to
be underlying in the formation of hamartomatous lesions
in patients with TSC. Currently, Rapamycin and
its analogs are known as the inhibitors of mTORC1.
Rapamycin is used as a treatment option in many other diseases, particularly in TSC.[22,23] In the light of this information, the relationship between the mTOR pathway and the Hamartin and Tuberin proteins is summarized in Figure 2 in details.
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THE DIAGNOSTIC CRITERIA IN TSC
The diagnosis in TSC is made according to the diagnostic
criteria determined by the International TSC
Consensus Group in 2012. The diagnostic criteria are divided into two as genetic diagnostic criteria, and
clinical diagnostic criteria. The genetic diagnostic criteria
include the demonstration of a pathogenic mutation
in one of the TSC1 or TSC2 genes with a genetic
test to be made from a normal tissue and can provide
a definitive diagnosis. The pathogenic mutation described
here is the changes which inactivate the function
of Hamartin or Tuberin proteins to be produced
from the TSC1 or TSC2 genes, or the changes that prevent
protein synthesis.[5,24] As stated under the heading
"genetics of TSC," approximately 90% of individuals
with TSC have a mutation in either TSC1 or TSC2
genes. However, in the remaining 10%, mutations may
not be detected in the regions targeted by conventional
genetic tests. In this context, the fact that genetic
testing showing no presence of mutation or that the
patient has one of the non-pathogenic mutation variants[8] does not exclude TSC. When the presence of
mutations in TSC1 or TSC2 genes is demonstrated in
a patient with TSC, genetic testing has high predictive
value for other family members as well. However, it
should be kept in mind that clinical features can show
wide variation even among family members with TSC
who have the same mutation. In addition, it should be
taken into account that in most countries individuals
will not have the opportunity to access genetic testing.
Therefore, the genetic diagnostic criteria and clinical
diagnostic criteria should be considered and evaluated
separately for a definitive diagnosis. The clinical diagnostic
criteria consist of a set of major and minor criteria
as shown in Table 3. For the "definitive" diagnosis
of TSC, 2 major criteria, or 1 major criterion and 2 minor
criteria must be met simultaneously. Individuals
with only one major criterion, or with only 2 or more
of the minor criteria at the same time, are reported as
"potential" TSC patients.[5]
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THE CLINICAL FEATURES OF THE TSC
TSC affects many organs at the same time and with
different severity and shows high clinical heterogeneity.
The most characteristic findings in TSC are the
cutaneous lesions, occurring in approximately 90%
of cases.[25] Different dermatological symptoms can
be encountered at each stage from birth to adulthood.
The most common lesions of ash-leaf spots, are
the hypmelanotic macules that can be visualized with
a wood lamp from infancy.[25,26] Angiofibromas,
also called adenoma sebaceum, constitute the second
most common lesion after an average of 9 years of age.
Other dermatological findings characterized by TSC
include the fibrous cephalic plaques on the forehead,
shagreen spots on the back, confetti skin lesions, ungual
and gingival fibromas, and dental enamel pits.
[27,28] Renal angiomyolipoma (AML) involvement is
detected in 80% of TSC patients, and kidney disorders
have the largest share in terms of TSC-related morbidity.
Rare cases of renal cell carcinoma have also been
reported. PKD is observed when TSC2-related mutations
affect the PKD1 gene.[29] Epileptic seizures, the
most prominent feature of neurological involvement,
together with dermatological findings, constitute the
primary reason for presenting to the clinic of TSC patients.
Although epileptic seizures are commonly seen
in the first 3 years of life, they can occur at any age. In
addition to epilepsy, ASD, mental retardation, behavioral
disorders, attention deficit, and hyperactivity are
among the TSC-associated neuropsychiatric disorders
(TAND).[30,31] The other neurological problems can
be listed as subependymal nodules causing structural
disorders in the brain, subependymal giant cell astrocytomas
(SEGA), cortical dysplasia, and cortical tubers.
[32,33] Although cardiac rhabdomyomas in the form of abnormal myocyte collections are observed in prenatal
ultrasound performed between the 20th and 30th
weeks of gestation in at least half of the individuals
with TSC, the lesions are reported to have usually regressed
spontaneously after the first 3 years of age.[34]
Although lymphangiomyomatosis (LAM), which progresses
with cough, hemoptysis, pneumothorax, and
shortness of breath, is a pulmonary disorder affecting
40% of individuals with TSC, it almost always occurs
in adult women and is rarely encountered in symptomatic
men.[35] The most important ophthalmologic involvement
in TSC is the retinal astrocytic hamartomas,
which is detected in almost half of the patients. These
lesions rarely cause visual impairment. Less frequently,
some other abnormalities may be encountered in the
retina, such as hypopigmented macules, palpebral angiofibromas,
colobomas, and iris depigmentation.[36]
In the light of this information, it can be suggested that
the organs mostly affected by TSC are the skin, brain,
kidney, heart, lung, and eye; however, abnormal tubers
and cysts can be encountered in other parts of the body
due to uncontrolled cell division and proliferation associated
with loss of function in TSC1 and TSC2 tumor
suppressor genes.[4,37] Hamartomas and polyps in the
gastrointestinal tract, detected especially in the stomach,
intestines and/or colon, are usually small and rarely
cause symptoms; rectal polyps may be seen in some
cases.[4,38,39] Sclerotic and hypertrophic lesions in the
bones, benign liver tumors that are 5 times more common
in women, pancreatic neuroendocrine tumors in
some cases, and large and progressive hamartomas may
be present in the spleen in some patients.[4,37,39,40]
THE FOLLOW?UP AND TREATMENT IN TSC
TSC is a chronic and rare genetic disease. The vast majority
of cases have a near-normal life expectancy, however,
the high morbidity and TSC-associated mortality
rates, which vary depending on symptoms, are also at
a substantial level.[41,42] This requires individuals with
TSC to be followed-up clinically with a multidisciplinary
approach specific to TSC at frequent intervals after diagnosis
and needs the continuity of surveillance. The optimal
treatment for new symptoms emerging during the
follow-up period should be decided with the patient and
caregivers. The mTOR pathway inhibition by rapamycin
and its analogues (sirolimus and everolimus approved
for TSC) is a great source of hope for patients, however
its long-term effects are not well understood since its
clinical use began in 2003.[15,43] The other treatment
options vary according to the affected organ. In the follow-up process of TSC patients, the most comprehensive examination is neurological examination. The patients
are recommended to have MRI in every 1-3 years
for the development of SEGA until the age of 25 years. In
the case of SEGA, the classical treatment is surgical resection,
although mTOR pathway inhibition with everolimus
is considered successful.[44] The need of EEG for
epileptic seizures varies according to clinical need; and
the use of steroids, anticonvulsants, clobazan and vigabatrin,
vagal nerve stimulation, ketogenic diet, and surgical
resection options are evaluated for the treatment of
epilepsy and infantile spasms.[45,46] Another group of
TSC findings that require periodic screening is TAND,
and special education programs, neuropsychiatric evaluation
and rehabilitation are of great importance.[47,48]
The screening approach for signs of LAM includes highresolution
CT imaging every 2-3 years, as well as annual
repeat pulmonary tests such as pulmonary function
tests, diffusion capacity measurement, and oxygen
monitoring during exercise.[49,50] For signs of LAM,
inhibition of the mTOR pathway with sirolimus demonstrates
successful results.[49,50] Annual clinical examination
is recommended for skin, eye and oral lesions,
and it is critical to monitor the shape changes in the lesions.
Patients should be protected from sunlight. Treatment
options for dermatological lesions include carbon
dioxide laser ablation and surgical resection, as well as
topical application of rapamycin for mTOR pathway inhibition.[26,51] The follow-up of kidney functions and
the development of AML is also an important issue in
the TSC. It is recommended to perform renal function
tests such as annual blood pressure measurement and
annual glomerular filtration rate measurement, as well
as abdominal MRI and CT imaging every 1-3 years
after TSC diagnosis.[29,52] Nephron-sparing surgical
resection and percutaneous embolization are among
the treatment options, however surgery is avoided as
much as possible. Inhibition of the mTOR pathway by
everolimus has been found successful in the treatment
of AML.[52,53] Cardiological follow-up is generally important
in the presence of rhabdomyoma in TSC. Since
cardiac rhabdomyomas may regress spontaneously after
childhood, echocardiogram every 1-3 years and an
ECG every 3-5 years are recommended until recovery
is observed.[54] Although some studies emphasized the
contribution of the use of everolimus and sirolimus with
mTOR pathway inhibition to cardiac rhabdomyoma
regression, there are uncertainties in the clinical use.
[55,56] Apart from these, the follow-up and treatment
options for less common organ involvements vary according
to the clinical features of the cases.
GENETIC COUNSELING IN TSC
TSC is an automosally dominant inherited disease,
and the affected individual has a 50% chance of transmitting
the pathogenic variant of the TSC1 and TSC2
genes to their offspring. Detection of the pathogenic
variant as a result of genetic testing in an affected
family member provides the genetic counselor with
the opportunity to predict the disease for other family
members. If a high-risk pathogenic variant is detected
in the TSC patient, they must be informed on
the risks of pregnancy, prenatal tests and pre-implantation
genetic diagnosis. Apart from this, the family
tree should be drawn including at least three generations
of the patient, and other affected individuals
and their symptoms should be recorded in the family
tree in details. Even among family members carrying
the same mutation in TSC, the reflection of the symptoms
related to the disease to the phenotype can show
wide variation. Therefore, family trees can show the
affected, asymptomatic and high-risk individuals at
the same time and with a holistic view and can give an
idea to the consultant about the penetrance of the disease.
Apart from these, if possible, a copy of the previous
clinical tests and imaging reports, especially the
pathology reports, should be requested from the people
who will be given genetic counseling and added to
the patient's file. In the briefing by the consultant, the
family tree, genetic test result and previous clinical
reports of the patient should be evaluated together.
Conclusion
TSC is a chronic and rare genetic disease. This neurocutaneous disease with an autosomal-dominant inheritance pattern is not only genetically heterogeneous, but also highly variable phenotypically and clinically. Investigation of genetic variations of TSC1 and TSC2 genes and other TSC-related genes responsible for the disease with powerful genetic tools such as NGS technologies in patients with suspected TSC is important in terms of elucidating cellular signaling mechanisms and developing therapeutic targets. The expansion of our current knowledge of the TSC-related intracellular signaling cascade has implications for the development of new therapeutic targets that can reverse the clinical phenotype of the disease. Diagnosis of patients in accordance with the diagnostic criteria established by the International TSC Consensus Group, lifelong followup of patients and appropriate genetic counseling will contribute to reducing the prevalence of TSC.Peer-review: Externally peer-reviewed.
Conflict of Interest: The authors declare no conflicts of interest.
Financial Support: The authors received no financial support for the publication of this article.
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