Tuberous sclerosis is a multisystem disorder that is mainly associated with dermatological and neurological symptoms. It may be caused by mutations in genes TSC1 or TSC2. Although it is generally inherited in an autosomal dominant manner, de-novo mutations account for a significant proportion of cases without a family history of the disease. Patients diagnosed with tuberous sclerosis type 2 (TS2) carry mutations in the TSC2 gene.
The clinical presentation of tuberous sclerosis is highly variable . It is generally referred to as a neurocutaneous syndrome because skin lesions and symptoms of central nervous system involvement tend to dominate the clinical picture. In fact, angiofibroma, epilepsy, and mental retardation have once been defined as the characteristic symptom triad of tuberous sclerosis. However, none of these findings is pathognomonic of the disease . By now, diagnostic criteria that are based on the presentation of patients suffering from tuberous sclerosis have been defined (see Workup, ).
The vast majority of patients suffering from tuberous sclerosis shows dermatological characteristics, such as hypomelanotic maculae, Shagreen patch, angiofibromas, and fibromas, which are easily detectable on physical examination . While hypomelanotic maculae may be present at birth or develop shortly thereafter, benign tumors are not usually detected before childhood. Angiofibromas and fibromas typically develop at the age of 2-5 years, most commonly in a butterfly distribution. Adult-onset angiofibromas may, by contrast, suggest Birt-Hogg-Dubé syndrome or multiple endocrine neoplasia type 1 . Fibrous cephalic plaques most commonly develop on the forehead and are considered a rather specific finding of tuberous sclerosis.
Deficiencies in brain development, particularly in the migration of neurons to their target regions, give rise to a characteristic form of focal cortical dysplasia. It can be observed in up to 90% of affected individuals, is known as cortical tuber and accounts for the name of the disease . Despite it being a congenital feature, it is not usually diagnosed until brain imaging is carried out. Patients who present with dermatological features as described above or who suffer from intractable epilepsy, mental retardation, or neuropsychiatric disorders may be referred for magnetic resonance imaging of the brain. Neuropsychiatric disorders reported in tuberous-sclerosis patients comprise, but are not limited to, autism and autism spectrum disorders, attention deficit-hyperactivity disorder, mood swings, anxiety, depression, and obsessive-compulsive disorder  . Diagnostic imaging may also reveal subependymal mass lesions. Occasionally, they have been observed prenatally, but they are more likely to develop in childhood or adolescence. Nodules and astrocytomas may cause obstructive hydrocephalus and increase the intracranial pressure, thereby aggravating neurological deficiencies .
Ophthalmological features like retinal hamartomas and achromic patches may be present in childhood, but they don't usually interfere with vision . They may thus be overlooked if patients presenting characteristic neurocutaneous symptoms don't undergo an ophthalmological examination.
Finally, tuberous sclerosis is generally associated with cardiovascular and renal complications. Cardiac rhabdomyoma is a rare tumor mainly encountered in tuberous-sclerosis patients; it may interfere with ventricular function . Lymphangioleiomyomatosis typically manifests in reduced tolerance to exercise, dyspnea, and pneumothorax. Pulmonary complications are more common in females than in males. Angiomyolipomas may develop in the kidneys or liver and may cause lower back and flank pain, or epigastric pain, respectively. Laboratory analyses may reveal functional impairment of these organs. Due to renal involvement in the regulation of blood pressure, tuberous sclerosis predisposes to hypertension, which may be detected in a general examination or during a long-term assessment of blood pressure.
- Cafe-Au-Lait Spots
Other signs of NF2 may include seizures, tumors of the membranes around the brain and spinal cord (meningiomas), skin nodules (neurofibromas), and cafe-au-lait spots. [urmc.rochester.edu]
- Subcutaneous Nodule
nodules Café-au-lait spots Subungual fibromas, which can develop any time during childhood or early adulthood Clinical criteria Identification of the skin lesions Imaging of affected organs Genetic testing A definite diagnosis of TSC by these criteria [merckmanuals.com]
Common behavioral problems may include hyperactivity, self-injury or aggression, or issues with social and emotional adjustment. Kidney problems. [mayoclinic.org]
Neuropsychiatric features (intellectual disability, attention-deficit/hyperactivity disorder, autism spectrum disorders (ASD), self-injury, anxiety and obsessive compulsive tendencies have also been reported. [orpha.net]
The tumours caused by tuberous sclerosis can result in a range of associated health problems, including: epilepsy – a condition that causes seizures (fits) learning disabilities behavioural problems – such as hyperactivity or an autistic spectrum disorder [nhs.uk]
주의력결핍 과잉행동장애(Attention Deficit Hyperactive Disorder:ADHD) 환아의 뇌전증 유무에 따른 임상 양상 The Comorbidity of Attention Deficit Hyperactivity Disorder in Children with Epilepsy 1청주성모병원 소아청소년과 2충북대학교 의과대학 정신건강의학과학교실 3청주성모병원 소아과학교실 초록 목 적 : 최근의 연구에 따르면 ADHD를 가진 환아들 [kci.go.kr]
Tuberous sclerosis complex often affects the brain, causing seizures, behavioral problems such as hyperactivity and aggression, and intellectual disability or learning problems. [ghr.nlm.nih.gov]
- Cognitive Impairment
Patients with TSC have tumors or abnormalities that manifest at different ages and in multiple organs, including the Brain Heart Eyes Kidneys Lungs Skin CNS tubers interrupt neural circuits, causing developmental delay and cognitive impairment and may [merckmanuals.com]
In addition to the benign tumors that frequently occur in TSC, other common symptoms include seizures, cognitive impairment, behavior problems, and skin abnormalities. [ninds.nih.gov]
The diagnosis of tuberous sclerosis is based on clinical features, but the distinction of types 1 and 2 requires molecular genetic analyses and the identification of mutations in the respective genes. It is important to remember that de-novo mutations are common - they may account for as much as 70% of all cases -, so tuberous-sclerosis patients may not have a family history of the disease .
With regard to the clinical presentation, major and minor diagnostic criteria have been defined at the International Tuberous Sclerosis Complex Consensus Conference in 2012 . A definite diagnosis of tuberous sclerosis requires the presence of either two major features or one major feature and two minor features. If one major criterion and one minor criterion are fulfilled, the patient may be diagnosed with probable tuberous sclerosis although this diagnostic class is no longer defined in the guidelines  . If a single major feature or at least two minor features are observed, possible tuberous sclerosis is diagnosed . In detail, the following criteria should be considered :
- Hypomelanotic maculae (≥3, ≥5 mm in diameter)
- Shagreen patch
- Facial angiofibromas (≥3) or fibrous cephalic plaque
- Ungual fibromas (≥2)
- Cortical dysplasia including tuber and white matter radial migration lines
- Subependymal nodules
- Subependymal giant cell astrocytoma
- Multiple retinal nodular hamartomas
- Cardiac rhabdomyoma
- Angiomyolipomas (≥2)
- Intraoral fibromas (≥2)
- Dental enamel pitting (≥3)
- Confetti skin lesions
- Retinal achromic patch
- Non-renal hamartoma
- Multiple renal cysts
It should be noted that the mere presence of angiomylipomas and lymphangioleiomyomatosis is insufficient for a definite diagnosis of tuberous sclerosis . These symptoms may also be observed in patients suffering from sporadic lymphangioleiomyomatosis, a rare disorder that has occasionally been referred to as an atypical form of tuberous sclerosis .
Northrup and colleagues point out the usefulness of genetic studies to support the diagnosis of tuberous sclerosis: Mutations in genes TSC1 or TSC2 are detected in 75-90% of patients who fulfill the requirements for the definite diagnosis of tuberous sclerosis. Beyond that, the identification of such a mutation may warrant the diagnosis of tuberous sclerosis regardless of the clinical presentation, which is particularly useful in young patients who have not yet developed any symptoms. Nevertheless, in a minor proportion of obviously affected individuals, genetic analyses don't yield conclusive results, which is why clinical criteria are still applied .
Other Test Results
- Cortical Tubers
[…] of cortical tubers in TSC. [journals.plos.org]
The disorder is directly related to the presence of cortical tubers, the histological entities most representative of TSC. [elsevier.es]
Two types of lesions are static (hamartias) ; cortical tubers, and subcortical heterotopic nodules, whereas subependymal nodules are often progressive (hamartoma), hence the term subependymal giant cell astrocytoma. [atlasgeneticsoncology.org]
Three types of brain tumors are associated with TSC: cortical tubers, which generally form on the surface of the brain; subependymal nodules, which form in the walls of the ventricles (the fluid-filled cavities of the brain); and giant-cell astrocytomas [childneurologyfoundation.org]
Antenatal diagnosis CR, cortical tubers and/or subependymal lesions may be detected by fetal MRI. Prenatal genetic screening may be performed in families with a known mutation. [orpha.net]
Guidelines for the surveillance and management of tuberous sclerosis have been established at the International Tuberous Sclerosis Complex Consensus Conference . In general, symptomatic treatment as appropriate for the lesion and clinical context is recommended, and due to the broad spectrum of symptoms associated with tuberous sclerosis, patients benefit from a multidisciplinary approach to treatment:
- Dermatologists should be consulted for periodic skin examinations and are best trained to decide on the need for the surgical excision or laser therapy of rapidly evolving, disfiguring, or debilitating skin lesions . Dentists should assume similar tasks regarding intraoral lesions.
- Neurologists and psychiatrists should evaluate the results of brain imaging, electroencephalography, and psychiatric tests. Shunts may be placed to allow for the drainage of cerebrospinal fluid, but the surgical removal of subependymal tumors often remains the only option to alleviate neurological symptoms  . Vigabatrin is the compound of choice to treat tuberous-sclerosis-related spasms; adrenocorticotropic hormone may be considered as a second-line treatment option . Beyond that, general guidelines for the treatment of epilepsy should be followed. School-aged children may require an individual education plan .
- Eye examinations including dilated funduscopy should be realized by qualified ophthalmologists. Visual acuity may diminish in case of large retinal hamartomas, macular involvement, retinal detachment, and vitreous hemorrhages, conditions that should be addressed accordingly .
- Finally, patients should be referred to internists and specialists in related disciplines if internal-organ involvement is suspected and for surveillance regarding such complications. Surgery may be required to remove large tumors developing in the kidneys or other organs, but alternatives should be evaluated to maintain organ functions for as long as possible, considering that tuberous-sclerosis patients are at high risks of recurrence.
Furthermore, mammalian target of rapamycin complex 1 inhibitors like everolimus and sirolimus may be administered. They constitute a causal therapy . The topical application of such agents may decelerate the progression of skin lesions  . Pharmacotherapy with everolimus, sirolimus, or related compounds is also indicated in case of angiomylipomas or lymphangioleiomyomatosis, and frequently contributes to the reduction of tumor volumes . There are few data regarding the efficacy of such agents in the treatment of subependymal nodules and astrocytomas, but they are certainly applied to this end .
Tuberous sclerosis follows a progressive course. Additional symptoms may manifest throughout life. The results of preliminary studies suggest that patients who are diagnosed early, before the onset of epilepsy, may have less severe seizures and a better neurocognitive outcome . Still, central nervous system involvement remains the leading cause of tuberous-sclerosis-related death in childhood  . By contrast, adult mortality is generally related to renal insufficiency and end-stage renal failure. Cortical dysplasia is non-progressive and subependymal mass lesions are unlikely to develop in adulthood, but angiomyolipomas accumulate over time and tend to cause life-threatening organ damage in adult patients. Pulmonary complications don't usually occur in children, but may significantly lower an adult's life quality and even lead to death .
TS2 is caused by mutations in the TSC2 gene. It is located on the short arm of chromosome 16 and encodes for tuberin, a protein that interacts with hamartin to form a stable cytosolic protein complex with GTPase activity. In detail, enzymatic activity is mediated by tuberin while the main role of hamartin is to stabilize the complex. In its entirety, it is called the hamartin-tuberin complex and suppresses the activity of mammalian target of rapamycin complex 1. The latter is known to regulate protein synthesis depending on the availability of nutrients and energy . Therefore, TSC2 has been classified as a tumor suppressor gene. By now, several hundred TSC2 mutations have been reported, with small deletions and small insertions most commonly accounting for the disease, but few genotype-phenotype correlations have been established to date  .
On a larger scale, it has been shown that TSC2 mutations are more frequently associated with subependymal nodules and astrocytomas than mutations in the TSC1 gene . TS2 patients also tend to have more cortical tubers, more seizures and more severe kidney involvement  . Retinal hamartomas are more commonly found in TS2 patients . These differences may explain why TS2 is said to be correlated with a more severe phenotype  , but they don't allow for a distinction of tuberous sclerosis types based on clinical findings, and there may be TSC2 mutations, such as R905Q, that give rise to a rather mild disease .
Of note, large deletions at 16p13.3 may affect TSC2 and the adjacent PKD1 gene. Affected individuals are diagnosed with TSC2/PKD1 contiguous deletion syndrome . The disease is associated with a typical phenotype of tuberous sclerosis and severe infantile polycystic kidney disease; it is considered an entity different from TS2.
The overall incidence of tuberous sclerosis has been estimated to 1-2 in 10,000 life births  . In Europe, the prevalence of tuberous sclerosis is approximately 9 per 100,000 inhabitants , but it should be noted that the disease may be encountered worldwide. Patients belonging to distinct ethnic groups and individuals of either gender may be affected. Data regarding the frequencies of pathogenic variants of TSC1 and TSC2 among tuberous-sclerosis patients, and thus the proportions of tuberous sclerosis type 1 and TS2, are contradictory. According to a Japanese study on the epidemiology of tuberous sclerosis, both contribute equally to the incidence and prevalence of the disease . By contrast, earlier studies accounted for a much higher frequency of mutations in the TSC2 gene and yielded estimates of a 3:1 ratio  . In this context, it has been suggested that de-novo mutations more commonly affect the TSC2 gene while familial tuberous sclerosis is caused by pathogenic variants of TSC1 and TSC2 at a similar frequency . First symptoms of tuberous sclerosis may manifest at any age, but the majority of patients presents in infancy or childhood . TS2 patients tend to present symptoms at a younger age than those suffering from tuberous sclerosis type 1 .
As has been indicated above, tuberin is an essential component of a cytosolic protein complex that diminishes the activity of mammalian target of rapamycin complex 1. It thus seems evident that carriers of pathogenic TSC2 mutations have to face the consequences of an overactive or constitutively active mammalian target of rapamycin complex 1 . This complex is an important regulator of cell growth, metabolism, and proliferation, so its pathological activation may promote tumor growth  . However, tumor development is unlikely to occur unless both alleles of the TSC2 gene are inactivated, a fact that seems to be in disagreement with the classification of tuberous sclerosis as a genetic disorder that is inherited in an autosomal dominant manner. This apparent contradiction is generally explained by a two-hit theory: The first hit consists in an inherited germline mutation in TSC2. The second hit is a somatic mutation of the other allele. It may undergo DNA sequence changes, its promoter may be affected, or patients may lose their heterozygosity regarding the TSC2 gene  .
Carriers of pathogenic TSC2 mutations can be identified prenatally, and preimplantation tests are also feasible . Similarly, tuberous-sclerosis-associated tumors may be detected by means of fetal echocardiography, and parents should be informed about the possible consequences of these conditions. On the other hand, family members of patients newly diagnosed with tuberous sclerosis may be tested for pathogenic variants of TSC2.
Tuberous sclerosis, sometimes also referred to as tuberous sclerosis complex, is a neurocutaneous syndrome associated with a broad spectrum of neurological and dermatological symptoms, and a predisposition for tumor development in multiple organ systems . It may be caused by mutations in the TSC1 or TSC2 genes and types 1 and 2 of the disease are distinguished accordingly. TSC1 and TSC2 encode for hamartin and tuberin, respectively, two components of the same cytosolic protein complex. Therefore, pathogenic mutations in either of the two genes are related to a single pathophysiological mechanism and result in largely the same symptoms  . Recent evidence suggests that mutations in the TSC1 and TSC2 genes cause the constitutive activation of mammalian target of rapamycin complex 1, so inhibitors of this complex are emerging as new treatment strategies. Beyond that, patients suffering from tuberous sclerosis receive symptomatic treatment.
Tuberous sclerosis is a multisystem disorder associated with skin lesions, neurological symptoms, and a predisposition for the development of tumors. Certain symptoms may be present at birth, such as ash-leaf spots and benign cardiac neoplasias, while others develop throughout life. Patients often suffer from epilepsy and mental retardation, and tend to develop multiple skin, brain, and renal tumors.
Tuberous sclerosis is caused by mutations in genes TSC1 or TSC2, and types 1 and 2 of the disease are distinguished accordingly. These genes fulfill similar functions, so there are very few differences regarding the clinical presentation, diagnosis, therapy, and prognosis of tuberous sclerosis type 1 and tuberous sclerosis type 2. Until recently, only symptomatic treatment could be offered to affected individuals. Although it still is the mainstay of therapy, new insights give hope for a causal treatment with so-called mTOR inhibitors. In any case, patients suffering from tuberous sclerosis require the attention of a multidisciplinary team, are recommended to undergo regular follow-ups throughout life, and, unfortunately, have to face the prospect of a reduced quality life.
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