Tuberin and hamartin, the two proteins related to the inhibition of cellular growth and differentiation are responsible for mediating these processes in the entire body. Their failure to serve their purpose practically implies that tumors, benign in nature, are allowed to develop nearly everywhere throughout the body. A defined set of diagnostic criteria have been established by the Diagnostic Criteria Committee of the National Tuberous Sclerosis Association (USA) [4].

Patients affected by tuberous sclerosis may present with the following tumors and symptoms:

• Skin: Patients may present with facial angiofibromas [5], ash-leaf spots, confetti lesions, shagreen patches, fibrous plaques, and periungual fibromas.
• Heart: Rhabdomyomas are the type of tumor that most commonly forms.
• Brain: The brain constitutes on of the most common locations for the generation of tumors. Histologically, both glial and neuronal cells are observed within the lesion and myelination is considerably affected. It is believed that, in some cases, a greater number of cortical tubers (brain tumors) is associated with severer epileptic manifestations. SEN (subependymal nodules) and SEGA (subependymal giant cell astrocytomas) tumors are also a manifestation of tuberous sclerosis: SEN lesions are the first to appear and, under some circumstances, lead to the development of SEGA tumors, which form in the foramen of Monro and might lead to hydrocephalus.
• Kidneys: Angiomyolipomas, cystic lesions. Angiomyolipomas are constituted of blood vessels, adipose tissue and connective tissue.
• Lungs: Lymphangioleiomyomatosis (LAM) and cysts.
• Eyes: Hamartomas of the retina and astrocytomas usually appear as symptoms of tuberous sclerosis. Calcification is expected but visual impairment is not common.
• Extremities: Cysts that usually form in the feet and hands, pelvic region or spine.
• Bones: Potential skeletal abnormalities include primarily cystic lesions.

It has been observed that in more than half of the patients affected by tuberous sclerosis, pulmonary lymphangioleiomyomatosis and renal angiomyolipomas exist simultaneously [6].

• Epilepsy

  Calcification can be used to evaluate pharmacoresistant epilepsy in patients with TSC. Copyright © 2018 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved. [ncbi.nlm.nih.gov]

• Developmental Delay

  The condition can manifest in many ways, but the effects that most strongly impact quality of life are seizures, developmental delay, intellectual disability, and autism. [uabmedicine.org]

  A combination of symptoms may include seizures, intellectual disability, developmental delay, behavioral problems, skin abnormalities, and lung and kidney disease. [dbpedia.org]

  The brain abnormalities of tuberous sclerosis are mainly benign cortical tumors (tubers) that cause seizures, developmental delay, and mental retardation. [medicinenet.com]

  The patient had no history of seizures or developmental delay, and he had no family history of similar cutaneous findings. Tuberous sclerosis complex is an autosomal dominant condition that affects cellular differentiation and proliferation. [nejm.org]

  The disorder is characterized by seizures, developmental delays, kidney disease, behavioral problems, and the growth of benign tumors (tubers) on vital organs such as the brain, kidneys, and heart. [cdmrp.army.mil]

• Weight Loss

  loss, high levels of cholesterol, and nose bleeds. [globenewswire.com]

• Dyspnea

  The patient was hospitalized 3 months earlier for dyspnea at the Department of Cardiology, where she was diagnosed with heart failure (left ventricle injection fraction: 25-30%), pulmonary hypertension, chronic kidney disease (serum creatinine: 1.58 mg [ncbi.nlm.nih.gov]

  Lymphangioleiomyomatosis (LAM), multifocal micronodular pneumocyte hyperplasia (MMPH) and pulmonary cysts develop during adulthood and manifest with dyspnea, pneumothorax, or chylothorax. [orpha.net]

  This may be progressive and result in dyspnea, cor pulmonale, recurrent pneumothorax, and respiratory failure. Gastrointestinal tumors may be associated. Microhamartomatous polyps are present in the rectum in 75% of cases. [emedicine.medscape.com]

• Nausea

  Other ophthalmic signs and symptoms are relatively rare in this disease.We describe the case of a young woman with tuberous sclerosis who presented with horizontal binocular diplopia and decreased visual acuity without complaints of nausea, vomiting or [ncbi.nlm.nih.gov]

  Although TSC tumors aren’t cancerous, they often can cause serious problems by inhibiting proper function of the organs in which they develop, and they can lead to behavioral changes, nausea, headaches, and a number of other symptoms. [uabmedicine.org]

  Tuberous sclerosis symptoms include: Brain: Seizures or epilepsy Headache Nausea Vomiting Difficulty with movement (increased clumsiness, difficulty walking, etc.) [uvahealth.com]

  Various signs and symptoms include an unexpectedly large head size, nausea, headaches and behavior changes. Heart complications. Growths in the heart, usually in infants, can block blood flow or cause problems with heart rhythm (dysrhythmia). [mayoclinic.org]

• Vomiting

  Other ophthalmic signs and symptoms are relatively rare in this disease.We describe the case of a young woman with tuberous sclerosis who presented with horizontal binocular diplopia and decreased visual acuity without complaints of nausea, vomiting or [ncbi.nlm.nih.gov]

  Tuberous sclerosis symptoms include: Brain: Seizures or epilepsy Headache Nausea Vomiting Difficulty with movement (increased clumsiness, difficulty walking, etc.) [uvahealth.com]

  […] reported with Votubia LE/HE vs placebo included stomatitis (54.7%/63.8% vs 9.2%), diarrhea (17.1%/21.5% vs 5.0%), nasopharyngitis (13.7%/16.2% vs 16.0%), upper respiratory tract infection (12.8%/15.4% vs 12.6%), pyrexia (fever) (19.7%/13.8% vs 5.0%), vomiting [globenewswire.com]

  They can present with headache, vomiting, deterioration in seizure control and focal neurological signs. Subependymal nodules (SENs) can also occur. They are small lesions found in the lining of the ventricles. [patient.info]

• Abdominal Pain

  These disorders may cause high blood pressure, abdominal pain, and blood in the urine. Solid, raised areas (nodules) may develop in the lungs, particularly in adolescent girls. This condition is called lymphangioleiomyomatosis. [msdmanuals.com]

  This can present as haematuria, abdominal pain and hypovolaemia. Obstruction can occur as they enlarge. [patient.info]

• Abdominal Mass

  Renal angiomyolipomas (AML) develop during childhood with a higher risk of growth during adolescence and adulthood and manifest by pain, hematuria/retroperitoneal hemorrhage, abdominal masses, hypertension and renal failure. [orpha.net]

  Image in a 15-year-old boy with a right-sided abdominal mass, which is a renal cell carcinoma. [emedicine.com]

  An abdominal CT identified a soft tissue mass in the left kidney (size, 6×7 cm) and multiple uniform density masses in the right kidney (size, between 0.5 and 2 cm). [spandidos-publications.com]

• Gingival Fibroma

  fibromas, and hypopigmented macules. synonyms Tuberous Sclerosis, Tuberous Sclerosis, Bourneville-Pringle's Disease [dermis.net]

  Isolated gingival fibromas can occur in persons who do not have TSC. However, gingival fibroma(s) in association with large numbers (>10) of dental pits is highly suggestive of TSC and should prompt further diagnostic evaluation. [emedicine.medscape.com]

  Detailed examination of the skin and mucosa revealed Shagreen patches, nontraumatic subungual and gingival fibroma, all features of tuberous sclerosis complex. [content.sciendo.com]

  (Koenen's tumor) Gingival fibromas and dental pitting Axial cut section from the same case shows bilateral subependymal giant cell astrocytomas Axial graphic of typical brain involvement in tuberous sclerosis complex shows a giant cell astrocytoma in [slideshare.net]

• Hypertension

  hypertensive retinopathy, and sleep-apnea syndrome. [ncbi.nlm.nih.gov]

  Kidney disease may cause hypertension. Pulmonary lesions, such as lymphangioleiomyomatosis, may develop, particularly in adolescent girls. Symptoms and Signs Manifestations vary greatly in severity. Skin lesions are typically present. [msdmanuals.com]

  Renal angiomyolipomas (AML) develop during childhood with a higher risk of growth during adolescence and adulthood and manifest by pain, hematuria/retroperitoneal hemorrhage, abdominal masses, hypertension and renal failure. [orpha.net]

• Heart Failure

  /dl), and resistant hypertension and discharged with optimal heart failure treatment. [ncbi.nlm.nih.gov]

  Other organs like the heart and lungs may be involved during early or late life, presenting as heart failure, conduction abnormalities, palpitations and breathlessness. Later in life, TSC can make its mark with kidney tumors and kidney failure. [my.clevelandclinic.org]

  Failure Cardiac rhabdomyomas can lead to hemodynamic compromise and congestive heart failure, and while this occurrence is rare, it remains one of the most frequent causes of death among TSC children 49 Heart failure occurs in 2% to 5% of infants and [doi.org]

• Retinal Lesion

  The fingernails and toenails should also be examined for ungual fibromas, the teeth and gums for dental pits and gum fibromas, and the eyes for retinal lesions. [aocd.org]

  tu·ber·ous scle·ro·sis [MIM*191100] phacomatosis characterized by the formation of multisystemic hamartomas producing seizures, mental retardation, and angiofibromas of the face; the cerebral and retinal lesions are glial nodules; other skin lesions [medical-dictionary.thefreedictionary.com]

  EYE INVOLVEMENT [ edit ] Manifestations [ edit ] The appearance of retinal lesions varies from the classic mulberry lesions adjacent to the optic disk to the more common plaque-like hamartoma. [en.wikibooks.org]

  Sclerotic lesions can develop in the pelvis or spine. Retinal hamartomas or astrocytomas can also occur but they rarely cause visual symptoms (but do cause an abnormal red reflex). [patient.info]

• Visual Impairment

  He was subsequently registered with severe visual impairment. [ncbi.nlm.nih.gov]

  Calcification is expected but visual impairment is not common. Extremities: Cysts that usually form in the feet and hands, pelvic region or spine. Bones: Potential skeletal abnormalities include primarily cystic lesions. [symptoma.com]

  Most retinal hamartomas remain dormant, although occasionally individuals with TSC have visual impairment resulting from a large hamartoma in the macular region. [en.wikibooks.org]

  Symptoms included blurred vision, constriction of visual field, and visual impairment. Retinal achromic patch (53 [2.5%]) and other TSC-related ophthalmological lesions (73 [3.5%]) were also reported but less commonly. [ojrd.biomedcentral.com]

• Facial Angiofibroma

  BACKGROUND/OBJECTIVES: Tuberous sclerosis complex (TSC) is a genetic disorder and facial angiofibromas are disfiguring facial lesions. [ncbi.nlm.nih.gov]

  Skin lesions, particularly facial angiofibromas, may be psychologically distressing for some patients. Laser treatment or electrosurgery can be used to remove angiofibromas. [dermnetnz.org]

  The physical examination revealed erythematous papules on the chin, nose, and cheeks consistent with facial angiofibromas (Panel A) and small, fleshy periungual fibromas of the toenails (Panel B). [nejm.org]

• Shagreen Patch

  Overall, 120 lesions from 55 patients were classified by size; 46 lesions (38%) were collagenomas; 39 lesions (32%) were small shagreen patches; 21 lesions (18%), medium shagreen patches; and 14 lesions (12%), large shagreen patches. [ncbi.nlm.nih.gov]

  (A) Facial angiofibromas, (B) shagreen patch and (C) periungual or subungual fibromas (also known as Koenen tumours). [adc.bmj.com]

  patch Flesh coloured orange-peel connective tissue naevi of varying sizes, usually on the lower back Shagreen patches Shagreen patch in tuberous sclerosis Shagreen patch in tuberous sclerosis Shagreen patch in tuberous sclerosis Ovoid or ash leaf-shaped [dermnetnz.org]

  Skin involvement includes: hypomelanotic macules (ash leaf) present within the first years of life; angiofibromas that appear at age 3-4 years as erythematous and papulonodular lesions; ungual fibromas; cephalic and lumbar (shagreen patch) fibrous plaques [orpha.net]

• Hypopigmented Macule

  Hypopigmented macules are the earliest sign. [ncbi.nlm.nih.gov]

  The earliest finding, and the most common in the skin, consists of hypopigmented macules (ash leaf). In addition, numerous small hypopigmented macules (confetti-like macules) occur in the pretibial region. [omicsonline.org]

  macules. synonyms Tuberous Sclerosis, Tuberous Sclerosis, Bourneville-Pringle's Disease [dermis.net]

• Skin Rash

  Differential diagnosis The differential diagnosis includes vitiligo, Ito hypomelanosis, cardiac myxoma, isolated brain tumors, pulmonary emphysema, acne, skin rash. [orpha.net]

  Skin symptoms of tuberous sclerosis The skin rashes of tuberous sclerosis can take a range of forms, including: ash leaf patch – patches of skin are white because they lack pigment. [betterhealth.vic.gov.au]

  Symptoms of hepatitis B or infection may include the following: fever, chills, skin rash, joint pain and inflammation, tiredness, loss of appetite, nausea, pale stools or dark urine, yellowing of the skin, or pain in the upper right side of the stomach [us.afinitor.com]

• Eruptions

  Polcari, Morphology-Based Diagnosis of Acneiform Eruptions, Pediatric Annals, 44, 8, (e188), (2015). E. D. Belousova, M. Yu. Dorofeeva, A. M. Pivovarova and O. V. [doi.org]

  Historical note and terminology Désiré-Magloire Bourneville reported “tuberous sclerosis of cerebral circumvolutions” with “confluent vesiculopapular eruption on her nose, cheeks and forehead” in the necropsy of a young girl who had recurrent status epilepticus [medlink.com]

• Anxiety Disorder

  ASD, ADHD, anxiety disorder, depressive disorder Level 3 Intellectual level This level measures intellectual ability as defined by standardized IQ‐type measures. [doi.org]

  (ASD) – typical behaviours associated with autism include the tendency to avoid eye contact, and problems with communication and social development mental health issues – many people with TSC experience anxiety disorders and depression. [betterhealth.vic.gov.au]

  Depressive disorders. Anxiety disorders. Sleep disorders. Epilepsy-related psychotic disorders. Cardiac involvement Cardiac rhabdomyomas are seen in the majority of young children with tuberous sclerosis. [patient.info]

• Impulsivity

  In adults with TSC, poorer communication and socialisation skills, gastric health problems and impulsivity were associated with self-injury; compulsive behaviour and impulsivity were associated with aggression. [ncbi.nlm.nih.gov]

  More nuanced studies of overactivity and impulsivity are warranted to identify priorities for intervention for these problematic behaviors in TSC, particularly given robust associations between impulsivity and self‐injury and aggression in TSC (Eden et [doi.org]

  TAND can be investigated and considered at six levels: behavioural, psychiatric, intellectual, academic, neuropsychological and psychosocial.[6] Behavioural problems most commonly seen include overactivity, impulsivity and sleeping difficulties. [en.wikipedia.org]

  An electrocardiogram records the heart’s electrical impulses and may reveal abnormal electrical patterns. Standard Therapies Treatment Treatment may require the coordinated efforts of a team of specialists. [rarediseases.org]

• Abnormal Behavior

  After the second year of life, abnormal behaviors including hyperactivity, rituals, repetitive behaviors, and temper tantrums can appear (Jeste et al., 2008 ). [doi.org]

• Kidney Failure

  Lungs: Breathlessness Kidneys: Cysts on kidneys can cause pain, weakness or kidney failure. Eyes: Tumors in the eyes can appear as white patches on the retina in individuals with TSC. [kennedykrieger.org]

  Kidneys: Increased blood pressure Problems with kidney functioning or kidney failure Kidney tumors occur are most common in TSC, although most patients do not have any noticeable symptoms. [uvahealth.com]

  Kidneys: Hamartomas in the kidneys can cause problems with how they work and even lead to kidney failure. Heart: Hamartomas can block blood flow or change the heart's rhythm. Heart hamartomas usually get smaller as a child grows. [kidshealth.org]

  Kidney damage. Growths in the kidney can be large and cause potentially serious — even life-threatening — kidney problems. Growths in the kidney can cause high blood pressure or bleeding or lead to kidney failure. [mayoclinic.org]

• Hematuria

  The 22-year-old man was admitted due to bilateral flank pain, gross hematuria, and abdominal fullness. He had history of epilepsy, mental retardation, and delayed development during childhood. He had angiofibroma on his face since 10 years ago. [ncbi.nlm.nih.gov]

  Renal angiomyolipomas (AML) develop during childhood with a higher risk of growth during adolescence and adulthood and manifest by pain, hematuria/retroperitoneal hemorrhage, abdominal masses, hypertension and renal failure. [orpha.net]

  They may be the cause of intense hematuria, which is more common in tumors larger than 4 cm, and may lead to loss of renal function. [scielo.br]

• Flank Pain

  The 22-year-old man was admitted due to bilateral flank pain, gross hematuria, and abdominal fullness. He had history of epilepsy, mental retardation, and delayed development during childhood. He had angiofibroma on his face since 10 years ago. [ncbi.nlm.nih.gov]

  They often produce nonspecific complaints such as flank pain. Of rather more concern is potentially life-threatening retroperitoneal hemorrhage from rupture of dysplastic, aneurysmal blood vessels. [emedicine.medscape.com]

  Usually, hamartomas are asymptomatic; however, they can cause flank pain, hematuria, or an abdominal mass, which may be palpable. Hamartomas usually are multiple and bilateral. [emedicine.com]

  In some instances, they may cause flank pain or kidney (renal) dysfunction. Angiomyolipomas are prone to rupturing and bleeding (hemorrhaging), which can potentially become life-threatening (approximately 20% of the time). [rarediseases.org]

• Amenorrhea

  The most common events were amenorrhea (24.1%) and irregular menstruation (17.0%). Seven patients (6.3%) experienced grade 3/4 amenorrhea. [ncbi.nlm.nih.gov]

  Reproductive abnormalities were noted in a small number of patients and included menstrual cycle disorders (67 [6.2%]), amenorrhea (female patients > 11 years, 38 [3.5%]), abnormal onset of puberty (93 [4.4%]), other abnormal reproductive conditions [ojrd.biomedcentral.com]

• Seizure

  Infantile spasms and severely epileptogenic EEG patterns are related to the poor seizure outcome, poor intellectual capabilities and autistic behavior. Higher tubers numbers is associated with poor seizure outcome and autistic behavior. [en.wikipedia.org]

  Our patients were started on vigabatrin after the onset of focal seizures with the aim of preventing seizure recurrence, halting the possible progression to infantile spasms or focal seizures, and preventing neurodevelopmental decline. [ncbi.nlm.nih.gov]

• Headache

  Other ophthalmic signs and symptoms are relatively rare in this disease.We describe the case of a young woman with tuberous sclerosis who presented with horizontal binocular diplopia and decreased visual acuity without complaints of nausea, vomiting or headache [ncbi.nlm.nih.gov]

  Although TSC tumors aren’t cancerous, they often can cause serious problems by inhibiting proper function of the organs in which they develop, and they can lead to behavioral changes, nausea, headaches, and a number of other symptoms. [uabmedicine.org]

• Confusion

  It may be confused with autism. Bourneville, Désiré-Magloire, French physician, 1840-1909. Bourneville disease - phacomatosis characterized by the formation of multisystem hamartomas. [medical-dictionary.thefreedictionary.com]

  Can be confused with acne. Fibrous plaques (M): yellow-brown patches seen on the scalp/forehead Ungual/periungual fibromas: flesh-colored/pink bumps seen in the nail plate or on the side of the nail. Typically appear around adolescence. [epilepsy.com]

  Hypomelanotic macules are often the earliest and most frequently reported cutaneous finding in TSC. 9, 10 They present as hypopigmented macules and patches of various morphologies and should not be confused with de-pigmented patches seen in other pigmentary [adc.bmj.com]

  Sometimes multiple renal cysts can be confused with true polycystic kidney disease. The presence of significant symptoms such as hypertension or failure to thrive, as well as the absence of associated AMLs, strongly suggest the latter diagnosis. [emedicine.medscape.com]

• Sleep Disturbance

  Secondary objectives Comparison of absolute change from baseline in frequency of epileptiform events as recorded on seizure diaries between patients taking RAD001 vs. placebo Comparison of sleep disturbances between patients taking RAD001 vs. placebo, [clinicaltrials.gov]

  Disturbances in Children With Neurodevelopmental Disabilities Completed NCT01906866 Phase 3 Circadin 2/5/10 mg;Placebo 17 A Phase 2/3, Multi-Center, Double-Blind, Placebo-Controlled, Randomized, Parallel-Group, Dose-Response Comparison of the Efficacy [malacards.org]

  Individuals can potentially develop a range of neuropsychiatric disorders including autism spectrum disorder, attention deficit hyperactivity disorder (ADHD), sleep disturbances or disorders, learning and cognitive impairments, or behavioral issues including [rarediseases.org]

  Behaviour problems are common in TS, particularly autism, autistic spectrum disorders and attention deficit hyperactivity disorder.4 Sleep disturbance is a common problem in children. [nature.com]

• Generalized Tonic-Clonic Seizure

  Infantile spasms, generalized-tonic clonic seizures, poor seizure control, cardiac rhabdomyomas, SEGA and developmental delay were not associated with quantitative tuber characteristics. [ncbi.nlm.nih.gov]

  If they spread to involve a large enough area of the brain, partial seizures can turn into a generalized tonic-clonic seizure. So it is possible for a patient to have both types of seizures. [my.clevelandclinic.org]

Patients with tuberous sclerosis present with fluctuating clinical pictures, due to the multiplicity of the locations where the tumors may form.

In order to diagnose tuberous sclerosis, either of the two diagnostic criteria must be met:

• 2 major features or 1 major feature plus 2 minor: The patient definitely suffers from tuberous sclerosis
• 1 major feature or 2 or more minor features: The patient possibly suffers from tuberous sclerosis.

Under the category of major features fall the following abnormal findings:

• More than three hypomelanotic macules
• Subependymal nodule
• Lymphangioleiomyomatosis
• Cardiac rhabdomyoma
• Connective tissue nevus
• Nontraumatic ungual or periungual fibroma
• Facial angiofibroma
• Multiple retinal nodular hamartoma
• Renal
• Subependymal giant cell astrocytoma
• Cortical tuber, alone or accompanied by cerebral white matter migration tracts

Minor features:

• Skeletal cysts
• Gingival fibromas
• Renal cysts
• Confetti-type skin lesions
• Nonrenal hamartoma
• Achromic patch of the retina
• Cerebral white matter radial migration lines
• Hamartomatous rectal polyps
• Multiple randomly distributed pits in dental enamel

Depending on the pathological findings, various other laboratory or imaging tests can be performed. Renal hamartomas can be monitored with urinalysis and an electrolyte test. Cortical tubers, SENs and SEGAs can be illustrated and followed-up with the use of a magnetic resonance imaging scan (MRI) [7] or a computerized tomography scan (CT).

Renal abnormalities are best pictured with the use of ultrasonography. CT and MRI scans can further be used to monitor patients with renal dysfunction due to lesions every six to twelve months; CT scans should be conducted as less frequently as possible, due to the radiation the patient is exposed to. Cardiac rhabdomyomas usually subside as the disease progresses and can be revealed and monitored with the use of echocardiography; an electrocardiogram is also useful in order to perform an adequate follow up. Pulmonary lesions are visible on an x-ray or a CT scan.

With reference to additional affected systems, fundoscopy is the examination of choice in order to detect and closely monitor patients with tuberous sclerosis and ocular irregularities. Up to 80% of retinal hamartomas are visible via fundoscopy.

• Multiple Renal Cysts

  On magnetic resonance imaging, 18 children exhibited subependymal nodules, and 16 ones showed cortical nodules. 5 cases of non-renal hamartomas, 5 cases of multiple renal cysts, and 5 cases of cardiac rhabdomyomas were observed. [ncbi.nlm.nih.gov]

  Confetti skin lesions Multiple renal cysts Skin lesions Skin lesions [14] are found in 70-80% of cases of tuberous sclerosis. [emedicine.medscape.com]

  […] fibromas (≥2); CR; LAM; AML (≥2)) and minor (dental enamel pits (≥3); intraoral fibromas; confetti skin lesions; nonrenal hamartoma; multiple renal cysts; retinal achromatic patches) features. [orpha.net]

  […] pits in dental enamel - Hamartomatous rectal polyps - Bone cysts - Cerebral white matter radial migration linesa - Gingival fibromas - Nonrenal hamartoma - Retinal achromic patch - 'Confetti’ skin lesions - Multiple renal cysts The following are major [health.cdc.go.kr]

• Pericardial Effusion

  Fetal cardiac tumors may present in utero as a mass on ultrasonography, irregular heart rhythm, hydrops fetalis, or pericardial effusion. [doi.org]

• Hypsarrhythmia

  PATIENT: The patient had a series of epileptic spasms (ES) and hypsarrhythmia at age 3 months. [ncbi.nlm.nih.gov]

  Hypsarrhythmia is seen on EEG. [medbullets.com]

  They can begin in very early childhood as infantile spasms, sometimes with hypsarrhythmia. The presence of these spasms at an early age often means more significant learning problems and more significant epilepsy later on. [autism-help.org]

  Included subjects had documented clinical IS, hypsarrhythmia on electroencephalography (EEG), and parental consent to start the KD. Efficacy was assessed through phone communication, clinic visits, and EEG every 3 months. [doi.org]

• Cortical Tubers

  Tuberous sclerosis complex (TSC) is a disorder that frequently leads to the development of refractory seizures by multiple cortical tubers. The multiple cortical tubers cause multiple or wide epileptic networks in these cases. [ncbi.nlm.nih.gov]

  Cortical tubers, or hamartomas, are the most characteristic lesions of tuberous sclerosis; they are detected on MRIs in 95% of patients. The appearance of cortical tubers on MRIs varies with patient age. [emedicine.com]

  It is also associated with cortical tuber and hamartomas formation throughout the body, especially the heart, kidneys, and eyes. [icd9data.com]

The most challenging and potentially life-threatening symptom related to tuberous sclerosis is epilepsy. Epilepsy should be treated in the same way a non-TSC epilepsy is managed: a single medication is administered in the minimum dosage, which is progressively increased until a therapeutic effect is attained. In cases of drug inefficacy, the antiepileptic drug is changed. A double-drug regime is followed only if the monotherapy does not produce the necessary control. In cases of patients with brain lesions, the administration of anticonvulsive medications should be initiated before seizures start to occur [8] [9] [10].

Should a patient present with lymphangioleiomyomatosis, hormonotherapy may be chosen to treat the symptom. Progesterone in combination with an oophorectomy is the treatment of choice. Hypertension occurring as a result of renal dysfunction can be managed with antihypertensive medications and inotropic agents can help to improve the heart's contractility, if the patient suffers from cardiac disease.

The two drugs exclusively used for the management of tuberous sclerosis are everolimus and sirolimus. Given that the products of the TSC1 and TSC2 genes, tuberin and hamartin, actually inhibit the mammalian target of rapamycin complex 1 and tuberous sclerosis patients posses mutated genes, these drugs aim at the compensation of this inadequacy. They act in replacement of the dysfunctional proteins and hinder cellular growth, in order to prevent tumors from forming.

Tuberous sclerosis leads to the formation of benign hamartomas in various locations of the body. Even though the tumors may be quite extensively dispersed, the absence of malignancy renders their prognosis better than it was originally believed. Naturally, the location of the tumor stipulates the rates of morbidity and mortality.

Patients with tuberous sclerosis may have a relatively low quality of living, given that even benign hamartomas can disrupt the functionality of the organs. Death or serious complications, however, are a result of tumors located in the brain and is usually brought on by epileptic seizures or falls and traumatizations that occur as a result of epileptic phenomena. Brain tumors can also lead to an elevated intracranial pressure (hydrocephalus) and antiepileptica can also lead to fatal complications when administered for a long period of time or in an excessive manner. Additionally, hamartomas located on the heart can cause life-threatening arrhythmia, even though they are usually self-restricting.

Another factor that considerably contributes to the elevated morbidity and/or mortality that accompanies tuberous sclerosis is the difficulty to diagnose and effectively manage cases of the disease. A significant number of patients remain undiagnosed or undergo unnecessary and/or possibly risky surgical operations in order to excise a tumor that could also be monitored.

Tuberous sclerosis is a genetic disease; it is inherited via the autosomal dominant inheritance pathway.

The genetic abnormality that leads to such a clinical picture has been identified as a mutation in the TSC1 or TSC2 gene: they encode for tuberin and hamartin, proteins that inhibit the mammalian target of rapamycin complex 1 (mTORC1). The latter controls the process of cellular growth and metabolic process and without the inhibitory effect of hamartin and tuberin, hyperplasias and benign tumors can form in virtually every part of the body. It has been calculated that the most common mutations affect the TSC2 gene.

Tuberous sclerosis is not commonly encountered in the daily clinical practice, as it affects 40,000 people in the USA. The prevalence has been exhibiting a steady increase during the past years, which has been attributed to the establishment of different criteria and the improvement of diagnostic efficacy.

At an international level, tuberous sclerosis seems to affect approximately 2,000,000 people in the whole world. The type of gene affected by the mutation seems to be dependent upon ethnicity, with some populations presenting with a higher ratio of TSC1/TSC2 mutations when compared to others.

The pathophysiological background of tuberous sclerosis has been mapped since approximately 1993, mutations in the genes TSC1 and TSC2 are responsible for the occurrence of tuberous sclerosis. They are located on chromosomes 9 and 16 respectively and, although their role has yet to be fully illustrated, they are known to play an inhibitory role in the process of cellular growth and differentiation through an interaction with beta-catenin.

Both genes exert an inhibitory effect on the process of cellular growth; they are therefore responsible for controlling the expansion of tumors and preventing tumorigenesis throughout the entire organism. Mutations in those two genes result in an unregulated proliferation of cells and hamartomas. The exact pathway seems to require a second-hit mutation and a LOH (loss of heterozygosity) for a hamartoma to occur, with the exception of brain tumors comprising giant cells.

TSC1 and TSC2 constitute the standard genes that are subject to mutations and induce the condition known as tuberous sclerosis. The types of mutations responsible for the disease vary, with more than 1,800 distinct mutations recognized.

Tuberous sclerosis is a genetic condition which is inherited in an autosomal dominant way and can therefore not be prevented. However, the possibility for a diagnosis before a child is born exists and genetic testing should be performed if a parent is diagnosed with the disease.

Tuberous sclerosis complex (TSC) or, simply, tuberous sclerosis, is a genetic disease which induces multiple tumors to form in diverse regions of the body. These tumors have no malignant characteristics but nevertheless interfere with each organ's function. The organs that are primarily affected are the lungs, brain, heart and kidneys.

Depending on the location of the tumors, the functionality of the organs may be severely compromised and life-threatening sequelae may be caused, such as hydrocephalus and epilepsy. Disfigurement due to skin tumors may lower the quality of life for a patient and the multitude of the symptoms that can arise definitely renders the individuals affected by the disease considerably disabled. Various degrees of mental disability accompany the clinical picture almost in 80% of the cases and developmental disorders may also be present [1] [2] [3].

Tuberous sclerosis is a rare genetic condition. It leads to the formation of benign tumors in various locations of the body, which interfere with the normal function of the organs they are found on.

The condition is a result of a mutation on two specific genes, TSC1 and TSC2. These genes produce two proteins, which prevent the formation of tumors because they prevent cells from growing excessively. The mutations produce faulty proteins, which cannot stop the rapid reproduction of cells and, therefore, tumors are allowed to develop.

Since patients with tuberous sclerosis can have lesion in many organs, the symptoms they experience are multiple and depend on the organ that is affected. The most severe and possibly life-threatening symptom is epilepsy, caused by brain tumors.

Tuberous sclerosis is diagnosed based on a set of criteria, depending on the symptoms. Treatment follows a symptomatic plan, which means that each patient is treated accordingly, depending on the clinical picture they present with. Two drugs, everolimus and sirolimus, are currently studied for their potential contribution to the management of tuberous sclerosis patients in general.

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