Sandbox Jose2

Not to be confused with tuberculosis.

Tuberous sclerosis
Synonyms	Tuberous sclerosis complex (TSC), Bourneville disease
File:Patient with facial angiofibromas caused by tuberous sclerosis.jpg
A case of tuberous sclerosis showing facial angiofibromas in characteristic butterfly pattern
Specialty

Tuberous sclerosis skin lesion - Angiofibromas - image taken from: www.atlasdermatologico.com.br

Overview

Tuberous sclerosis complex (TSC), is a rare autosomal dominant congenital disorder that affects multiple organ systems and is characterized by an abnormal growth of ectodermal and mesodermal cells that causes non-cancerous tumours to grow in the brain and on other vital organs such as the kidneys, heart, liver, eyes, lungs, and skin.

A combination of symptoms may include seizures, intellectual disability, developmental delay, behavioral problems, skin abnormalities, and lung and kidney disease. TSC is caused by a mutation of either of two genes, TSC1 and TSC2, which code for the proteins hamartin and tuberin, respectively. These proteins act as tumor growth suppressors, agents that regulate cell proliferation and differentiation.

The disease presents with a myriad of symptoms, having been described by multiple doctors throughtout the 19th century and called by many different names, but it is now called tuberous sclerosis complex, and the relationship between benign brain tumors and the symptoms of the disease was first described by Désiré-Magloire Bourneville in 1880.

Classification

There is no established system for the classification of tuberous sclerosis.

Historical Perspective

Tuberous Sclerosis was described as a specific disease in the 19th century, being initially referred to adenoma sebaceum, epiloia, Pringle's disease or Bourneville's disease. Rayer, a French dermatologist, was the one to first describe the disease and the fibrovascular papules that characterize it, making illustrations of it. He described two cases of tuberous sclerosis in patients who had the nasolabial papular eruption with telangiectasias at the base. In 1850 the first written report of tuberous sclerosis appeared in "Vitiligoidea", published by Addison and Gull. It was not recognized as a distinct disease but was classified as "vitiligoidea tuberosa". In 1862, von Recklinghausen reported a tumor of the heart found in a newborn during autopsy, and by that he is credited to be the first that described the microscopic appearance of tuberous sclerosis. Bourneville in 1880, a French neurologist, described the case of a girl who presented at the age of 3 with facial eruption and died at 15 years of age due to epilepsy, which complicated with pneumonia and inanition. He found brain and kidney tumors on the autopsy which were correctly believed to be the cause of her seizures and mental retardation. In 1911, E. B. Sherlock, superintendent of Belmont Asylum of Idiots, London, coined the word "epiloia" that indicated a clinical triad of epilepsy, low intelligence and adenoma sebaceum.

In 2002, treatment with rapamycin was found to be effective at shrinking tumours in animals. This has led to human trials of rapamycin as a drug to treat several of the tumors associated with TSC.

Pathophysiology

Patients with tuberous sclerosis have loss-of-function germline mutations in both alleles of the following tumor suppressor genes: TSC1 or TSC2. One third of the mutations is inherited, two thirds are de novo mutations. The mutations causes the loss of one allele, but as long as the second one remains intact, the cell won't present any metabolic change. When there is a second TSC1 or TSC2 mutation, which typically occurs in multiple cells over a person's lifetime, then the disease starts to manifest (fitting the "two-hit" tumor-suppressor gene model, with the germline mutation inactivating one gene and then a somatic event inactivating the remaining other one). TSC1 codes for a protein called hamartin, and TSC2 codes for a protein called tuberin. They belong to a protein complex that inhibits the mammalian target of rapamycin (mTOR) complex 1 via RAS homologue enriched in brain (RHEB) which regulates cell growth. In a normal patient, RHEB activates mTORC1 when bound to GTP, but in TSC there is a hyperactivarion of RHEB and consequently of mTORC1. mTOR regulates cellular proliferation, autophagy, growth and protein and lipid synthesis and it enhances protein translation when activated, reprograming the cell metabolism, which increases cell proliferation but also may make it vulnerable to death in nutrient-restricted media. Besides the TSC-RHEB-mTORC1 pathway, there is evidence of alternate pathways also having a role in the disease that are mTORC1 independent, but they are currently under investigation.

NIH - Tuberous Sclerosis - https://ghr.nlm.nih.gov/condition/tuberous-sclerosis-complex#genes - accessed at 06/10/2020

Henske, Elizabeth P., et al. "Tuberous sclerosis complex." Nature reviews Disease primers 2.1 (2016): 1-18.

Differentiating Tuberous Sclerosis from other Diseases

Tuberous sclerosis must be differentiated from other diseases that cause myxoma or other benign tumors and/or seizures, such as Sturge Weber, hypomelanosis of Ito, Birt-Hogg-Dube syndrome, multiple endocrine neoplasia and various seizures disorders.

NORD: National Organization for Rare Diseases - Tuberous Sclerosis - available at: https://rarediseases.org/rare-diseases/tuberous-sclerosis/#:~:text=Examples%20of%20such%20disorders%20include,be%20differentiated%20from%20tuberous%20sclerosis. accessed at 06/12/2020

Epidemiology and Demographics

Tuberous sclerosis complex affects about 1 in 6,000 people, occurring in all races and ethnic groups, and in both genders. Prior to the invention of CT scanning to identify the nodules and tubers in the brain, the prevalence was thought to be much lower and the disease associated with those people diagnosed clinically with learning disability, seizures, and facial angiofibroma. Whilst still regarded as a rare disease, TSC is common when compared to many other genetic diseases, with at least 1 million individuals worldwide.

REF Curatolo P, ed. (2003). "Diagnostic Criteria". Tuberous Sclerosis Complex: From Basic Science to Clinical Phenotypes. International review of child neurology.

London: Mac Keith Press. ISBN 978-1-898683-39-1. OCLC 53124670. NIH - Tuberous Sclerosis - https://ghr.nlm.nih.gov/condition/tuberous-sclerosis-complex#genes - accessed at 06/10/2020

Risk Factors

There are no established environmental risk factors for tuberous sclerosis. One third of the cases are familial, so family history can be a risk factor for the disease.

Screening

As it is a rare disease, screening is not recommended.

Diagnosis

Tuberous sclerosis skin lesion - Ash-leaf spot - image taken from: www.atlasdermatologico.com.br

Tuberous sclerosis complex is diagnosed if a set of diagnostic criteria are met. These criteria include major and minor features. If a case meets the clinical diagnostic criteria, then it is performed a genetic molecular testing which is seem mostly as corroborative. Most of the patients seek medical assistance due to their dermatologic lesions or seizures but for making this diagnosis an evaluation that assesses all the clinical features of the tuberous sclerosis complex is necessary, as these manifestations have variable penetrance. REF NEJM The latest diagnostic criteria was developed by the 2012 International Tuberous Sclerosis Complex Consensus Conference, and it is showed at the table below:

Diagnostic Criteria for Tuberous Sclerosis Complex

Major Features
	Location	Sign	Onset	Note
1	Skin	Hypomelanotic macules	Infant – child	At least three, at least 5 mm in diameter.
2	Head	Facial angiofibromas or fibrous cephalic plaque	Infant – adult	At least three angiofibromas
3	Fingers and toes	Ungual fibroma	Adolescent – adult	At least two
4	Skin	Shagreen patch (connective tissue nevus)	Child
5	Eyes	Multiple retinal nodular hamartomas	Infant
6	Brain	Cortical dysplasias (includes tubers and cerebral white matter radial migration lines)	Fetus
7	Brain	Subependymal nodule	Child – adolescent
8	Brain	Subependymal giant cell astrocytoma	Child – adolescent
9	Heart	Cardiac rhabdomyoma	Fetus
10	Lungs	Lymphangioleiomyomatosis	Adolescent – adult
11	Kidneys	Renal angiomyolipoma	Child – adult	At least two. Together, 10 and 11 count as one major feature.
Minor Features
	Location	Sign	Note
1	Skin	"Confetti" skin lesions
2	Teeth	Dental enamel pits	At least three
3	Gums	Intraoral fibromas	At least two
4	Eyes	Retinal achromic patch
5	Kidneys	Multiple renal cysts
6	Liver, spleen and other organs	Nonrenal hamartoma

TSC can be first diagnosed at any stage of life. Prenatal diagnosis is possible by chance if heart tumours are discovered during routine ultrasound. In infancy, white patches on the skin may be noticed, or the child may present with epilepsy, particularly infantile spasms, or developmental delay may lead to neurological tests. In childhood, behavioural problems and autism spectrum disorder may also lead to a clinical investigation and a diagnosis. During adolescence it is usually that skin problems appear while in adulthood, kidney and lung problems may become evident. An individual may also be diagnosed at any time as a result of genetic testing of family members of another affected person.

External links

Classification	[[d: |D]] ICD-10: Q85.1 ICD-9-CM: 759.5 OMIM: 191100 613254 DiseasesDB: 13433
External resources	MedlinePlus: 000787 eMedicine: neuro/386 derm/438 ped/2796 radio/723 Patient UK: Sandbox Jose2 NCI: Sandbox Jose2 GeneReviews: Tuberous Sclerosis Complex Orphanet: 805

• tuberous-sclerosis at NIH/UW GeneTests
• GeneReview/NCBI/NIH/UW entry on Tuberous Sclerosis Complex

Case courtesy of Dr Ian Bickle, Radiopaedia.org, rID: 76157

Syncope classification

Vasovagal

Micturation

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Case courtesy of Dr Vinay V Belaval, Radiopaedia.org, rID: 66974

Disease	Type	Sign		Symptom

Syncope is classified into three categories:

• Neurally mediated
• Cardiac
• Vasovagal

Disease Name	Age of Onset	Gender Preponderance	Signs/Symptoms	Imaging Feature(s)	Macroscopic Feature(s)	Microscopic Feature(s)	Laboratory Findings(s)	Other Feature(s)	ECG view