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Tuberous sclerosis complex
Tuberous sclerosis complex (TSC) is a neurocutaneous disorder characterized by multisystem hamartomas and associated with neuropsychiatric features.
ORPHA:805Classification level: Disorder
The prevalence is estimated to be 1/25,000-1/11,300 in Europe.
TSC is characterized by multisystem hamartomas, most commonly skin, brain, kidney, lung and heart, appearing at different ages. 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; and ''confetti'' skin lesions appearing in childhood to early adolescence. Brain is involved in almost all cases of TSC, with the presence of different neuropathological lesions, such as cortico/subcortical tubers, radial migration lines, subependymal nodules, SEGA. SEGA can cause hydrocephalus (growth risk higher in the first 3 decades). Early-onset epilepsy (infantile spasms and/or focal seizures) is present in 85% of patients. Neuropsychiatric features (intellectual disability, attention-deficit/hyperactivity disorder, autism spectrum disorders (ASD), self-injury, anxiety and obsessive compulsive tendencies have also been reported. 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. Lymphangioleiomyomatosis (LAM), multifocal micronodular pneumocyte hyperplasia (MMPH) and pulmonary cysts develop during adulthood and manifest with dyspnea, pneumothorax, or chylothorax. Cardiac rhabdomyomas (CR) appear during the fetal period and may become symptomatic (outflow tract obstruction or by interfering with valvular function) during infancy and early childhood. Additional features include dental enamel pitting, intraoral fibromas and skeletal dysplasias.
TSC is due to mutations in TSC1 (9q34) and TSC2 (16p13.3) which encode proteins that indirectly inhibit mTOR. In excess, mTOR causes disproportionate glutamate activity leading to disrupted synaptic plasticity. Expressivity is variable and is due to mosaicism and to genetic-epigenetic modifiers.
Diagnosis is based on presence of major (cortical dysplasias; subependymal nodules; SEGA; hypomelanotic macules (≥3, diameter ≥5 mm); shagreen patch; angiofibromas (≥3) or fibrous cephalic plaque; multiple retinal hamartomas; ungual 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. A definite diagnosis is defined as presence of ≥2 major features or 1 major and ≥2 minor features. Possible TSC is considered in the presence of 1 major or ≥2 minor features. TSC can be diagnosed by genetic screening regardless of the clinical findings.
The differential diagnosis includes vitiligo, Ito hypomelanosis, cardiac myxoma, isolated brain tumors, pulmonary emphysema, acne, skin rash.
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.
Transmission is autosomal dominant and genetic counseling is recommended. Two thirds of affected individuals have TSC as the result of a de novo pathogenic variant.
Management and treatment
Management of TSC is multidisciplinary and includes the use of vigabatrin (GABA transaminase inhibitor), effective in infantile spasms and early onset seizures; everolimus (mTOR pathway inhibitor) may be used to treat SEGA not suitable for surgery in adults and children, and for treatment of AML in adults.
TSC is a chronic, life-long condition. As patients transition into adulthood seizures may persist; renal and/or pulmonary issues may become more important, and may pose risks of significant morbidity and occasionally mortality; and psychological and behavioral concerns may appear, persist, or become more significant.
- Summary information
- Slovak (2005, pdf)
- Emergency guidelines
- Français (2018, pdf)
- Deutsch (2007, pdf)
- English (2007, pdf)
- Português (2007, pdf)
- Polski (2007, pdf)
- Italiano (2007, pdf)
- Español (2007, pdf)
- Practical genetics
- English (2006, pdf)
- Guidance for genetic testing
- English (2013)
- Clinical genetics review
- English (2018)