Tuberous Sclerosis Complex
A rare neurocutaneous disorder characterized by multisystem hamartomas, most commonly involving the skin, brain, kidneys, lungs, eye, and heart, and associated with neuropsychiatric disorders.
Epidemiology
The birth prevalence of tuberous sclerosis complex (TSC) is estimated to be 1/6,000.
Clinical description
Skin involvement is almost constantly present, beginning as hypomelanotic macules in the first years life and evolving to facial angiofibromas by 3-4 years, followed by ungual fibromas, cephalic and lumbar (shagreen patch) fibrous plaques, and ''confetti'' skin lesions appearing in childhood to early adolescence. Brain involvement includes cortical dysplasias (tubers), subependymal nodules, and/or subependymal giant cell astrocytoma (SEGA), and is seen in almost all cases. SEGA affects 10 to 20% of TSC patients, almost exclusively children and young adults. Early-onset epilepsy (focal seizures and/or infantile spasms) is present in 85% of patients. TSC-Associated Neuropsychiatric Disorders (TAND) include intellectual disability, attention-deficit/hyperactivity disorder, autism spectrum disorders (ASD), psychiatric disorders, neuropsychological deficits, as well as school and occupational difficulties. 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, multifocal micronodular pneumocyte hyperplasia and pulmonary cysts develop during adulthood and manifest with dyspnea, pneumothorax, or chylothorax. Cardiac rhabdomyomas appear during the fetal period, are rarely symptomatic, and tend to decrease in size in early childhood. Additional features include retinal and liver hamartomas, dental enamel pitting, intraoral fibromas, and skeletal dysplasias.
Etiology
TSC is due to mutations in either TSC1 (9q34) or TSC2 (16p13.3) which encode proteins that indirectly inhibit the mTOR pathway. In excess, mTOR causes increased cell growth and proliferation, as well as disproportionate glutamate activity leading to disrupted synaptic plasticity. Expressivity of TSC is variable due to mosaicism and to genetic-epigenetic modifiers.
Diagnostic methods
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. The identification of a pathogenic variant, confirms the diagnosis regardless of the clinical findings.
Differential diagnosis
Autosomal dominant polycystic kidney disease type 1 with tuberous sclerosis is seen in up to 5% of patients presenting with TSC and should be excluded. Other differential diagnoses include vitiligo, Ito hypomelanosis, acne, skin rash, cardiac myxoma, isolated brain tumors, pulmonary emphysema, and kidney cysts.
Antenatal diagnosis
Cardiac rhabdomyomas, cortical tubers and/or subependymal lesions may be detected by fetal MRI or ultrasound. Prenatal mutational analysis is also possible.
Genetic counseling
The disorder is autosomal dominant; however, two thirds of cases are the result of a de novo pathogenic variant. In one third of cases, TSC is inherited from one of the parents and, in such cases, genetic counseling is recommended to inform the parents that the risk of having an affected child is 50% for each pregnancy.
Management and treatment
Management is multidisciplinary and includes frequent clinical follow-up as well as treatment of epilepsy, tumors, and TAND. Early referral to a specialized pediatric epilepsy center is strongly recommended. Epilepsy treatment includes the use of vigabatrin (GABA transaminase inhibitor) for infantile spasms and early onset focal seizures. For pre-symptomatic infants, video electroencephalogram monitoring is recommended to identify subtle or electrographic seizures. If vigabatrin fails, other antiseizure medicine, ketogenic diet, vagal nerve stimulation, or mTOR pathway inhibitor (everolimus) might be helpful. Early identification of candidates for epilepsy surgery is highly recommended. The developing tumors require frequent follow-up and can be treated with mTOR inhibitors or surgery.
Prognosis
TSC is a chronic, life-long condition. As patients transition into adulthood, seizures may persist; renal and/or pulmonary issues may become more frequent and clinically significant.