Tuberous sclerosis complex (TSC)

TSC affects virtually all organ systems, with characteristic involvement of skin, central nervous system, kidneys, heart, lungs, eyes, and bone. Skin findings are present in nearly 100% of affected individuals and include hypomelanotic macules (~90%), facial angiofibromas (~75%), shagreen patches (~50%), ungual fibromas (20% overall, up to 80% in older adults), confetti skin lesions (3% in children up to 58% overall) and fibrous cephalic plaques. CNS manifestations include subependymal nodules (SENs) and cortical tubers (~80% of individuals, respectively), as well as subependymal giant cell astrocytomas (SEGAs; up to 25% of individuals). More than 80% of affected individuals develop seizures, with seizure onset before two years of age in up to 75% of patients. TAND describes the functional and clinical manifestations of brain dysfunction in individuals with TSC which occurs to varying degrees in more than 90% of patients during their lifetime. TAND includes behavioral, psychiatric, intellectual, academic, neuropsychological, and psychosocial difficulties and may manifest as autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), learning and cognitive impairment as well as disruptive behaviors and emotional problems. Renal lesions include benign renal angiomyolipoma (AMLs; 70% of affected individuals), epithelial cysts (20%-30%), and renal cell carcinoma (RCC; <3%). Kidney lesions are identifiable in ~80% of affected children by a mean age of 10.5 years. Kidney disease is the leading cause of early death (50%) in individuals with TSC. Cardiac rhabdomyomas are the earliest detectable TSC manifestation occurring prenatally or in the neonatal period. They are present in ~50% of individuals with TSC, regressing with time and eventually disappearing. Pulmonary lymphangioleiomyomatosis (LAM) occurs predominantly in adult women with an age dependent frequency between 30 and 80%. Ocular findings include retinal hamartomas and achromic patches, both observed in 34% of individuals with TSC. The clinical presentation shows marked inter- and intrafamilial variability.

The estimated incidence is 1/6,000 to 1/10,000 live births.

TSC is inherited in an autosomal dominant manner. Approximately 66% of affected individuals carry a de novo TSC1 or TSC2 pathogenic variant; the remaining one-third have inherited the variant from an affected parent. Individuals representing simplex cases are more likely to have a TSC2 pathogenic variant than a TSC1 pathogenic variant. Each child of an affected individual has a 50% risk of inheriting the pathogenic variant. Predictive testing for at-risk asymptomatic family members and prenatal molecular testing is technically possible once the pathogenic variant in the family has been identified. Although the penetrance of TSC is thought to be 100%, clinical variability is observed among affected family members.

The diagnosis is established using the . The diagnostic criteria update takes into account clinical diagnostic criteria and genetic diagnostic criteria independently. Clinical diagnostic criteria include 11 major features and seven minor clinical features enabling a definite clinical diagnosis if either 2 major features or 1 major feature with 2 minor features are present, and a possible clinical diagnosis TSC if either 1 major feature or >2 minor features are fulfilled. The genetic diagnosis TSC means the identification of a pathogenic variant in TSC1 or TSC2 which is sufficient for the diagnosis or prediction of TSC regardless of clinical findings. Brain MRI identifies cortical tubers, subependymal nodules, and SEGA; abdominal MRI detects renal angiomyolipomas and cysts; echocardiography identifies cardiac rhabdomyomas; and high-resolution chest CT identifies LAM.

Main differential diagnoses include:

• : kidney cysts predominate without TSC-typical renal AMLs, pulmonary LAM, cardiac rhabdomyomas, or characteristic skin and brain features; PKD1, PKD2, and others
• : pulmonary cysts predominate, facial angiofibromas have been reported; different characteristic skin lesions in BHDS including fibrofolliculomas, no TSC-typical multisystem hamartomas; FLCN

• Molecular genetic testing is recommended when the diagnosis of TSC is suspected or in question but cannot be clinically confirmed. An independent genetic diagnosis of TSC to an individual prior meeting clinical criteria for TSC is beneficial to ensure that those individuals undergo necessary surveillance to identify manifestations of TSC as early as possible to enable optimal clinical outcomes.
• Identification of a pathogenic variant enables the implementation of specific, individualised surveillance and management recommendations for individuals with newly diagnosed TSC.
• Genetic testing of at-risk relatives is recommended for genetic counseling purposes to clarifiy their variant status and family planning. In case a genetic diagnosis of TSC can be established, necessary clinical and therapeutic follow-up strategies can be implemented.

• Northrup H, Koenig MK, Pearson DA, Au KS. Tuberous sclerosis complex. 1999 Jul 13 [updated 2024 Aug 1]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. PMID: 20301399.
• Northrup H, Aronow ME, Bebin EM, Bissler J, Darling TN, de Vries PJ, et al. Updated International Tuberous Sclerosis Complex diagnostic criteria and surveillance and management recommendations. Pediatr Neurol. 2021;123:50-66. PMID: .
• Peron A, Au KS, Northrup H. Genetics, genomics, and genotype-phenotype correlations of TSC: insights for clinical practice. Am J Med Genet C Semin Med Genet. 2018;178(3):281-290. PMID: .