What are the diagnostic criteria for tuberous sclerosis complex (TSC)?

Diagnostic Criteria for Tuberous Sclerosis Complex (TSC)

The diagnosis of tuberous sclerosis complex (TSC) requires meeting either genetic diagnostic criteria through identification of a pathogenic TSC1 or TSC2 mutation, or clinical diagnostic criteria based on specific combinations of major and minor features.

Genetic Diagnostic Criteria

• Identification of a pathogenic mutation in either TSC1 or TSC2 genes is sufficient for a definite diagnosis of TSC 1
• Genetic testing is recommended for all patients with definite or suspected TSC, barring financial or accessibility limitations 2
• Variants of unknown significance (VUS) should not be used for clinical decision-making 2
• High-sensitivity genetic analysis is recommended if standard testing is negative in patients with clinical features of TSC, as mosaicism is common (detectable at allele frequencies as low as 1-2%) 2

Clinical Diagnostic Criteria

Definite TSC Diagnosis (requires either):

• Two or more major features
• One major feature plus two or more minor features 1, 3

Possible TSC Diagnosis:

• One major feature
• Two or more minor features 3

Major Features:

• Hypomelanotic macules (≥3, at least 5mm diameter) 1, 3
• Angiofibromas (≥3) or fibrous cephalic plaque 1
• Ungual fibromas (≥2) 1, 3
• Shagreen patch 1, 3
• Multiple retinal hamartomas 1, 3
• Cortical dysplasias (includes radial migration lines and/or multiple cortical tubers) 2
• Subependymal nodules 1, 3
• Subependymal giant cell astrocytoma (SEGA) 1, 3
• Cardiac rhabdomyoma 1, 3
• Lymphangioleiomyomatosis (LAM) 1, 3
• Angiomyolipomas (≥2) 1, 3

Minor Features:

• "Confetti" skin lesions 1, 3
• Dental enamel pits (>3) 1, 3
• Intraoral fibromas (≥2) 1, 3
• Retinal achromic patch 1, 3
• Multiple renal cysts 1, 3
• Nonrenal hamartomas 1, 3
• Sclerotic bone lesions (recently reintroduced as a minor criterion) 2, 4

Important Clinical Considerations

• TSC affects approximately 1 in 5,800 newborns, with over one million affected patients worldwide 1
• 65-75% of TSC cases are due to de novo mutations rather than inherited from parents 1, 5
• Less than 40% of patients present with the classic triad of facial angiofibromas, developmental delay, and intractable epilepsy 1
• TSC2 mutations generally cause more severe disease than TSC1 mutations, particularly regarding neurological manifestations and kidney involvement 2
• Combined deletion of TSC2 and PKD1 genes results in an accelerated cystic kidney disease phenotype 2

Diagnostic Pitfalls and Special Considerations

• 10-15% of patients meeting clinical criteria for TSC have no identifiable mutation in TSC1 or TSC2 genes, often due to mosaicism 2
• Mosaicism can make genetic diagnosis challenging, as the pathogenic variant may be present at very low levels or only in specific tissues 2
• Parents of a child with seemingly sporadic TSC have a 1-2% risk of having another affected child due to possible germline mosaicism 2, 6
• TSC is often underrecognized by clinicians without specialist knowledge due to its variable presentation 1
• Genetic counseling is strongly recommended for all patients with TSC who are considering having children 2

Surveillance Recommendations After Diagnosis

• Brain MRI every 1-3 years until age 25 to monitor for SEGA 2
• Renal imaging: Abdominal ultrasound every 1-3 years until age 12, then transition to MRI every 1-3 years 2
• Annual blood pressure measurement and kidney function assessment 2, 1
• Chest CT at age 18 for females and symptomatic males to screen for lymphangioleiomyomatosis 2
• Coordinated multidisciplinary approach involving specialists from neurology, nephrology, pulmonology, dermatology, and other disciplines 1