TABLE.

Updated diagnostic criteria for tuberous sclerosis complex 2012

Genetic diagnostic criteria The identification of either a TSC1 or TSC2 pathogenic mutation in DNA from normal tissue is sufficient to make a definite diagnosis of tuberous sclerosis complex (TSC). A pathogenic mutation is defined as a mutation that clearly inactivates the function of the TSC1 or TSC2 proteins (e.g., out-of-frame indel or nonsense mutation), prevents protein synthesis (e.g., large genomic deletion), or is a missense mutation whose effect on protein function has been established by functional assessment (www.lovd.nl/TSC1, www.lovd/TSC2, and Hoogeveen-Westerveld et al., 2012 and 2013). Other TSC1 or TSC2 variants whose effect on function is less certain do not meet these criteria, and are not sufficient to make a definite diagnosis of TSC. Note that 10% to 25% of TSC patients have no mutation identified by conventional genetic testing, and a normal result does not exclude TSC, or have any effect on the use of clinical diagnostic criteria to diagnose TSC. Clinical diagnostic criteria Major features Hypomelanotic macules (≥3, at least 5-mm diameter) Angiofibromas (≥3) or fibrous cephalic plaque Ungual fibromas (≥2) Shagreen patch Multiple retinal hamartomas Cortical dysplasias* Subependymal nodules Subependymal giant cell astrocytoma Cardiac rhabdomyoma Lymphangioleiomyomatosis (LAM)† Angiomyolipomas (≥2)† Minor features “Confetti” skin lesions Dental enamel pits (>3) Intraoral fibromas (≥2) Retinal achromic patch Multiple renal cysts Nonrenal hamartomas

Definite diagnosis: Two major features or one major feature with ≥2 minor features

Possible diagnosis: Either one major feature or ≥2 minor features

^*Includes tubers and cerebral white matter radial migration lines.

^†A combination of the two major clinical features (LAM and angiomyolipomas) without other features does not meet criteria for a definite diagnosis.