A 6-month-old boy presents to the pediatric clinic with infantile spasms (West syndrome) and developmental delay. Dermatologic examination with a Wood lamp reveals the lesions marked **A** in the diagram. Genetic testing confirms a TSC2 mutation. Which of the following best explains the pathophysiology underlying this patient's multi-organ disease?

Explanation

## Why Loss of TSC1/TSC2 → mTOR hyperactivation is right The hypopigmented ash-leaf macules marked **A** are the earliest and most common dermatologic manifestation of tuberous sclerosis complex (TSC), present in ~90% of patients and best visualized with Wood lamp examination. TSC is caused by autosomal dominant mutations in TSC1 (chromosome 9q34) or TSC2 (chromosome 16p13.3; ~80% of cases, more severe phenotype). Loss of TSC1/TSC2 protein function removes the inhibitory brake on mTOR (mammalian target of rapamycin), leading to constitutive mTOR hyperactivation. This drives uncontrolled proliferation of benign tumors (hamartomas) in multiple organs: dermatologic (ash-leaf macules, adenoma sebaceum, shagreen patches, periungual fibromas), neurologic (cortical tubers, subependymal nodules, SEGA), renal (angiomyolipomas), cardiac (rhabdomyomas), and pulmonary (LAM in women). The TSC2 mutation in this patient explains the severe neurologic phenotype (infantile spasms, developmental delay) and justifies mTOR inhibitor therapy (everolimus) as disease-modifying treatment. This mechanism is the foundational pathophysiology of TSC and is cited in Nelson 21e and Harrison 21e Ch 471. ## Why each distractor is wrong - **Defective PTEN signaling**: PTEN loss causes Cowden syndrome and Lhermitte-Duclos disease, not TSC. While both affect mTOR indirectly, PTEN mutations do not cause the specific constellation of TSC features (ash-leaf macules, cortical tubers, SEGA, infantile spasms) or respond to TSC genetic testing. - **Impaired AMPK-mediated energy sensing**: AMPK dysfunction is not the primary mechanism in TSC. Although mTOR is downstream of AMPK, TSC mutations directly impair the TSC1/TSC2 complex's ability to inhibit mTOR, independent of AMPK status. - **BRAF mutations causing MAPK activation**: BRAF mutations are associated with Noonan syndrome and sporadic melanoma, not TSC. The MAPK pathway is not the primary driver of TSC pathology; mTOR hyperactivation is the key mechanism. **High-Yield:** TSC = mTOR hyperactivation from TSC1/TSC2 loss → hamartomas in skin (ash-leaf macules earliest), brain (tubers, SEGA), kidney (AML), heart (rhabdomyoma), lung (LAM). Wood lamp reveals ash-leaf spots in 90% — critical screening tool in infantile spasms. [cite: Nelson 21e; Harrison 21e Ch 471]