A 12-year-old girl with intellectual disability is brought to the office for evaluation of recurrent generalized seizures. The patient takes multiple antiepileptic medications. Physical examination shows several hypopigmented skin macules and the findings seen in the exhibit. Brain imaging reveals periventricular subependymal nodules. This patient's genetic defect directly affects function of which of the following cellular components?
Tuberous sclerosis complex | |
Pathophysiology |
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Classic findings |
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This patient has classic skin (ie, ash-leaf macules, malar angiofibromas) and neurologic (ie, seizures, intellectual disability) manifestations of tuberous sclerosis complex (TSC).
TSC is an autosomal dominant neurocutaneous disorder caused by a loss-of-function mutation in TSC1 or TSC2, tumor suppressor genes responsible for encoding hamartin and tuberin, respectively. In general, these proteins form the tuberin-hamartin complex, which plays a role in regulating cell growth by limiting signaling to the mTOR pathway.
In patients with TSC, dysregulation and enhanced signaling of the mTOR pathway due to mutated tuberin-hamartin complex lead to unrestricted cellular proliferation and tumor formation (eg, hamartomas) in various tissues. For example, in addition to cortical tubers (glioneural hamartomas) and subependymal nodules in the brain, patients with TSC are also predisposed to periungual fibromas, renal angiomyolipomas, and cardiac rhabdomyomas. Notably, targeted therapy with an mTOR inhibitor (eg, everolimus) can be used to shrink expanding or symptomatic TSC brain tumors.
(Choice A) JAK/STAT signaling pathway promotes gene transcription of hormones such as erythropoietin, and activating JAK2 mutations are associated with myeloproliferative disorders such as polycythemia vera.
(Choice B) RAS/RAF/MAPK signaling is involved in cell cycle progression, and mutations within the pathway are implicated in the development of numerous cancers (eg, colon, lung, pancreatic).
(Choice C) Telomerase is an enzyme that maintains telomere length; when mutated, rapidly dividing cells lose chromosomal integrity, triggering premature cell death. Characteristic findings of abnormal telomerase activity (eg, dyskeratosis congenita) include oral leukoplakia, dystrophic nails, bone marrow failure, and pulmonary fibrosis.
(Choice E) Von Hippel-Lindau (VHL) syndrome is an autosomal dominant hereditary cancer syndrome caused by a mutation affecting VHL tumor suppressor protein, which normally functions as a ubiquitin ligase to facilitate proteasomal degradation. Characteristic tumors include hemangioblastoma, clear cell renal carcinoma, and pheochromocytoma.
Educational objective:
Tuberous sclerosis complex is a neurocutaneous disorder in which enhanced mTOR signaling due to defective tuberin-hamartin complex results in uncontrolled cellular proliferation and tumor formation (eg, subependymal nodules).