Abstracts

Rationale: Tuberous Sclerosis Complex (TSC) is an autosomal dominant trait in which dysregulation of cellular proliferation and differentiation results in the development of hamartomatous growths in many organs. Two genes for this disorder, TSC1 and TSC2, have been identified. Methods: We present a 51 year-old woman with TSC and severe multi-organ involvement. The patient's clinical history and phenotypic findings are described in detail. The patient was tested for a genetic defect employing both deletion and duplication analysis and sequencing of the TSC2 gene. Results: This 51 year-old patient was diagnosed in childhood with TSC with the manifestation of epilepsy and skin lesions. On her current treatment with phenobarbital and clobazam, she has several brief complex partial seizures a day. At 49 years of age, routine and sleep deprived electroencephalogram showed a moderate intermittent non-specific disturbance of cerebral activity over the right frontotemporal region. During wakefulness but mostly during sleep, there were interictal epileptic abnormalities arising from the right anterior temporal region. During sleep, there was also activation of rare interictal epileptic abnormalities arising independently from the left anterior temporal region. Her brain MRI showed multiple calcified subependymal nodules, two masses enhancing with contrast and suggestive of small (9-9.5 mm) subependymal giant cell astrocytomas (SEGAs), as well as various bilateral cortical and subcortical signal abnormalities consistent with various areas of dysplasia and tubers. She also has lung lymphangioleiomyomatosis (LAM), small non enhancing masses within the myocardium and the pericardial space most likely representing angiomyolipomas, non enhancing angiomyolipomas in the liver, spleen and kidneys, as well as some enhancing renal masses possibly renal carcinoma. She had a splenectomy, and at age 23 years distal pancreatectomy for resection of pancreatic neuroendocrine tumors. At age 50, the patient had a recurrence of the neuroendocrine tumor of the pancreas requiring re-operation. Molecular analysis revealed no deletions or duplications of the TSC2 gene but a nonsense variant c.4993 C>T predicted to result in premature protein termination (p.Gln1665), previously reported as pathogenic. Conclusions: This patient with TSC and severe multi-organ involvement has a rare nonsense pathogenic variant in the TSC2 gene. She has had a number of surgical interventions, including pancreatectomy on two occasions, as well as splenectomy. Despite the severe multi-organ involvement, including SEGA, the patient's epilepsy is relatively well controlled on antiepileptic medication. Treatment with an mTOR inhibitor is being planned.