Case Report # [] Submitted by:Ladi Oki, MSIV Faculty reviewer:Dr. Sandra Oldham, MD Date accepted:28 September 2011 Radiological Category:Principal Modality (1): Principal Modality (2): Neurology CT Chest/Abdomen MRI

Case History HPI: PB is a 30 yo woman who presented with lethargy and apathy. She was diagnosed with partial seizures at 2 ½ months of age that was treated and has not recurred since age 8. She also has a developmental delay. The patient was in her normal state of health until the last couple of months where she became lethargic and decreased desire for activity and per her parents “is not like herself”. Was referred from Neurology clinic for furthur workup of suspected brain pathology based on outside CT scan. PMH: Seizures at 2 ½ months Removal of a renal tumor of some kind Developmental Delay SH: Walked at 15 months, spoke at 4 years. Reads at a kindergarten age. Lives with parents. Does not smoke, or drink. Can dress and feed herself.

Case History FH: Both grandmothers had breast cancer. One had cervical cancer. No history of seizures, genetic disorders, hypertension or diabetes. Meds: Zyprexa 5mg daily Physical Exam: T: 98.0 P: 80 BP: 118/79 RR: 16 General: AAO x3. No acute distress Chest: RRR. Normal S1 and S2. Lungs clear bilaterally. Skin: Subungal fibromas under toenails, and areas of hypomelanotic discoloration on back and shoulders. Redness of her cheeks. Neuro: PERRLA. Mild right facial droop and left ptosis. DTR 3+. Muscle strength 5/5. Toes dowgoing bilaterally.

Radiological Presentations

Which one of the following is your choice for the appropriate diagnosis? After your selection, go to next page. Test Your Diagnosis Li Fraumeni Syndrome Tuberous Sclerosis Von- Hippel Lindau Neurofibromatosis

MRI: Multiple subependymal nodules and Multiple cortical tubers Li -Fraumeni Von-Hipple-Lindau Tuberous Sclerosis Neurofibromatosis Findings: Differentials: Findings and Differentials

Li-Fraumeni syndrome is associated with a p53 mutation that causes malignancies to develop at early ages and in multiple places. Neurological malignancies can be seen however brain hamartomas are not common. Also, Li- Fraumeni would not explain physical findings of subungal fibromas and discoloration of the skin. Discussion

Li-Fraumeni syndrome is associated with a p53 mutation that causes malignancies to develop at early ages and in multiple places. Neurological malignancies can be seen however brain hamartomas are not common. Also, Li- Fraumeni would not explain physical findings of subungal fibromas and discoloration of the skin. Von-Hippel-Lindau is associated with cerebellar hemangioblastomas not ventricular growths. Discussion

Li-Fraumeni syndrome is associated with a p53 mutation that causes malignancies to develop at early ages and in multiple places. Neurological malignancies can be seen however brain hamartomas are not common. Also, Li- Fraumeni would not explain physical findings of subungal fibromas and discoloration of the skin. Von-Hippel-Lindau is associated with cerebellar hemangioblastomas not ventricular growths. Neurofibromatosis is associated with skin lesions such as café au lait spots and freckling along with neurofibromas of the skin. Neural malignancies can also be seen such as astrocytomas, meningiomas. However cortical hamartomas are not common, neither are ventricular/subependymal masses. Discussion

Tuberous Sclerosis is a neurocutaneous disorder that can involve the brain, kidney, skin, retina, heart, lung and bone with the brain being the most frequently affected organ. Discussion

Tuberous Sclerosis is a neurocutaneous disorder that can involve the brain, kidney, skin, retina, heart, lung and bone with the brain being the most frequently affected organ. TS is inherited in an Autosomal Dominant but 60-75% arise spontaneously. The mutations arise on the TSC 1 gene (chr 9) or the TSC 2 gene (chr 16). Discussion

Tuberous Sclerosis is a neurocutaneous disorder that can involve the brain, kidney, skin, retina, heart, lung and bone with the brain being the most frequently affected organ. TS is inherited in an Autosomal Dominant but 60-75% arise spontaneously. The mutations arise on the TSC 1 gene (chr 9) or the TSC 2 gene (chr 16). Skin findings (96%): - 1 or more hypomelanotic macules (ash leaf spots) - Facial angiofibromas (usually with reddish hue) - Ungal fibromas - Shagreen patches - Café au Lait spots Neurological clinical Findings: - Seizures - Mental Retardation - Developmental Delay Discussion

Renal Lesions: –Renal Cysts –Angiomyolipomas Discussion

Radiological Presentations

Cardiopulmonary Involvement –Rhabdomyomas of the heart can be present with symptomatic presentations more likely in infants –Rarely cystic lung disease may occur which is known as lymphangioleiomyomatosis where disorderly smooth muscle growth which can block airways causing pneumatoceles (air cysts) Discussion

Radiological Presentations

Neural lesions: –A hallmark of Tuberous Sclerosis are cortical tubers. They can be observed on MRI as hyperintense areas on T2 images or as hypodense areas on CT. They are thought to be areas of abnormal neuronal migration Discussion

Neural lesions: –A hallmark of Tuberous Sclerosis are cortical tubers. These cortical tubers are actually hamartomas of the gray matter. They can be observed on MRI as hyperintense areas on T2 images. –Another very specific lesion to Tuberous Sclerosis is the subependymal nodules and subependymal giant cell astrocytoma (SEGA). Subependymal nodues occur in the ventricles and are not on their own terribly worrisome. However these lesions can transform into subependymal giant cell astrocytomas and cause hydrocephalus and obstruct CSF drainage as was the concern in this patient. Discussion

Radiological Presentations

Other Lesions: –- Retinal hamartomas often near the disk – Cystic rarefactions of the bones of the fingers or toes Discussion

Diagnosis The diagnosis is often made clinically with the triad of early seizures, dermatologic findings and mental retardation/developmental delay. Discussion

Diagnosis The diagnosis is often made clinically with the triad of early seizures, dermatologic findings and mental retardation/developmental delay. Once a diagnosis is suspected CT of the chest, abdomen and MRI of the head should be performed to assess for any of the previous states abnormalities and for the need for surgical intervention. Echocardiogram should be used in children to monitor for heart pathology. Subependymal nodules and SEGAs should be monitored frequently (annually for those under 21 and every 2-3 years there after) for enlargment and obstructive hydrocephalus. Discussion

Treatment There is no prevention. Antiepileptics are used for control of seizures. It is usually considered useless to remove tumors except those in the kidney that impair renal function and angiofibromas of the face for cosmetic reasons although it must be understood that the lesions will grow back. Rapamycin is used to treat SEGA to try and decrease the size. Otherwise treatment is supportive In PB’s case Neurosurgeons felt that the subependymal nodues were not causing significant hydrocephalus or CSF blockage and that surgery wasn’t needed and the patient was treated with rapamycin and told to follow up with imaging. Discussion

PB had a history of Tuberous Sclerosis and was diagnosed with multiple subependymal nodules and a possible mild hydrocephalus. Diagnosis

DeAngelis LM, Wen PY. Chapter 379. Primary and Metastatic Tumors of the Nervous System. In: Longo DL, Kasper DL, Hauser SL, Jameson JL, Loscalzo J, Fauci AS, eds. Harrison's Principles of Internal Medicine. 18th ed. New York: McGraw-Hill; Inoue, Yuichi, Y. Nemoto, R. Murata, M. Shakudo, K. Kohno, O. Matsuoka, and K. Mochizuki. "CT and MR Imaging of Cerebral Tuberous Sclerosis." Brain Development 20.4 (1998): Print. Ropper AH, Samuels MA. Chapter 38. Developmental Diseases of the Nervous System. In: Ropper AH, Samuels MA, eds. Adams and Victor's Principles of Neurology. 9th ed. New York: McGraw-Hill; 2011 References