Dr.Ch.Venkat Kumar Raju , Dr.Sajitha Nair, Dr.Vaishakh Anand, Dr.Wesley, Dr.C Jayakumar
Department of Pediatrics and medical oncology
Amrita, Kochi
9 yr. old case of tuberous sclerosis came with complaints of increased frequency of seizures and Right eye ptosis from 1 month.
No h/o fever, drug faltering, altered sensorium, facial asymmetry, or speech abnormalities
Background History- 1 child of NCM
Antenatal history- Mother had regular antenatal checkups. Antenatal echo showed multiple intra cardiac tumors which were suggestive of rhabdomyomas.
Natal history – 39wk/LSCS(NPOL)/CIAB/3.25kg
Post-natal Echo showed multiple rhabdomyomas
At 1 months she was evaluated in pediatric neurology, MRI showed cortical and subependymal tubers s/o tuberous sclerosis, EEG showed b/l temporal and occipital epileptiform abnormalities. At 4 months genetic testing was done , which showed mutation in TSC2 (Novel mutation with shift). At 8 months she had 1 event of seizure, AEDs were started. On routine ophthalmology check at 4 years she was noticed to have bilateral eye astrocytoma away from fovea, with U/L hypertrophy. USG abdomen done during this time showed Small renal angiomyolipoma’s
Development – Achieved age appropriate milestones, IQ testing was done at 6 years showed score of 40, she is poor scholastically and very hyperactive, occasionally ill sustained attention span
On examination – afebrile , alert and consious
No PICCLE, vitals stable
Head to foot- Right hemi hypertrophy, Numerous adenoma sebaceoum over face, multiple ash leaf macules, Right eye ptosis
Neurologically – Cranial nerve normal, apart from right eye ptosis, Tone, power, reflexes normal, no meningeal signs
At this point out D/D
1) Sub ependymal giant cell astrocytoma
2) Hydrocephalus due to tubers
3) 3rd nerve palsy
4) Raised ICP
5) New onset seizures
MRI was done – Showed subependymal giant cell astrocytoma in right lateral ventricle increased in size with mild prominence of ventricles
EEG- right occipital and generalized epileptiform abnormalities
Dose of AEDs were increased, In view of Increase in size of SEGA, Neurosurgery and Medical oncology consults were availed. After discussions it was decided to start on everolimus and follow up the tumpur size after 1 month
MRI on the left shows a small subependymal nodule at 1 month, MRI on the right shows Sub ependymal giant astrocytoma with Midline shift
Tuberous Sclerosis and Everolimus
Tuberous sclerosis complex (TSC) is a multisystemdisease character- ized an autosomal dominant mode of inheritance, variable expres- sivity, and a prevalence of 1 in 6,000-10,000 newborns. Spontaneous pathogenic variants occur in 65% of the cases. Molecular genetic stud- ies have identified two foci for TSC: the TSC1 gene (located on chro- mosome 9q34) and the TSC2 gene (located on chromosome 16p13). The TSC1 gene encodes a protein called hamartin, and the TSC2 gene encodes a protein called tuberin. Within a cell, these two molecules form a complex along with a third protein, TBC1D7 (Tre2-Bub2- Cdc16 1 domain family, member 7). Consequently, a pathogenic variant in either the TSC1 gene or the TSC2 gene results in a similar disease in patients, though individuals with TSC2 variants tend to be more severely affected.
Tuberin and hamartin are involved in a key pathway in the cell that regulates protein synthesis and cell size (see Fig.). One of the ways cells regulate their growth is controlling the rate of protein synthe-sis. A protein called mechanistic target of rapamycin (mTOR) is one of the master regulators of cell growth (mTOR has additional roles in the CNS, where it helps regulate neuronal development and synaptic plasticity). mTOR, in turn, is controlled Ras homolog enriched in brain (RHEB), a small cytoplasmic guanosine triphosphatase. When RHEB is activated, the protein synthesis machinery is turned on, most likely via mTOR signaling, and the cell grows. Under normal conditions, the tuberin/hamartin complex keeps RHEB in an inactive state. However, in TSC, there is disinhibition of RHEB and subsequent overactivation of the mTOR pathway. Accordingly, the TSC1 and TSC2 genes can be considered tumor-suppressor genes. The loss of either tuberin or hamartin protein results in the formation of numerous benign tumors (hamartomas).
Patient’s with large or growing SEGAs, or with SEGAs causing ventricular enlargement without other manifestations, should undergo MRI scans more frequently, and the patients and their families should be educated regarding the potential of new symptoms caused increased intracranial pressure. Surgical resection should be performed for acutely symptomatic SEGA. For growing but otherwise asymptomatic SEGAs, either surgical resection or medical treatment with an mTOR inhibitor (sirolimus, everolimus) may be used. Treat- ment with everolimus can be effective in slowing the growth or even reducing the size of SEGAs. Everolimus is also effective in treating renal angiomyolipomas. Sirolimus is also effective in treating lymphangi- oleiomyomatosis, renal angiomyolipomas, and cardiac rhabdomyomas