Tuberous sclerosis complex, a neurocutaneous disorder primarily affecting children, is characterised by facial angiomas, multiple benign calcified multi-organ hamartomas, epileptogenic cortical tubers and subependymal nodules in the brain, pulmonary lymphangioleiomyomatosis, renal angiomyolipomas, and cardiac rhabdomyomas.
Description
Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder leading to the formation of benign, hamartomatous tumours in numerous organ systems. Belonging to the group of phakomatoses, or neurocutaneous syndromes, TSC has wide-ranging clinical manifestations due to its multi-systemic involvement. It’s the most common cause of epilepsy in children, a
Pathogenesis
TSC arises due to mutations in two genetic loci, TSC1 or TSC2, encoding hamartin and tuberin, respectively. These proteins form a complex that inhibits the mTOR pathway, controlling cell growth and proliferation. Mutations lead to loss of this inhibitory control, resulting in unregulated cell growth, proliferation, and differentiation – giving rise to hamartomas in various organs. Renal cysts are common due to the collocation of the TSC2 gene with the PCKD1 gene of polycystic kidney disease.
Subtypes
There are no established subtypes of tuberous sclerosis, although clinical manifestations and severity can vary based on the specific genetic mutation and its penetrance.
Epidemiology, Risk Factors & Associations
- Occurs in about 1 in 6,000 live births
- Usually present in infancy or childhood
- No known gender or racial predilection
- Majority of cases (two-thirds) result from spontaneous mutation, with the remainder due to autosomal dominant inheritance
Clinical Features
Classically described with pathognomonic Vogt triad of:
- Epilepsy (80 – 90%)*
- Cognitive impairment (autism, mental retardation 50 – 80%)*
- Adenoma sebaceum
* Due to cortical tubers in the brain (most common manifestation)
The Vogt triad is however only seen in a third of patients. Other common features include:
- Cutaneous manifestations include facial angiofibromas (90%), shagreen patches, hypomelanotic macules, and ungual fibromas
- Renal angiomyolipoma may cause abdominal pain, haematuria or lead to renal impairment
- Cardiac rhabdomyoma are the most common benign myocardial tumour in infants, typically found in the ventricles and can cause arrhythmias or obstructive symptoms
- Pulmonary lymphangioleiomyomatosis usually affects adult women and may cause dyspnoea, pneumothorax, or chylothorax
- Retinal glial hamartomas
- Subependymal giant cell astrocytoma (WHO Grade 1)
- Multiple cysts in liver, kidneys, pancreas
Complications
- Rare risk of malignant transformation of renal angiomyolipomas to renal cell carcinoma
- Neurological complications include intractable seizures, cognitive impairment, behavioural problems, and autism spectrum disorder
- Renal failure due to growth and bilateral nature of angiomyolipomas
- Cardiac rhabdomyoma can lead to life-threatening arrhythmias in infants
- Respiratory failure from progressive lymphangioleiomyomatosis in adult women
Pathological Features
Histopathology
- Macroscopic: Visible hamartomas in affected organs. Cortical tubers are firm (potato-like, hence tuber).
- Microscopic: Presence of hamartomas consisting of disorganised tissues native to the organ
Serology
- Genetic testing showing mutations in TSC1 or TSC2 genes
Biochemistry
- Non-specific and varies depending on affected organs
Radiological Features
General Features
- Multiple hamartomas across various organ systems, commonly the brain, kidneys, and heart
- Osseous manifestations include cyst-like lesions, hyperostosis of the inner table of the calvaria, osteoblastic changes, periosteal new bone formation and scoliosis. Can occur anywhere in bone, commonly in the calvaria, short tubular bones of the hand or foot, spine and pelvis.
- The cyst-like lesions are usually irregularly circumscribed and have a sclerotic appearance peripherally
XR
- Chest: Pulmonary lymphangioleiomyomatosis (LAM) may present as numerous, thin-walled cysts dispersed throughout the lung fields. In advanced stages, a honeycomb pattern may be evident.
CT
- Brain: Subependymal nodules appear as calcified nodules along the ventricles. Cortical/subcortical tubers appear as hypodense areas due to calcification.
- Kidneys: Renal angiomyolipomas are usually hypodense on non-contrast scans due to the presence of fat.
- Chest: Pulmonary LAM presents as thin-walled, round, well-defined, diffusely distributed cysts often with no zonal predominance.
MRI
Brain
- T1: Subependymal nodules are hypointense, and cortical/subcortical tubers can also demonstrate hypointensity due to calcification.
- T2/FLAIR: Subependymal nodules can show hyperintensity. Cortical/subcortical tubers often display a mixed signal due to calcification and gliosis, but predominantly appear hyperintense.
- T1 Gad+: Subependymal giant cell astrocytomas (SEGAs), which can arise from subependymal nodules, show enhancement.
Kidneys
- T1: Renal angiomyolipomas are hyperintense due to the presence of macroscopic fat.
- T2: Renal angiomyolipomas are typically hypointense.
Cardiac
- T1: Cardiac rhabdomyomas are isointense to adjacent myocardium
- T2: Cardiac rhabdyomyomas hyperintense to adjacent myocardium
US
- Heart: Cardiac rhabdomyomas are typically homogeneously echogenic, often appearing as multiple, non-obstructive, intramural masses within the myocardium. They most frequently occur in relation to the ventricles.
- Kidneys: Renal angiomyolipomas typically appear as hyperechoic masses due to fat content.
Grading and Staging
There is no established grading or staging system for TSC.
Diagnosis
The diagnosis of TSC is typically based on a combination of clinical, radiological, and genetic findings, using the updated diagnostic criteria from the 2012 International Tuberous Sclerosis Complex Consensus Conference.
Differential Diagnosis
- Neurofibromatosis Type 1: Characterised by café-au-lait spots, FASIs, neurofibromas, and optic gliomas, but lacks the systemic involvement of TSC
- Sturge-Weber syndrome: Port-wine stains, glaucoma and leptomeningeal angiomas are distinctive, but lacks renal and pulmonary involvement
- Von Hippel-Lindau disease: Haemangioblastomas, renal cell carcinomas (clear cell), pheochromocytomas, but lacks cutaneous involvement
Management
Management of TSC involves a multidisciplinary approach including neurology for seizure management, dermatology for skin lesions, nephrology for renal complications, and pulmonology for LAM. Genetic counselling is crucial. Pharmacotherapy with mTOR inhibitors has shown promise in controlling the growth of SEGAs and renal angiomyolipomas.