Tuberous Sclerosis – Causes, Symptoms and Treatment

What is Tuberous Sclerosis?

Tuberous sclerosis, also known as Tuberous Sclerosis Complex (TSC), is a rare, genetically caused multisystem disorder. It leads to the growth of benign tumours called hamartomas in multiple organs, most commonly the brain, skin, kidneys, lungs, and heart. The name derives from the Latin word tuber (knob or swelling), referring to the tuber-like growths found in the brain. TSC belongs to the group of conditions known as phakomatoses and occurs in approximately 1 in 6,000 live births.

Causes

Tuberous sclerosis is caused by mutations in one of two genes:

• TSC1 gene (chromosome 9): encodes the protein hamartin
• TSC2 gene (chromosome 16): encodes the protein tuberin

Together, these proteins form a complex that regulates the mTOR signalling pathway (mechanistic target of rapamycin). A mutation in either gene leads to excessive activation of this pathway, resulting in uncontrolled cell growth and the development of hamartomas. TSC is inherited in an autosomal dominant pattern, meaning a single mutated copy of the gene is sufficient to cause the disease. In approximately two-thirds of cases, TSC arises from a spontaneous new mutation with no family history.

Symptoms

The clinical presentation of tuberous sclerosis is highly variable. Common signs and symptoms include:

Neurological Symptoms

• Epilepsy: affects up to 90% of individuals with TSC, often beginning in infancy as infantile spasms
• Cortical tubers: abnormal, tuber-like formations in the cerebral cortex
• Subependymal giant cell astrocytomas (SEGAs): benign brain tumours that may obstruct cerebrospinal fluid flow
• Cognitive impairment and developmental delays
• Autism spectrum disorder

Skin Manifestations

• Hypomelanotic macules (ash-leaf spots): pale, leaf-shaped skin patches, often the first sign in newborns
• Facial angiofibromas: reddish nodules on the face, typically distributed in a butterfly pattern around the nose and cheeks
• Shagreen patches: rough, leathery skin lesions in the lumbar region
• Periungual fibromas: fibrous growths around the finger and toenails

Kidneys and Other Organs

• Renal angiomyolipomas: benign kidney tumours that can cause serious bleeding if they rupture
• Renal cysts
• Pulmonary lymphangioleiomyomatosis (LAM): cyst formation in the lungs, predominantly affecting women
• Cardiac rhabdomyomas: benign heart tumours, most common in newborns

Diagnosis

The diagnosis of tuberous sclerosis is based on clinical criteria divided into major and minor features (revised diagnostic criteria from 2012). Two major criteria, or one major and two minor criteria, are sufficient for a definite diagnosis. Diagnostic tools include:

• Molecular genetic testing: identification of a pathogenic mutation in TSC1 or TSC2
• Brain MRI: detection of cortical tubers, subependymal nodules, and SEGAs
• Renal ultrasound and MRI: identification of angiomyolipomas and cysts
• Echocardiography: detection of cardiac rhabdomyomas, especially in newborns
• CT of the lungs: assessment for LAM
• Ophthalmologic examination: detection of retinal hamartomas

Treatment

There is currently no cure for tuberous sclerosis. Treatment is tailored to the organs and symptoms affected:

Medical Therapy

• mTOR inhibitors (everolimus, sirolimus): target the overactivated mTOR pathway and can reduce tumour growth; approved for SEGAs, renal angiomyolipomas, and LAM
• Antiepileptic drugs: to control seizures; vigabatrin is considered the drug of choice for TSC-associated infantile spasms
• Cannabidiol (CBD): approved in the EU since 2019 as an adjunctive therapy for TSC-associated epilepsy

Surgical and Interventional Measures

• Surgical resection of symptomatic tumours (e.g., SEGAs)
• Embolisation or ablative therapy for growing angiomyolipomas
• Epilepsy surgery for drug-resistant seizures

Supportive Therapies

• Physiotherapy, occupational therapy, and speech therapy for developmental delays
• Psychological support and social care services
• Regular monitoring at specialised TSC centres

Prognosis and Outlook

The course of tuberous sclerosis varies greatly between individuals. Mildly affected people can lead near-normal lives, while those with severe manifestations may require intensive and lifelong medical care. Regular follow-up examinations are essential to detect and treat new or growing tumours at an early stage. With modern treatment options, particularly mTOR inhibitors, the prognosis for many patients has improved considerably in recent years.

References

1. Northrup H, Krueger DA; International Tuberous Sclerosis Complex Consensus Group. Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatric Neurology. 2013;49(4):243-254.
2. Franz DN et al. Everolimus for subependymal giant cell astrocytoma in patients with tuberous sclerosis complex: 2-year open-label extension of the randomised EXIST-1 study. The Lancet Oncology. 2014;15(13):1513-1520.
3. European Reference Network on Rare Neurological Diseases (ERN-RND). Clinical Practice Guidelines for Tuberous Sclerosis Complex. 2022. Available at: https://www.ern-rnd.eu