Genetic neurocutaneous syndromes - tuberous sclerosis

Description

AD neurocutaneous disorder - benign hamartomas in brain, skin, kidney, heart, lung, eye
Triad taught historically (epilepsy + intellectual disability + adenoma sebaceum) is present in only ~30% - do not rely on it

Skin - usually the first clue

Hypomelanotic macules ("ash-leaf") >=3, >=5 mm - Wood's lamp to see them
Facial angiofibromas (adenoma sebaceum) - malar, butterfly distribution, appear age 3-5
Shagreen patch - lumbosacral connective tissue naevus
Ungual/periungual fibromas (Koenen tumours) - appear later, may be the only sign in an adult
"Confetti" lesions, forehead fibrous plaque, dental enamel pits, intraoral fibromas

Other organs

Brain - cortical tubers, subependymal nodules, SEGA (subependymal giant cell astrocytoma)
Kidney - angiomyolipoma (bilateral, multiple), renal cysts, rarely RCC
Lung - lymphangioleiomyomatosis (LAM) - almost exclusively women of reproductive age
Heart - rhabdomyoma (regresses spontaneously; often the antenatal presentation)
Eye - retinal hamartoma, achromic patch
Sclerotic bone lesions, hepatic AML

~1:6,000-10,000 births; M=F
~2/3 are de novo mutations - a negative family history is the rule, not the exception
Parental mosaicism explains recurrence in apparently unaffected families

AD; TSC1 (9q34, hamartin) or TSC2 (16p13, tuberin)
- TSC2 ~70-80% and more severe; TSC1 milder
- No mutation identified in ~10-15% - often mosaic (normal blood testing does not exclude TSC)
Hamartin-tuberin complex normally inhibits mTORC1
- Loss -> constitutive mTOR activation -> unchecked cell growth, proliferation, hamartoma formation
- *This is why mTOR inhibitors (sirolimus, everolimus) treat the disease rather than just the symptoms*
TSC2 is contiguous with PKD1 on 16p13 - large deletion -> TSC + severe early-onset polycystic kidney disease

Definite diagnosis

2 major, OR 1 major + >=2 minor
OR a pathogenic TSC1/TSC2 variant on genetic testing - sufficient alone, regardless of clinical findings

Major (11)	Minor
>=3 hypomelanotic macules (>=5 mm)	"Confetti" skin lesions
>=3 angiofibromas or fibrous cephalic plaque	>=3 dental enamel pits
>=2 ungual fibromas	>=2 intraoral fibromas
Shagreen patch	Retinal achromic patch
Multiple retinal hamartomas	Multiple renal cysts
Multiple cortical tubers and/or radial migration lines	Non-renal hamartomas
Subependymal nodules (>=2)	Sclerotic bone lesions
SEGA
Cardiac rhabdomyoma
LAM
Angiomyolipomas (>=2)

*LAM + angiomyolipoma together count as only ONE major feature*
2021 update: "multiple cortical tubers and/or radial migration lines" replaced "cortical dysplasias"; sclerotic bone lesions reinstated as minor

Baseline workup at diagnosis

Brain MRI with contrast; EEG (routine EEG in infancy to detect pre-symptomatic epileptiform activity)
Renal MRI
Echo + ECG
Dilated ophthalmoscopy
Dermatological and dental examination; Wood's lamp
HRCT chest in all women >=18 (LAM); baseline lung function
TAND checklist (TSC-associated neuropsychiatric disorders) - the most under-recognised burden
Genetic testing + genetic counselling for the whole family

A. mTOR inhibitors - disease-directed therapy

Everolimus
- SEGA - growing or symptomatic (alternative to resection)
- Renal angiomyolipoma >=3 cm - shrinks the lesion, prevents haemorrhage
- Refractory TSC-associated epilepsy - adjunctive (EXIST-3)
Sirolimus for LAM (inc/stabilises FEV1) and topically for facial angiofibromas
Adverse effects: stomatitis, hyperlipidaemia, cytopenias, infection, non-infectious pneumonitis, impaired wound healing

B. Epilepsy - the main cause of morbidity

Vigabatrin is first line for infantile spasms in TSC (monitor visual fields - irreversible constriction)
Cannabidiol (pharmaceutical formulation) and everolimus both have RCT evidence as adjuncts
- No comparative data favour one over another
Refractory after 3 agents -> epilepsy surgery assessment (tuber resection, callosotomy, VNS), ketogenic diet

C. Renal

Angiomyolipoma is the leading cause of death in adults (retroperitoneal haemorrhage)
>=3 cm (or aneurysm >5 mm) -> everolimus, or selective embolisation
*Avoid nephrectomy* - preserve nephrons; disease is bilateral and lifelong
BP control; monitor renal function

D. LAM

E. TAND

Screen at least annually - autism spectrum, ADHD, intellectual disability, anxiety, aggression
Behavioural and educational intervention; this drives quality of life more than seizure count

F. Surveillance intervals

Brain MRI every 1-3 yr until age 25 (SEGA risk falls after); symptom-driven thereafter
Renal MRI every 1-3 yr lifelong
Annual skin, dental, neurodevelopmental review; ophthalmology if on vigabatrin
Women: lung function +/- HRCT every 5-10 yr if baseline normal

Epilepsy (~80-90%), infantile spasms
Intellectual disability, autism spectrum disorder, ADHD (TAND)
Renal angiomyolipoma, renal cysts, polycystic kidney disease (TSC2/PKD1 contiguous deletion), rare RCC
Lymphangioleiomyomatosis, multifocal micronodular pneumocyte hyperplasia, chylothorax
Cardiac rhabdomyoma, arrhythmia (WPW)
Retinal hamartoma
Hepatic and pancreatic angiomyolipoma/neuroendocrine tumours

Highly variable - from incidental skin findings in adulthood to infantile spasms with profound disability
Cardiac rhabdomyomas regress spontaneously; skin and renal lesions accumulate with age
SEGA grows in adolescence -> obstructive hydrocephalus; new headache, vomiting, behaviour change or seizure deterioration in a TSC teenager = image urgently
Leading causes of death: renal disease (AML haemorrhage, renal failure) in adults; neurological (status epilepticus, SUDEP) in children; LAM in women
Early seizure control is associated with better cognitive outcome - the rationale for EEG surveillance before seizures start

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