Tuberous Sclerosis Complex

Slide 1 · Tuberous Sclerosis Complex

Multisystem hamartoma syndrome • mTOR dysregulation

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Map the lesions of TSC to organ systems and symptoms.

Explain TSC1/TSC2–hamartin/tuberin control of mTOR.

Recognize cortical tubers, subependymal nodules and SEGA.

Apply contemporary diagnostic and surveillance principles.

Molecular defect

Brain + organ lesions

Diagnostic reasoning

Slide 3 · TSC is a multisystem hamartoma syndrome

Autosomal dominant disorder with variable clinical expression.

Characteristic hamartomas and benign neoplasms affect brain and extracranial tissues.

Seizures and neurodevelopmental difficulties frequently dominate recognition.

CNS

Tuber • SEN • SEGA

Skin

Macules • fibromas

Kidney

AML • cysts

Other

Heart • retina • lung

Slide 4 · TSC belongs to familial tumor syndromes

Inherited syndromes can predispose to specific tissue growths.

TSC is defined by distinctive CNS lesions and multisystem findings.

The underlying defect affects growth regulation rather than a single organ.

Familial tumor syndrome

Hamartomas + neoplasms

CNS and multiple organ sites

Slide 5 · Frequency and population context

A birth frequency of approximately 1 in 6,000.

Both familial inheritance and apparently isolated presentations occur.

Absence of an affected parent does not exclude TSC.

Affected parent

TSC1 or TSC2 variant

Child with variant

50% risk

Child without variant

50% risk

Slide 6 · Inheritance: Autosomal dominant

A heterozygous pathogenic variant can establish disease.

Each child of an affected individual has a 50% transmission risk.

GeneReviews reports approximately two thirds of cases result from de novo variants.

Affected parent

TSC1 or TSC2 variant

Child with variant

50% risk

Child without variant

50% risk

Slide 7 · Phenotypic variability

Clinical expression differs markedly between affected individuals.

Different organ systems may come to attention at different ages.

Normal findings in one organ do not exclude manifestations elsewhere.

Seizures and cognition

Renal / skin / cardiac signs

Variable timing and severity

Slide 8 · Hamartoma and benign neoplasm: Distinct concepts

A hamartoma is a disorganized growth of tissue components native to its site.

Cortical tubers and subependymal nodules are hamartomatous CNS lesions.

SEGA is designated a benign neoplasm, often associated with subependymal nodules.

Hamartoma

Benign neoplasm

Disorganized native tissue

Proliferative tissue mass

Both may be clinically significant

Slide 9 · TSC1: The hamartin-encoding gene

TSC1 maps to chromosome 9q34.

Its protein product is hamartin.

Hamartin acts together with tuberin in a growth-regulatory complex.

TSC1 9q34

→ hamartin

TSC2 16p13.3

→ tuberin

Hamartin–tuberin complex

MTOR control

Slide 10 · TSC2: The tuberin-encoding gene

TSC2 maps to chromosome 16p13.3.

Its protein product is tuberin.

TSC2 as more commonly mutated than TSC1.

TSC1 9q34

→ hamartin

TSC2 16p13.3

→ tuberin

Hamartin–tuberin complex

MTOR control

Slide 11 · Hamartin and tuberin function together

The two proteins operate as a functional inhibitory complex.

An intact complex restrains mTOR kinase signaling.

Pathogenic disruption releases this restraint on cell growth pathways.

TSC1 / TSC2 products

Hamartin–tuberin restraint

Controlled mTOR activity

Protein synthesis • cell size

Slide 12 · MTOR regulates anabolic metabolism

MTOR is a kinase central to protein synthesis and cellular anabolism.

Physiologic activity is controlled by upstream growth-regulatory signals.

TSC1/TSC2 normally act as a brake on this pathway.

TSC1 / TSC2 products

Physiologic restraint

Controlled mTOR activity

Protein synthesis • cell size

Slide 13 · Loss of TSC restraint increases mTOR activity

Pathogenic TSC1 or TSC2 alteration disrupts hamartin–tuberin control.

MTOR signaling becomes excessive or inadequately regulated.

Anabolic signaling contributes to abnormal cell size and tissue growth.

TSC1 / TSC2 products

Hamartin–tuberin restraint

Excess mTOR activity

Protein synthesis • cell size

Slide 14 · Why TSC cells can be unusually large

MTOR participates in the control of cellular size.

Large cells with abundant cytoplasm are characteristic in some TSC lesions.

The voluminous cytoplasm of SEGA cells illustrates the molecular–morphologic link.

Large nucleus + voluminous cytoplasm

Slide 15 · From variant to tissue phenotype

Genetic alteration affects growth regulation in affected tissues.

Disturbed cell size, organization and expansion help explain hamartomas.

The brain expresses this disturbance as disorganized cortical and periventricular lesions.

TSC1 / TSC2 defect

MTOR dysregulation

Cell growth + disorganization

Tissue hamartoma / neoplasm

Slide 16 · Organ-system expression is heterogeneous

CNS: Cortical tubers, subependymal nodules, SEGA.

Other major sites: Skin, kidney, heart, retina and lung.

A lesion in one system should trigger consideration of the full phenotype.

CNS

Tuber • SEN • SEGA

Skin

Macules • fibromas

Kidney

AML • cysts

Other

Heart • retina • lung

Slide 17 · Three major CNS lesion classes

Cortical tubers: Cortical hamartomas and frequent epileptogenic substrate.

Subependymal nodules: Ventricular lining-associated hamartomas.

SEGA: A benign neoplasm associated with ventricular outflow obstruction.

Cortex

Cortical tuber → Epilepsy

Ventricular wall

Subependymal nodule → Bulging nodules

Ventricular growth

SEGA → CSF obstruction

Slide 18 · Normal cortical architecture is laminated

The cerebral cortex has an organized, layered neuronal arrangement.

Laminar organization provides the reference for recognizing tuber dysplasia.

TSC tubers lose the usual orderly pattern of cortical neurons.

Normal layered cortex

Slide 19 · Cortical tuber: Disorganized cortex

Neurons within tubers are haphazardly distributed.

The usual cortical laminar organization is lost.

Dysplastic cells may display mixed neuronal and astroglial morphology.

Cortical tuber (schematic)

Disordered neurons / enlarged dysplastic cells

Slide 20 · Gross pathology of a cortical tuber

Tubers appear relatively firm compared with adjacent softer cortex.

The name “tuber” reflects a potato-like firmness and appearance.

The lesion represents a localized abnormality of cortical tissue organization.

Cortex in cross-section (schematic)

Firm tuber interrupts cortex

Slide 21 · Neuronal elements within tubers

Disordered neuronal arrangement is a defining microscopic feature.

Abnormally enlarged neurons can occur among mixed dysplastic cell populations.

The diagnostic context is cortical architectural disorganization, not a single isolated cell.

Cortical tuber (schematic)

Disordered neurons / enlarged dysplastic cells

Slide 22 · Dysplastic cells cross morphologic categories

Some cells look intermediate between neurons and astrocytes.

Large vesicular nuclei with nucleoli resemble neuronal nuclei.

Abundant eosinophilic cytoplasm resembles gemistocytic astrocytes.

Large nucleus + voluminous cytoplasm

Slide 23 · Mixed neuronal–glial immunophenotype

Dysplastic tuber cells may express neurofilament proteins.

Expression of GFAP can coexist in the same abnormal population.

Dual lineage-associated staining supports mixed differentiation; Interpret with morphology.

GFAP + neurofilament expression

Slide 24 · Molecular mechanism and cell morphology align

Increased mTOR activity contributes to cell enlargement.

Ballooned, cytoplasm-rich cells are a conspicuous pathologic correlate.

Architecture and cellular composition together identify cortical hamartomas.

TSC1 / TSC2 defect

MTOR dysregulation

Cell growth + disorganization

Tissue hamartoma / neoplasm

Slide 25 · Cortical tubers can generate seizures

Cortical tubers are often epileptogenic.

Abnormal local cortical organization plausibly disrupts network function.

Seizures may persist despite antiseizure medication.

Cortical disorganization

Abnormal network activity

Seizures

Antiseizure treatment ± focal surgery

Slide 26 · When surgery enters epilepsy care

Medical treatment is the initial approach for many patients.

Focal resection can be beneficial in appropriately selected drug-resistant cases.

Referral to an experienced epilepsy surgery program is recommended.

Drug-resistant focal seizures

Epilepsy surgery evaluation

Selected focal resection

Slide 27 · Subependymal nodules: Anatomic location

Lesions cluster beneath the ventricular ependymal surface.

They can project into the ventricular lumen.

Their location contrasts with cortical parenchymal tubers.

Simplified ventricular outflow

Subependymal nodule

Ventricular wall bulge

Slide 28 · “Candle gutterings”: Gross description

Small wax-like protrusions can bulge into the ventricular system.

The appearance historically prompted the phrase “candle gutterings.”

This describes subependymal nodules, not the cortical tubers.

Simplified ventricular outflow

Subependymal nodule

Ventricular wall bulge

Slide 29 · Subependymal nodule histology

Hamartomatous tissue contains large astrocyte-like cells.

These cells are concentrated immediately beneath the ventricular lining.

Histologic similarities exist between nodules and SEGA.

Large nucleus + voluminous cytoplasm

Slide 30 · SEGA is a related but larger neoplasm

Subependymal giant cell astrocytoma is classified as benign.

An apparent relationship to hamartomatous nodules.

Larger size and growth create clinically important mass effects.

Cortex

Cortical tuber → Epilepsy

Ventricular wall

Subependymal nodule → Bulging nodules

Ventricular growth

SEGA → CSF obstruction

Slide 31 · Subependymal nodules versus SEGA

Feature

Subependymal nodule

SEGA

Nature

Hamartoma

Benign neoplasm

Site

Beneath ependyma

Ventricle-associated

Size / effect

Small protruding nodule

Larger mass; may obstruct CSF

Morphology

Large astrocyte-like cells

Related giant-cell morphology

Slide 32 · SEGA histology mirrors the growth defect

Prominent giant or astrocyte-like cells with abundant cytoplasm.

Histologic overlap with subependymal nodules is expected.

Tumor location and clinical behavior are essential to interpretation.

Large nucleus + voluminous cytoplasm

Slide 33 · How SEGA produces hydrocephalus

A growing ventricular-region lesion narrows the CSF passage.

Blocked CSF outflow produces upstream ventricular enlargement.

Symptomatic obstruction requires prompt assessment and management.

Simplified ventricular outflow

Growing SEGA

Obstruction → upstream CSF accumulation

Slide 34 · Clinical consequences of ventricular obstruction

Headache, vomiting and declining neurologic function warrant urgent evaluation.

Obstructive hydrocephalus reflects mass effect, not malignant transformation.

Brain imaging determines the presence and extent of ventricular obstruction.

Simplified ventricular outflow

Growing SEGA

Obstruction → upstream CSF accumulation

Slide 35 · CNS lesions: A practical localization map

Cortical parenchyma → tubers and epilepsy.

Ventricular wall → subependymal nodules.

Ventricular growth/CSF pathway → SEGA and hydrocephalus.

Cortex

Cortical tuber → Epilepsy

Ventricular wall

Subependymal nodule → Bulging nodules

Ventricular growth

SEGA → CSF obstruction

Slide 36 · Seizures are a major clinical presentation

Seizures are among the most frequent manifestations listed by Robbins.

Infantile spasms and focal seizures warrant active recognition in infants with TSC.

Clinical seizure evaluation should be paired with appropriate EEG assessment.

Cortical disorganization

Abnormal network activity

Seizures

Antiseizure treatment ± focal surgery

Slide 37 · TSC-associated neuropsychiatric problems

Autism and intellectual disability.

The modern TAND framework also covers behavioral, psychiatric, learning and psychosocial domains.

Symptoms require individual assessment; No single structural lesion predicts the entire profile.

Seizures and cognition

Renal / skin / cardiac signs

Variable timing and severity

Slide 38 · Renal angiomyolipomas

Renal angiomyolipomas are major extracranial benign neoplasms in TSC.

They can enlarge and become clinically significant through bleeding.

Longitudinal kidney imaging and renal function assessment are important.

KIDNEY

Angiomyolipoma / renal cysts

Bleeding / function

Slide 39 · Cystic manifestations

Cysts may involve kidneys, liver and pancreas.

Renal cystic disease is monitored alongside angiomyolipomas.

The presence of cysts broadens the phenotype beyond solid hamartomatous lesions.

CNS

Tuber • SEN • SEGA

Skin

Macules • fibromas

Kidney

AML • cysts

Other

Heart • retina • lung

Slide 40 · Retinal hamartomas

Retinal glial or astrocytic hamartomas are a characteristic manifestation.

Ophthalmologic examination contributes to clinical phenotyping.

Retinal disease can be asymptomatic or affect vision depending on location.

RETINA

Retinal glial hamartoma

Ophthalmic assessment

Slide 41 · Cardiac rhabdomyomas

Cardiac rhabdomyomas arise during childhood, sometimes recognized prenatally.

They can be associated with rhythm or outflow problems when clinically significant.

Echocardiographic surveillance is used until regression is documented.

HEART

Rhabdomyoma

Cardiac evaluation

Slide 42 · Pulmonary lymphangioleiomyomatosis

LAM is a pulmonary manifestation of TSC.

The disease is relevant particularly to adult women.

Symptoms or CT evidence of cystic lung disease drive pulmonary evaluation.

LUNG

Lymphangioleiomyomatosis

Cystic lung disease

Slide 43 · Cutaneous clues are highly informative

Hypopigmented macules, angiofibromas, shagreen plaques and ungual fibromas.

Cutaneous inspection is an accessible part of multisystem assessment.

Several characteristic lesion types are included in formal diagnostic criteria.

Macule

Angiofibroma

Shagreen

Ungual fibroma

Slide 44 · Hypomelanotic “ash-leaf” macules

These are localized hypopigmented skin lesions.

Under the 2021 criteria, at least three macules ≥5 mm constitute a major feature.

A single hypopigmented macule is not by itself diagnostic.

Hypopigmented area

Schematic

Slide 45 · Facial angiofibromas

Characteristic angiofibromas may develop on facial skin.

The 2021 major criterion is at least three angiofibromas or a fibrous cephalic plaque.

Their presence supports syndromic recognition, not a molecular diagnosis by itself.

Multiple small facial papules

Schematic

Slide 46 · Shagreen patches

Localized leathery skin thickening.

A shagreen patch is a major diagnostic feature in the 2021 consensus.

This finding complements pigmentary and facial lesions.

Leathery textured plaque

Schematic

Slide 47 · Ungual fibromas

Fibromas may develop around or beneath nails.

At least two ungual fibromas constitute a 2021 major criterion.

Distribution and number matter when applying diagnostic rules.

Periungual fibrous nodule

Schematic

Slide 48 · Systems and their index lesions

System

Representative finding

Main concern

Brain

Tubers; SEN; SEGA

Seizures; CSF obstruction

Kidney

Angiomyolipoma; cysts

Bleeding; renal health

Heart

Rhabdomyoma

Cardiac effects

Lung

LAM

Cystic lung disease

Skin / eye

Distinctive lesions

Recognition / vision

Slide 49 · Two complementary diagnostic routes

Clinical diagnosis is based on combinations of major and minor features.

Molecular diagnosis follows identification of a pathogenic TSC1 or TSC2 variant.

The diagnostic rules shown here use the 2021 international consensus.

Clinical feature assessment

Apply 2021 criteria

Clinical / molecular diagnosis

Slide 50 · Major criteria: Skin and oral-region findings

≥3 hypomelanotic macules, each ≥5 mm.

≥3 angiofibromas or a fibrous cephalic plaque.

≥2 ungual fibromas; Shagreen patch.

Count the features correctly

Major versus minor distinction

Apply clinical diagnostic rule

Slide 51 · Major criteria: CNS findings

Multiple cortical tubers and/or radial migration lines.

At least two subependymal nodules.

Subependymal giant cell astrocytoma.

Count the features correctly

Major versus minor distinction

Apply clinical diagnostic rule

Slide 52 · Major criteria: Other organ findings

Multiple retinal hamartomas or cardiac rhabdomyoma.

Pulmonary lymphangioleiomyomatosis.

At least two renal angiomyolipomas.

Count the features correctly

Major versus minor distinction

Apply clinical diagnostic rule

Slide 53 · Minor diagnostic criteria

Confetti skin lesions or a retinal achromic patch.

Dental enamel pits (≥3) or intraoral fibromas (≥2).

Multiple renal cysts, nonrenal hamartomas or sclerotic bone lesions.

Count the features correctly

Major versus minor distinction

Apply clinical diagnostic rule

Slide 54 · Definite versus possible clinical TSC

Definite: Two major features, or one major plus two minor features.

Possible: One major feature, or at least two minor features.

Apply the specific exception for LAM plus angiomyolipomas.

Clinical feature assessment

Apply 2021 criteria

Clinical / molecular diagnosis

Slide 55 · Important LAM + angiomyolipoma exception

LAM and renal angiomyolipomas can occur together without other TSC findings.

Those two major features alone do not establish definite clinical TSC.

Additional features or molecular evidence are needed for definitive classification.

LAM

Renal AML

+

Not sufficient alone for definite clinical TSC

Seek additional diagnostic features

Slide 56 · Interpreting TSC1/TSC2 genetic testing

Pathogenic or likely pathogenic variants can establish molecular TSC.

A variant of uncertain significance does not confirm or exclude TSC.

If suspicion persists after negative routine testing, consider mosaicism in specialist evaluation.

TSC1 9q34

→ hamartin

TSC2 16p13.3

→ tuberin

Hamartin–tuberin complex

MTOR control

Slide 57 · Clinical workup: Assemble organ evidence

Complete skin, dental and retinal examinations.

Brain MRI for cortical and subependymal manifestations.

Renal, cardiac and pulmonary assessment tailored to age and clinical context.

CNS

Tuber • SEN • SEGA

Skin

Macules • fibromas

Kidney

AML • cysts

Other

Heart • retina • lung

Slide 58 · Neurologic surveillance follows SEGA risk

Consensus recommends brain MRI every 1–3 years in asymptomatic patients younger than 25 years.

Growing or symptomatic SEGA warrants more frequent evaluation.

Surveillance seeks ventricular obstruction before acute deterioration.

Simplified ventricular outflow

Growing SEGA

Obstruction → upstream CSF accumulation

Slide 59 · Epilepsy assessment begins early

Teach families to recognize infantile spasms and focal seizures.

Infant EEG surveillance and prompt evaluation are emphasized by consensus.

Vigabatrin is first-line therapy for TSC-associated infantile spasms.

Cortical disorganization

Abnormal network activity

Seizures

Antiseizure treatment ± focal surgery

Slide 60 · Renal surveillance is lifelong

Abdominal MRI is recommended every 1–3 years for angiomyolipoma and cystic disease.

Assess blood pressure and renal function at least annually.

Acute angiomyolipoma hemorrhage requires an urgent kidney-sparing management strategy.

KIDNEY

Angiomyolipoma / renal cysts

Bleeding / function

Slide 61 · Other organ surveillance is targeted

Cardiac rhabdomyomas: Childhood echocardiography until regression.

Retinal lesions: Periodic specialist ophthalmic evaluation.

LAM: Adult respiratory assessment and lung imaging according to sex, symptoms and findings.

CNS

Tuber • SEN • SEGA

Skin

Macules • fibromas

Kidney

AML • cysts

Other

Heart • retina • lung

Slide 62 · Management integrates symptoms and mechanism

Antiseizure therapy addresses an important functional consequence.

Surgery may treat drug-resistant seizures or obstructive SEGA.

MTOR inhibitors target a growth-signaling mechanism shared across TSC lesions.

TSC1 / TSC2 products

Hamartin–tuberin restraint

Excess mTOR activity

Protein synthesis • cell size

Slide 63 · Why mTOR inhibitors are mechanistically rational

The underlying TSC1/TSC2 defect removes restraint on mTOR signaling.

Pharmacologic mTOR inhibition can reduce excessive anabolic drive.

Therapeutic responses are lesion- and context-dependent, not a reversal of genotype.

TSC1/TSC2 dysfunction

Excess mTOR activity

MTOR inhibitor ↓ pathway output

Targeted pathway modulation

Slide 64 · SEGA treatment depends on clinical behavior

Acutely symptomatic obstruction calls for urgent neurosurgical evaluation.

For growing, otherwise asymptomatic SEGA, surgery or mTOR inhibition may be considered.

Treatment planning balances lesion size, location, risks and follow-up feasibility.

SEGA: Assess growth and symptoms

Acutely symptomatic obstruction

Urgent surgical assessment

Growing asymptomatic SEGA: Surgery or mTOR inhibitor

Slide 65 · Renal lesion treatment: Protect kidney function

Growing asymptomatic angiomyolipomas may be treated with mTOR inhibition.

Acute hemorrhage is generally managed with selective embolization.

Avoid routine nephrectomy when kidney-sparing approaches are feasible.

KIDNEY

Angiomyolipoma / renal cysts

Bleeding / function

Slide 66 · Case 1: Multiple clinical features

An infant has multiple hypomelanotic macules and a cardiac rhabdomyoma.

Two major clinical feature categories are present if macule count/size meet criteria.

What tests identify the associated CNS and renal phenotype?

Observe phenotype

Test criteria and localization

Decide next evaluation

Slide 67 · Case 1: Diagnostic reasoning

Confirm ≥3 hypomelanotic macules, each ≥5 mm.

Cardiac rhabdomyoma provides a separate major criterion.

Brain MRI, renal imaging and specialist assessment complete initial phenotyping.

Observe phenotype

Test criteria and localization

Decide next evaluation

Slide 68 · Case 2: Ventricular obstruction

A patient with known TSC develops headache and vomiting.

Brain MRI shows a growing lesion adjacent to a ventricular CSF channel.

Recognize possible SEGA-associated obstructive hydrocephalus.

Simplified ventricular outflow

Growing SEGA

Obstruction → upstream CSF accumulation

Slide 69 · Case 2: Urgency and distinction

Hydrocephalus is a mechanical complication of lesion location and growth.

Benign histologic classification does not make the mass effect benign.

Expedited neurosurgical assessment is required for symptomatic obstruction.

Potential urgent implication

Do not equate benign with harmless

Integrate anatomy and clinical signs

Slide 70 · Case 3: Cortical epilepsy pathology

An epilepsy resection contains disorganized neurons and giant dysplastic cells.

Mixed neurofilament and GFAP expression is detected in characteristic cells.

The combined architecture and immunophenotype support a cortical tuber.

GFAP + neurofilament expression

Slide 71 · Differential: Familial CNS tumor syndromes

Feature

TSC

NF1

VHL

Key CNS lesion

Tubers / SEGA

Optic glioma

Hemangioblastoma

Skin clue

Macules; angiofibroma

Café-au-lait macules

Not defining here

Other lesion

Renal AML

Neurofibromas

Renal cell carcinoma

Slide 72 · Morphology synthesis: Cortical versus ventricular

Cortical tuber: Firm disorganized lamination and mixed dysplastic cells.

Subependymal nodule: Small ventricular-surface hamartoma.

SEGA: Larger related benign neoplasm with risk of obstruction.

Cortex

Cortical tuber → Epilepsy

Ventricular wall

Subependymal nodule → Bulging nodules

Ventricular growth

SEGA → CSF obstruction

Slide 73 · Clinicopathologic synthesis

TSC1/TSC2 disruption links defective growth regulation to abnormal tissues.

Tuber-associated epilepsy and SEGA-associated hydrocephalus reflect lesion localization.

Multisystem surveillance follows from the distribution of pathology.

TSC1 / TSC2 defect

MTOR dysregulation

Cell growth + disorganization

Tissue hamartoma / neoplasm

Slide 74 · References

Robbins, Cotran & Kumar. Pathologic Basis of Disease. 11th ed. (2026), Ch. 28, p. 1185.

Northrup H, et al. Updated International TSC Diagnostic Criteria and Surveillance and Management Recommendations. Pediatr Neurol. 2021;123:50–66.

Northrup H, et al. Tuberous Sclerosis Complex. GeneReviews. Updated 2024.