Tuberous Sclerosis Complex

Mendelian MONDO:0001734 Neurocutaneous Syndrome mTOR Pathway Disorder

Tuberous sclerosis complex (TSC) is an autosomal dominant multisystem disorder caused by loss-of-function mutations in TSC1 (hamartin) or TSC2 (tuberin), which form a complex that inhibits the mechanistic target of rapamycin (mTOR) signaling pathway. Constitutive mTOR activation leads to hamartoma formation in multiple organ systems including brain, skin, kidneys, heart, and lungs. Nearly 2 million people are affected worldwide. Major clinical features include cortical tubers, subependymal giant cell astrocytomas, cardiac rhabdomyomas, renal angiomyolipomas, facial angiofibromas, and pulmonary lymphangioleiomyomatosis. TSC-associated neuropsychiatric disorders (TAND) including epilepsy, intellectual disability, and autism spectrum disorder are among the most disabling manifestations.

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Definitions

Inheritance

Histopathology

Pathograph

Subtypes

Differentials

Datasets

Trials

Models

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Pathophysiology

TSC1/TSC2 Loss of Function and mTOR Hyperactivation

Loss-of-function mutations in TSC1 or TSC2 disrupt the TSC1-TSC2 protein complex, which normally acts as a GTPase-activating protein for Rheb, a direct activator of mTORC1. Loss of this complex leads to constitutive mTORC1 activation, resulting in increased cell growth, proliferation, autophagy dysregulation, and hamartoma formation in multiple organs.

neuron link

mTOR signaling pathway link cell growth link

brain link kidney link heart link

Show evidence (2 references)

PMID:27226234 SUPPORT Human Clinical

"TSC1 (also known as hamartin) and TSC2 (also known as tuberin) form the TSC protein complex that acts as an inhibitor of the mechanistic target of rapamycin (mTOR) signalling pathway, which in turn plays a pivotal part in regulating cell growth, proliferation, autophagy and protein and lipid synthesis."

The Nature Reviews Disease Primers article confirms that the TSC1/TSC2 complex inhibits mTOR signaling and its loss leads to dysregulated cell growth.

PMID:29478616 SUPPORT Human Clinical

"These proteins form a complex to constitutively inhibit the mammalian target of rapamycin (mTOR) signaling cascade, and as a consequence, mTOR signaling is constitutively active within all TSC-associated lesions."

Confirms that mTOR signaling is constitutively active in all TSC lesions due to loss of TSC1/TSC2 complex function.

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Phenotypes

Cardiovascular 1

Cardiac Rhabdomyoma FREQUENT Cardiac rhabdomyoma (HP:0009729)

Genitourinary 1

Renal Angiomyolipoma VERY_FREQUENT Renal angiomyolipoma (HP:0006772)

Show evidence (1 reference)

PMID:27226234 SUPPORT Human Clinical

"Major features of the disease include tumours of the brain, skin, heart, lungs and kidneys, seizures and TSC-associated neuropsychiatric disorders"

Kidney tumors including angiomyolipomas are listed as a major feature of TSC.

Integument 1

Shagreen Patch FREQUENT Shagreen patch (HP:0009721)

Nervous System 3

Epileptic Seizures VERY_FREQUENT Seizure (HP:0001250)

Show evidence (1 reference)

PMID:27226234 SUPPORT Human Clinical

"Major features of the disease include tumours of the brain, skin, heart, lungs and kidneys, seizures and TSC-associated neuropsychiatric disorders, which can include autism spectrum disorder and cognitive disability."

Seizures are listed as a major feature of TSC.

Intellectual Disability FREQUENT Intellectual disability (HP:0001249)

Show evidence (1 reference)

PMID:32222129 SUPPORT Human Clinical

"TSC associated neuropsychiatric disorders (TAND), including intellectual disability, mood disorders, and autism spectrum disorder, represent significant challenges but remain underdiagnosed and undertreated."

Confirms intellectual disability as a significant TAND feature in TSC.

Autism Spectrum Disorder FREQUENT Autism (HP:0000717)

Show evidence (1 reference)

PMID:27226234 SUPPORT Human Clinical

"TSC-associated neuropsychiatric disorders, which can include autism spectrum disorder and cognitive disability."

Autism spectrum disorder is identified as part of the TSC-associated neuropsychiatric disorder spectrum.

Neoplasm 4

Facial Angiofibromas VERY_FREQUENT Angiofibromas (HP:0010615)

Cortical Tubers VERY_FREQUENT Cortical tubers (HP:0009717)

Subependymal Nodules VERY_FREQUENT Subependymal nodules (HP:0009716)

Subependymal Giant Cell Astrocytoma OCCASIONAL Subependymal giant-cell astrocytoma (HP:0009718)

🧬

Genetic Associations

TSC1 (Pathogenic Mutations)

Show evidence (1 reference)

PMID:29478616 SUPPORT Human Clinical

"There are over 2000 known allelic variants for TSC, including nonsense and misssense mutation, and all pathogenic mutations are inactivating, leading to loss-of-function effects on the encoded proteins, TSC1 and TSC2."

Confirms TSC1 inactivating mutations as causative.

TSC2 (Pathogenic Mutations)

Show evidence (1 reference)

PMID:27226234 SUPPORT Human Clinical

"Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that affects multiple organ systems and is caused by loss-of-function mutations in one of two genes: TSC1 or TSC2."

Confirms TSC1 and TSC2 as the causative genes.

💊

Treatments

mTOR Inhibitor Therapy (Everolimus)

Action: pharmacotherapy MAXO:0000058

Everolimus is an mTOR inhibitor with FDA approval for TSC-associated subependymal giant cell astrocytomas, renal angiomyolipomas, and as adjunctive treatment for refractory seizures.

Show evidence (1 reference)

PMID:32222129 SUPPORT Human Clinical

"Subependymal giant cell astrocytomas, renal angiomyolipomas, and epilepsy are the three FDA-approved indications in relation to TSC for the use of everolimus, which is a first generation mTOR inhibitor."

Confirms FDA approval of everolimus for three TSC indications.

Vigabatrin for Infantile Spasms

Action: pharmacotherapy MAXO:0000058

Vigabatrin is the first-line treatment for TSC-associated infantile spasms, with high response rates specific to this population.

Epilepsy Surgery

Action: surgical procedure MAXO:0000004

Surgical resection may be considered for drug-resistant seizures when a single epileptogenic tuber can be identified.

Genetic Counseling

Action: genetic counseling MAXO:0000079

Genetic counseling is recommended for TSC families given the autosomal dominant inheritance pattern and variable expressivity.

{ }

Source YAML

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name: Tuberous Sclerosis Complex
creation_date: "2026-03-06T00:00:00Z"
updated_date: "2026-03-06T00:00:00Z"
description: >
  Tuberous sclerosis complex (TSC) is an autosomal dominant multisystem disorder
  caused by loss-of-function mutations in TSC1 (hamartin) or TSC2 (tuberin), which
  form a complex that inhibits the mechanistic target of rapamycin (mTOR) signaling
  pathway. Constitutive mTOR activation leads to hamartoma formation in multiple
  organ systems including brain, skin, kidneys, heart, and lungs. Nearly 2 million
  people are affected worldwide. Major clinical features include cortical tubers,
  subependymal giant cell astrocytomas, cardiac rhabdomyomas, renal angiomyolipomas,
  facial angiofibromas, and pulmonary lymphangioleiomyomatosis. TSC-associated
  neuropsychiatric disorders (TAND) including epilepsy, intellectual disability,
  and autism spectrum disorder are among the most disabling manifestations.
category: Mendelian
disease_term:
  preferred_term: Tuberous Sclerosis Complex
  term:
    id: MONDO:0001734
    label: tuberous sclerosis
parents:
- Neurocutaneous Syndrome
- mTOR Pathway Disorder
prevalence:
- population: Global
  percentage: "0.01"
  notes: Estimated prevalence of approximately 1 in 6,000-10,000 live births.
progression:
- phase: Onset
  age_range: Infancy to childhood
  notes: Cardiac rhabdomyomas may be detected prenatally; seizures often begin in infancy.
pathophysiology:
- name: TSC1/TSC2 Loss of Function and mTOR Hyperactivation
  description: >
    Loss-of-function mutations in TSC1 or TSC2 disrupt the TSC1-TSC2 protein complex,
    which normally acts as a GTPase-activating protein for Rheb, a direct activator
    of mTORC1. Loss of this complex leads to constitutive mTORC1 activation, resulting
    in increased cell growth, proliferation, autophagy dysregulation, and hamartoma
    formation in multiple organs.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: mTOR signaling pathway
    term:
      id: GO:0031929
      label: TOR signaling
  - preferred_term: cell growth
    term:
      id: GO:0016049
      label: cell growth
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  - preferred_term: kidney
    term:
      id: UBERON:0002113
      label: kidney
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  evidence:
  - reference: PMID:27226234
    reference_title: "Tuberous sclerosis complex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TSC1 (also known as hamartin) and TSC2 (also known as tuberin) form the
      TSC protein complex that acts as an inhibitor of the mechanistic target of
      rapamycin (mTOR) signalling pathway, which in turn plays a pivotal part in
      regulating cell growth, proliferation, autophagy and protein and lipid synthesis."
    explanation: The Nature Reviews Disease Primers article confirms that the TSC1/TSC2
      complex inhibits mTOR signaling and its loss leads to dysregulated cell growth.
  - reference: PMID:29478616
    reference_title: "Tuberous sclerosis complex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These proteins form a complex to constitutively inhibit the mammalian
      target of rapamycin (mTOR) signaling cascade, and as a consequence, mTOR
      signaling is constitutively active within all TSC-associated lesions."
    explanation: Confirms that mTOR signaling is constitutively active in all TSC lesions
      due to loss of TSC1/TSC2 complex function.
phenotypes:
- category: Neurologic
  name: Epileptic Seizures
  frequency: VERY_FREQUENT
  diagnostic: true
  description: >
    Seizures occur in approximately 80-90% of TSC patients, often beginning in
    infancy as infantile spasms. Epilepsy is the most common neurological
    manifestation and a major cause of morbidity.
  phenotype_term:
    preferred_term: Seizures
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:27226234
    reference_title: "Tuberous sclerosis complex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Major features of the disease include tumours of the brain, skin, heart,
      lungs and kidneys, seizures and TSC-associated neuropsychiatric disorders,
      which can include autism spectrum disorder and cognitive disability."
    explanation: Seizures are listed as a major feature of TSC.
- category: Neurologic
  name: Intellectual Disability
  frequency: FREQUENT
  description: >
    Cognitive impairment occurs in approximately 50% of TSC patients, ranging
    from mild learning difficulties to severe intellectual disability.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:32222129
    reference_title: "Tuberous sclerosis: a review of the past, present, and future."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TSC associated neuropsychiatric disorders (TAND), including intellectual
      disability, mood disorders, and autism spectrum disorder, represent
      significant challenges but remain underdiagnosed and undertreated."
    explanation: Confirms intellectual disability as a significant TAND feature in TSC.
- category: Behavioral
  name: Autism Spectrum Disorder
  frequency: FREQUENT
  description: >
    Autism spectrum disorder is present in approximately 40-50% of TSC patients
    and is associated with early-onset seizures and cortical tuber burden.
  phenotype_term:
    preferred_term: Autism
    term:
      id: HP:0000717
      label: Autism
  evidence:
  - reference: PMID:27226234
    reference_title: "Tuberous sclerosis complex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TSC-associated neuropsychiatric disorders, which can include autism
      spectrum disorder and cognitive disability."
    explanation: Autism spectrum disorder is identified as part of the TSC-associated
      neuropsychiatric disorder spectrum.
- category: Dermatologic
  name: Facial Angiofibromas
  frequency: VERY_FREQUENT
  description: >
    Facial angiofibromas are present in approximately 75% of TSC patients,
    typically appearing in early childhood as red papules on the malar regions.
  phenotype_term:
    preferred_term: Angiofibromas
    term:
      id: HP:0010615
      label: Angiofibromas
- category: Dermatologic
  name: Shagreen Patch
  frequency: FREQUENT
  description: >
    Shagreen patches are connective tissue nevi presenting as skin-colored or
    pigmented plaques, typically on the lower back.
  phenotype_term:
    preferred_term: Shagreen patch
    term:
      id: HP:0009721
      label: Shagreen patch
- category: Neurologic
  name: Cortical Tubers
  frequency: VERY_FREQUENT
  diagnostic: true
  description: >
    Cortical tubers are hamartomatous lesions at the gray-white matter interface
    containing abnormal glial and neural cells. They are a hallmark brain
    lesion in TSC.
  phenotype_term:
    preferred_term: Cortical tubers
    term:
      id: HP:0009717
      label: Cortical tubers
- category: Neurologic
  name: Subependymal Nodules
  frequency: VERY_FREQUENT
  description: >
    Subependymal nodules are small calcified masses along the lateral ventricle
    walls, present in approximately 80% of TSC patients.
  phenotype_term:
    preferred_term: Subependymal nodules
    term:
      id: HP:0009716
      label: Subependymal nodules
- category: Neurologic
  name: Subependymal Giant Cell Astrocytoma
  frequency: OCCASIONAL
  description: >
    SEGAs develop from subependymal nodules near the foramen of Monro and can
    cause obstructive hydrocephalus. They occur in approximately 5-20% of TSC patients.
  phenotype_term:
    preferred_term: Subependymal giant-cell astrocytoma
    term:
      id: HP:0009718
      label: Subependymal giant-cell astrocytoma
- category: Renal
  name: Renal Angiomyolipoma
  frequency: VERY_FREQUENT
  description: >
    Renal angiomyolipomas occur in approximately 80% of TSC patients and are
    benign tumors composed of fat, vascular, and smooth muscle elements. They
    are a major cause of morbidity due to risk of hemorrhage.
  phenotype_term:
    preferred_term: Renal angiomyolipoma
    term:
      id: HP:0006772
      label: Renal angiomyolipoma
  evidence:
  - reference: PMID:27226234
    reference_title: "Tuberous sclerosis complex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Major features of the disease include tumours of the brain, skin, heart,
      lungs and kidneys, seizures and TSC-associated neuropsychiatric disorders"
    explanation: Kidney tumors including angiomyolipomas are listed as a major feature
      of TSC.
- category: Cardiac
  name: Cardiac Rhabdomyoma
  frequency: FREQUENT
  description: >
    Cardiac rhabdomyomas are the earliest detectable lesion in TSC, often
    identified prenatally. They occur in approximately 50-65% of patients
    and typically regress spontaneously during childhood.
  phenotype_term:
    preferred_term: Cardiac rhabdomyoma
    term:
      id: HP:0009729
      label: Cardiac rhabdomyoma
genetic:
- name: TSC1
  association: Pathogenic Mutations
  presence: Positive
  notes: >
    TSC1 on chromosome 9q34 encodes hamartin. Loss-of-function mutations account
    for approximately 20-30% of TSC cases.
  evidence:
  - reference: PMID:29478616
    reference_title: "Tuberous sclerosis complex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There are over 2000 known allelic variants for TSC, including nonsense
      and misssense mutation, and all pathogenic mutations are inactivating, leading
      to loss-of-function effects on the encoded proteins, TSC1 and TSC2."
    explanation: Confirms TSC1 inactivating mutations as causative.
- name: TSC2
  association: Pathogenic Mutations
  presence: Positive
  notes: >
    TSC2 on chromosome 16p13.3 encodes tuberin. Loss-of-function mutations account
    for approximately 70-80% of TSC cases. TSC2 mutations are generally associated
    with more severe disease.
  evidence:
  - reference: PMID:27226234
    reference_title: "Tuberous sclerosis complex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that
      affects multiple organ systems and is caused by loss-of-function mutations in
      one of two genes: TSC1 or TSC2."
    explanation: Confirms TSC1 and TSC2 as the causative genes.
treatments:
- name: mTOR Inhibitor Therapy (Everolimus)
  description: >
    Everolimus is an mTOR inhibitor with FDA approval for TSC-associated subependymal
    giant cell astrocytomas, renal angiomyolipomas, and as adjunctive treatment
    for refractory seizures.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
  evidence:
  - reference: PMID:32222129
    reference_title: "Tuberous sclerosis: a review of the past, present, and future."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Subependymal giant cell astrocytomas, renal angiomyolipomas, and
      epilepsy are the three FDA-approved indications in relation to TSC for the
      use of everolimus, which is a first generation mTOR inhibitor."
    explanation: Confirms FDA approval of everolimus for three TSC indications.
- name: Vigabatrin for Infantile Spasms
  description: >
    Vigabatrin is the first-line treatment for TSC-associated infantile spasms,
    with high response rates specific to this population.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
- name: Epilepsy Surgery
  description: >
    Surgical resection may be considered for drug-resistant seizures when a
    single epileptogenic tuber can be identified.
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: MAXO:0000004
      label: surgical procedure
- name: Genetic Counseling
  description: >
    Genetic counseling is recommended for TSC families given the autosomal
    dominant inheritance pattern and variable expressivity.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: MAXO:0000079
      label: genetic counseling
datasets: