Definition:

Tuberous sclerosis is a hereditary condition characterized by the presence of hamartomas in multiple organs, but specifically the skin, brain, eye, kidney, and heart. Hamartomas are benign malformations characterized by excessive proliferation of cells and tissues that are typically found in the affected region, including naevi (birthmarks). Tuberous sclerosis is also referred to as epiloia.

Etiology:

Tuberous sclerosis is a hereditary condition caused by a mutation in either of two genes:

TSC1 gene is responsible for the production of hamartin protein in 10-30% of cases
TSC2 gene is responsible for the production of tuberin protein

Around one-third of all cases of tuberous sclerosis are passed down from a parent who has the condition. Most other cases arise from sporadic new mutations that occur during early development, with TSC2 mutations being the most common.

Clinical features:

Cutaneous lesions— Almost all individuals with TSC exhibit one or more of the skin lesions that are distinctive of the condition. The predominant cutaneous manifestations observed in TSC include hypomelanotic macules, angiofibromas, shagreen patches and fibrous plaques.

Hypomelanotic macules also referred to as ash-leaf spots: These are typically elliptical in shape and may need to be examined using a Wood’s lamp (ultraviolet light) in order to be seen.

It can manifest either at birth or during early infancy.

The presence of three or more white spots at birth indicates a diagnosis of tuberous sclerosis.

Fibrous cephalic plaques: These are unique brown fibrous plaques that can be easily identified on the forehead. They are often the first noticeable characteristic of TSC when examining affected newborns and infants.

Hypomelanotic macules and fibrous cephalic plaques generally manifest at an earlier stage compared to facial angiofibromas or ungual fibromas.

Angiofibromas: These are benign tumors that commonly occur in the malar regions of the face. They are also referred to as fibroadenomas.

Typically manifest between the ages of 3 and 10 and progressively grow in size and quantity until adolescence.

Additionally present on the nails, scalp, and forehead.

Shagreen patches: These are connective tissue nevi, which are typically observed on the lower back.

Ungual fibromas: also referred to as periungual or subungual fibromas (Koenen tumors).

Smooth, firm, flesh-colored lumps that appear from the nail folds.

Periungual sites, which are located around the nail, are more prevalent compared to subungual sites, which are found under the nail.

More frequently found on the feet rather than the hands.

Other organ involvement Tuberous sclerosis is associated with epilepsy in approximately 70% of cases. Typically, it starts during infancy or early childhood and can occur before the development of skin lesions by several years.
Developmental delay and behavioral problems may also arise. Manifestations include a range of cognitive impairments, including mild to severe intellectual disability, as well as conditions such as autism, attention deficit disorder (ADD), anxiety, depression, paranoia, and schizophrenia.
Other manifestations of tuberous sclerosis include ocular involvement with white spots on the iris and retina,and also tumors in the heart, gastrointestinal system, and kidneys, and other pulmonary manifestations.

Diagnosis:

Genetic criteria : Based on genetic criteria, the presence of a TSC1 or TSC2 pathogenic variant in nonlesional tissue is enough to confirm a diagnosis of TSC, regardless of any clinical findings.

Clinical criteria : The clinical criteria for TSC consist of 11 major features and 7 minor features.

To diagnose definite TSC, there must be either two major features or one major feature along with two or more minor features.

Major features – The following are major clinical features of TSC:

Hypomelanotic macules (≥3, at least 5 mm diameter)
Angiofibromas (≥3) or fibrous cephalic plaque
Ungual fibromas (≥2)
Shagreen patch
Multiple retinal hamartomas
Multiple cortical tubers and/or radial migration lines
Subependymal nodules (≥2)
Subependymal giant cell astrocytoma
Cardiac rhabdomyoma
Lymphangioleiomyomatosis (LAM)
Angiomyolipomas (≥2)

Minor features – The following are minor clinical features of TSC:

Confetti skin lesions (1 to 2 mm hypomelanotic macules)
Dental enamel pits (≥3)
Intraoral fibromas (≥2)
Retinal achromic patch
Multiple renal cysts
Nonrenal hamartomas
Sclerotic bone lesions

Management:

Tuberous sclerosis is a condition that affects multiple systems in the body, so in its management it typically requires a multidisciplinary approach.

Some patients may find skin lesions, especially facial angiofibromas, to be psychologically distressing. Angiofibromas can be effectively removed using laser treatment or electrosurgery.

The topical mTOR inhibitor sirolimus 0.2% gel, also known as rapamycin, showed potential in reducing angiofibromas.

Written by:

Mashael Alanazi, Medical Intern

Revised by:

Naif Alshehri, Medical Intern

Reference:

DermNet

UTD