Tuberous Sclerosis Abdullah M. Al-Olayan MBBS, SBP, ABP Tuberous Sclerosis Abdullah M. Al-Olayan MBBS, SBP, ABP. Assistant Professor of Pediatrics. Pediatric Pulmonologist.

Objectives : 1-Introduction. 2-Pathology and Pathogenesis. 3-Clinical Manifestations. 4-Diagnosis. 5-Management.

Introduction : Tuberous Sclerosis : Is a disorder of autosomal-dominant inheritance that affects multiple organ systems.

Introduction : It is one of the most common single-gene disorders seen in children and adults, with an estimated incidence of 1 in 5800 live births. Spontaneous genetic mutations occur in 2\3 of the cases.

Introduction : The TSC1 and TSC2 genes are tumor suppressor genes. TSC1 gene is located on chromosome 9q34 and encodes a protein called Hamartin. TSC2 gene is on chromosome 16p13 and encodes the protein Tuberin.

Introduction : The loss of either Hamartin or Tuberin results in the formation of numerous benign tumors (Hamartomas). The disease affects many organ systems including the skin , brain, heart, kidney, eyes, lungs, and bone.

Pathology and Pathogenesis : Tuberous sclerosis complex is a multisystem disorder of cellular migration, proliferation, and differentiation, resulting in the development of Hamartomas.

Pathology and Pathogenesis : The major pathologic features in the brain include Cortical tubers, Subependymal nodules, and Subependymal giant cell tumors.

Pathology and Pathogenesis : Tuberin and Hamartin interact with one another and function as tumor suppressor molecules. Loss of heterozygosity has been identified in hamartomas from persons with TSC1 and TSC2 mutations.

Pathology and Pathogenesis : Hamartin and Tuberin are components of the mammalian target of rapamycin (mTOR) pathway, which is involved in many functions, including regulation of cell size.

Pathology and Pathogenesis : In normal cells, the Tuberin/Hamartin complex acts as an inhibitor of mTOR activity.

Clinical Manifestations : The hallmark of TSC is the involvement of the CNS. The clinical presentation of tuberous sclerosis complex depends on : 1-Age of the patient. 2-Organs involved. 3-Severity of involvement.

Clinical Manifestations : Epilepsy is the most common presenting symptom in tuberous sclerosis. A majority of children with tuberous sclerosis have the onset of seizures during the first year of life, and approximately one-third develop infantile spasms.

Clinical Manifestations : Autistic spectrum and ADHD affect up to 50% of patients with tuberous sclerosis. Cutaneous manifestations are found in up to 96% of patients with tuberous sclerosis.

Clinical Manifestations : Angiofibroma, the skin manifestation initially described in the disorder as adenoma sebaceum, typically appears between the ages of 1 and 4 years and can progress through childhood and adolescence.

Clinical Manifestations : Hypopigmented, oval, or Ash leaf-spots ranging from a few millimeters to several centimeters in length and scattered over the trunk and limbs, are commonly seen. Using a Wood's light, an ultraviolet light that accentuates the hypopigmented spots.

Clinical Manifestations : Shagreen patch, a connective tissue hamartoma that is distributed asymmetrically on the dorsal body surfaces, particularly on the lumbosacral skin.

Clinical Manifestations : Subungual or Periungual fibromas are present in at least 20% of patients and usually first appear during adolescence.

Clinical Manifestations : The Kidneys are frequently affected in persons with tuberous sclerosis complex. After neurologic manifestations, renal involvement is the most common cause of morbidity and mortality. The two main types of renal lesions are Angiomyolipoma and Renal Cysts.

Clinical Manifestations : Polycystic Kidney Disease occurs in 3–5% of patients with tuberous sclerosis complex and, when present, usually reflects a contiguous gene syndrome, because the polycystic kidney disease gene is adjacent to the TSC2-tuberin gene on chromosome 16.

Clinical Manifestations : The Cardiac manifestation, Rhabdomyoma, is seen in 50–60% of persons with tuberous sclerosis. It is maximal at birth and early childhood, and undergo spontaneous regression during the first few years of life. If symptomatic, they result in outflow tract obstruction, valve dysfunction, or arrhythmias.

Clinical Manifestations : Pulmonary involvement in tuberous sclerosis complex includes : Lymphangioleiomyomatosis, Multifocal micronodular pneumocyte hyperplasia. Pulmonary cysts.

Clinical Manifestations : Retinal Hamartomas are relatively common, affecting at least 50% of patients.

Management : Management focuses on treatment of epilepsy and behavioral disorders and on identification of learning disabilities. Vigabatrin is particularly effective in treating infantile spasms in patients with tuberous sclerosis complex.

Management : Epilepsy surgery has a very important role in the management of patients who have failure medical treatment.

Management : Rapamycin : mTOR antagonist. Reduce the size of subependymal giant cell tumors and renal angiomyolipoma.

Follow up :

Summary : Tuberous sclerosis is a disorder of autosomal-dominant-inheritance that affects multiple organ systems. TSC1 gene is located on chromosome 9q34 and encodes a protein called Hamartin. TSC2 gene is on chromosome 16p13 and encodes the protein Tuberin.

Summary : The loss of either Hamartin or Tuberin results in the formation of numerous benign tumors (hamartomas). Epilepsy is the most common presenting symptom in tuberous sclerosis and one- third develop infantile spasms.

Summary : Clinical manifestations are involving many organs especially the brain, eyes, skin, kidneys, and heart. Neuroimaging studies, particularly MRI is important in confirming the diagnosis. Vigabatrin is the drug of choice for the patient with infantile spasm.

Summary : Rapamycin has been shown to reduce the size of subependymal giant cell tumors and renal angiomyolipoma.

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