Tuberous sclerosis complex

Hema R Murali MD MBBS (Dr. Murali of Marshfield Clinic has no relevant financial relationships to disclose.)
Narayana S Murali MD (

Dr. Murali of the Marshfield Clinic has no relevant financial relationships to disclose.

)
Bernard L Maria MD, editor. (Dr. Maria of Thomas Jefferson University has no relevant financial relationships to disclose.)
Originally released April 25, 1994; last updated February 6, 2019; expires February 6, 2022

This article includes discussion of tuberous sclerosis complex, Bourneville-Pringle disease, Bourneville disease, diffuse cortical histioatypia, epiloia (obsolete), Pringle disease, TSC, and tuberous sclerosis.

Overview

Tuberous sclerosis complex is a constellation of signs and symptoms that constitute the diagnosis. In this update, the authors give a succinct overview of the topic while outlining advances in the treatment of multiple manifestations of the disease. New trials for management of multiple clinical manifestations with precision medicine using mTOR inhibitors are discussed.

Key points

 

• Tuberous sclerosis is a neurocutaneous disorder with significant neurologic implications, especially with regards to epilepsy and cognition. There have been tremendous gains made in recognizing and managing the protean disease manifestations just in the last decade.

 

• Epilepsy is a common manifestation early in life.

 

• Autism is a very frequent manifestation of this disease, affecting about half of all patients.

 

• TAND, tuberous sclerosis complex associated neuropsychiatric disorders, are increasingly recognized and include a wide range of disorders such as behavioral, psychiatric, intellectual, academic, neuropsychological, and psychosocial difficulties.

 

• Tumors are common and have a significantly improved prognosis with advances in treatment.

 

• Significant progress has occurred in the last decade in management of the clinical features of the disease based on advances in understanding of the pathogenesis and pathophysiology, specifically with the use of mTOR inhibitors.

Historical note and terminology

Désiré-Magloire Bourneville reported “tuberous sclerosis of cerebral circumvolutions” with “confluent vesiculopapular eruption on her nose, cheeks and forehead” in the necropsy of a young girl who had recurrent status epilepticus (Bourneville 1880). The term “tuberous sclerosis” here refers solely to the discrete pathologic entity in the brain – a distinctive cortical pathology of raised, opaque, and sclerotic cerebral gyri with a potato-like firmness. Interestingly, almost 20 years previously, and perhaps unbeknownst to him, Von Recklinghausen had reported of a newborn infant with several cardiac "myomata" and numerous scleroses in the brain (Von Recklinghausen 1862a). Bourneville also reported periventricular white nodules projecting into the lateral ventricles of the brain, and tumors in the kidneys (Bourneville 1880).

Subsequently, dermatologists in France (Balzer and Menetrier 1885) and in England (Pringle 1890) described a facial hamartoma, namely adenoma sebaceum, which was subsequently linked to seizures and mental retardation. Later, many authors reported of the association of “tuberous sclerosis” with dermatologic (Pellizzi 1901; Perusini 1905), renal, cardiac, and pulmonary (Lutenbacher 1918) abnormalities. The term “tuberous sclerosis complex,” therefore, best reflects involvement of multiple organ systems with development of distinctive tumors, or hamartomas. These associations in general and the Vogt triad (epiloia, an acronym for epilepsy, low IQ, and "adenoma sebaceum") in particular helped diagnose tuberous sclerosis complex in the living (Vogt 1908).

Recognition of the hereditary nature (Berg 1913) of tuberous sclerosis, its wide clinical spectrum and evolution of the concept of "phacomatoses" (Greek "phakos" meaning "mother spot") (Van der Hoeve 1932) were seminal advances in the history of tuberous sclerosis complex. The radiological identification of intracranial calcification in tuberous sclerosis in 1924 (Marcus 1945) and the publication of a classic paper on this disease (Critchley 1932) were landmarks. Molecular techniques leading to identification of 2 tuberous sclerosis genes, TSC1 in chromosome 9q34.3 (Fryer et al 1987) and TSC2 in 16p13.3 (Kandt et al 1992) have been of momentous significance.

In 2006, the first case series reporting success in treating human astrocytomas with tuberous sclerosis complex by targeting mammalian (now mechanistic) target of rapamycin (mTOR) with oral rapamycin was published (Franz et al 2006). Subsequently, reports of success of rapamycin (sirolimus) and everolimus in renal angiomyolipoma and lymphangioleiomyomatosis were published (Wienecke et al 2006; Bissler et al 2008). Everolimus and sirolimus (rapamycin) are being evaluated for multiple indications in tuberous sclerosis complex including epilepsy, subependymal giant cell astrocytomas, angiolipomas, and other tumors in multiple trials.

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