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 in Marshfield, Wisconsin, has no relevant financial relationships to disclose.)
Bernard Maria MD, editor. (Dr. Maria of Icahn School of Medicine at Mount Sinai and Director of Pediatric Neurology and Developmental Medicine at Goryeb Children)
Originally released April 25, 1994; last updated May 16, 2016; expires May 16, 2019

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 recent advances in the treatment of multiple manifestations of the disease. Recent recommendations of the International TSC Consensus Conference for diagnosis, surveillance, and management of common neuropsychiatric features of tuberous sclerosis complex are detailed.

Key points

 

• Tuberous sclerosis is a neurocutaneous disorder with significant neurologic implications, especially with regards to epilepsy and cognition.

 

• Epilepsy is a common manifestation early in life.

 

• Autism is a known manifestation of this disease.

 

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

 

• Significant progress has occurred in the last few years in management of the clinical features of the disease based on advances in understanding of the pathogenesis and pathophysiology.

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 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). There are also successful trials of mTOR inhibitors for epilepsy and management of subependymal giant cell astrocytomas, in addition to other tumors.

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