Tuberous sclerosis complex

Historical note and nomenclature
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By Hema R Murali MBBS and Narayana S Murali MD

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, TSC1in chromosome 9q34.3 (Fryer et al 1987) and TSC2in 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.

In This Article

Historical note and nomenclature
Clinical manifestations
Clinical vignette
Pathogenesis and pathophysiology
Differential diagnosis
Diagnostic workup
Prognosis and complications
References cited