Clinical and Histologic Analysis of the Efficacy of Topical Rapamycin Therapy Against Hypomelanotic Macules in Tuberous Sclerosis Complex

Wataya‐Kaneda, Mari; Tanaka, Mari; Yang, Lingli; Yang, Fei; Tsuruta, Daisuke; Nakamura, Ayumi; Matsumoto, Shoji; Hamasaki, Toshimitsu; Tanemura, Atushi; Katayama, Ichiro

doi:10.1001/jamadermatol.2014.4298

Cited by 49 publications

(42 citation statements)

References 34 publications

(34 reference statements)

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“…We demonstrate that loss of the TSC protein complex, through loss of either of its constituent proteins, TSC1 or TSC2, leads to GSK3β activation, with a consequent loss of nuclear β-catenin and a marked reduction in MITF transcription and expression, resulting in loss of pigmentation. The conclusion that loss of TSC1 or TSC2 results in reduced pigmentation is supported by a recent clinical study, in which topical rapamycin treatment restored the pigmentation of TSC hypomelanotic macules (25). Our findings support the model that expression ( Figure 7C, top left).…”

Section: Discussionsupporting

confidence: 87%

“…Since these macules can be detected at birth, they were proposed as one of the earliest diagnostic markers of TSC 50 years ago (24). Ultrastructural studies have shown that melanocyte content in TSC hypomelanotic macules is normal, while intracellular pigment granules are reduced in size and number (22,25). Despite these morphologic and histologic studies, however, the mechanism of TSC-associated hypopigmentation has remained unknown.…”

Section: Introductionmentioning

confidence: 99%

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Tuberous sclerosis complex inactivation disrupts melanogenesis via mTORC1 activation

Cao¹,

Tyburczy²,

Moss³

et al. 2016

Journal of Clinical Investigation

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Section: Discussionsupporting

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Tuberous sclerosis complex inactivation disrupts melanogenesis via mTORC1 activation

Cao¹,

Tyburczy²,

Moss³

et al. 2016

Journal of Clinical Investigation

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“…d), hypomelanotic macules in TSC are usually stable for many years, and they can fade or disappear in adulthood. Recently, the efficacy of mTORC1 inhibitor for the treatment of hypomelanotic macules has been reported …”

Section: Clinical Features and Treatments Of Tuberous Sclerosis Complexmentioning

confidence: 99%

“…To avoid side‐effects from long‐term use of mTORC1 inhibitors, a topical sirolimus formulation has been developed for skin lesions with TSC …”

Section: Therapeutic Problems Of Mtorc1 Inhibitorsmentioning

confidence: 99%

Tuberous sclerosis complex: Recent advances in manifestations and therapy

et al. 2017

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Tuberous sclerosis complex is an autosomal dominant inherited disorder characterized by generalized involvement and variable manifestations with a birth incidence of 1:6000. In a quarter of a century, significant progress in tuberous sclerosis complex has been made. Two responsible genes, TSC1 and TSC2, which encode hamartin and tuberin, respectively, were discovered in the 1990s, and their functions were elucidated in the 2000s. Hamartin-Tuberin complex is involved in the phosphoinositide 3-kinase-protein kinase B-mammalian target of rapamycin signal transduction pathway, and suppresses mammalian target of rapamycin complex 1 activity, which is a center for various functions. Constitutive activation of mammalian target of rapamycin complex 1 causes variable manifestations in tuberous sclerosis complex. Recently, genetic tests were launched to diagnose tuberous sclerosis complex, and mammalian target of rapamycin complex 1 inhibitors are being used to treat tuberous sclerosis complex patients. As a result of these advances, new diagnostic criteria have been established and an indispensable new treatment method; that is, "a cross-sectional medical examination system," a system to involve many experts for tuberous sclerosis complex diagnosis and treatments, was also created. Simultaneously, the frequency of genetic tests and advances in diagnostic technology have resulted in new views on symptoms. The numbers of tuberous sclerosis complex patients without neural symptoms are increasing, and for these patients, renal manifestations and pulmonary lymphangioleiomyomatosis have become important manifestations. New concepts of tuberous sclerosis complex-associated neuropsychiatric disorders or perivascular epithelioid cell tumors are being created. The present review contains a summary of recent advances, significant manifestations and therapy in tuberous sclerosis complex.

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“…The study by Wataya-Kaneda et al 1 in this issue of JAMA Dermatology examines the response of hypopigmented macules in tuberous sclerosis (TS) to topical rapamycin. The authors found that topical rapamycin, 0.2%, gel led to substantial improvement of hypopigmented macules without systemic absorption and that the improvement was more marked in sun-exposed skin.…”

mentioning

confidence: 99%

Efficacy of Rapamycin in Tuberous Sclerosis–Associated Hypopigmented Macules

Arbiser

2015

JAMA Dermatol

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The study by Wataya-Kaneda et al 1 in this issue of JAMA Dermatology examines the response of hypopigmented macules in tuberous sclerosis (TS) to topical rapamycin. The authors found that topical rapamycin, 0.2%, gel led to substantial improvement of hypopigmented macules without systemic absorption and that the improvement was more marked in sun-exposed skin. This improvement was reflected in the normalization of melanosome abnormalities in treated skin. Finally, the authors note that knockdown of tuberin (tsc2) caused abnormalities in melanosome numbers compared with controls.This study is the first to examine the benefit of topical rapamycin for the treatment of TSassociated hypopigmentation. Rapamycin, an inhibitor of the target of rapamycin complex (mTOR), has been used topically for the treatment of cutaneous angiofibromas and systemically for other complications of TS, including renal angiomyolipomas, subependymal giant cell astrocytomas, and pulmonary lymphangiomyomatosis. 2,3 Mutations in the 2 genes responsible for TS (TSC1 and TSC2) have been shown to cause activation of the small GTPase Rheb, and downstream of Rheb activation is activation of mTOR, which can exist as 2 complexes, mTORC1 and mTORC2. 4

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Clinical and Histologic Analysis of the Efficacy of Topical Rapamycin Therapy Against Hypomelanotic Macules in Tuberous Sclerosis Complex

Abstract: Topical rapamycin treatment was effective and safe against hypomelanotic macules arising from TSC. This efficacy of rapamycin was corroborated as stemming from the improvement of impaired melanogenesis in TSC melanocytes.

Cited by 49 publications

References 34 publications

Tuberous sclerosis complex inactivation disrupts melanogenesis via mTORC1 activation

Tuberous sclerosis complex inactivation disrupts melanogenesis via mTORC1 activation

Tuberous sclerosis complex: Recent advances in manifestations and therapy

Efficacy of Rapamycin in Tuberous Sclerosis–Associated Hypopigmented Macules

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