Of sirolimus, shagreen, and chagrin
By Warren R. Heymann, MDJuly 24, 2017
Credit: JAAD
The tuberous sclerosis complex (TSC) is a neurocutaneous, autosomal dominant genetic disease affecting approximately one in 6,000 to 10,000 live births, although spontaneous mutations are common (1). TSC can affect the brain, skin, eyes, kidneys, heart, and lungs. A mutation of either TSC1 on chromosome 9 or TSC2 on chromosome 16 leads to dysfunction of hamartin or tuberin, respectively. These proteins form a functional complex that modulates the mammalian target of rapamycin (mTOR) pathway, thereby altering cellular proliferation and differentiation, resulting in hamartomas, tumors, and altered neuronal migration. Phenotyic expression is highly variable. Patients may have seizures, commonly including infantile spasms, and there is variable intellectual disability and autism. Neonates can present with cardiac failure due to intracardiac rhabdomyomas. The likelihood of renal angiomyolipomas increases with age, and renal disease is the most common cause of death in adults with TSC. Pulmonary involvement with lymphangioleimyomatosis occurs predominantly in women, with high morbidity and mortality. (2)
Dermatologists will readily recognize the cutaneous manifestations of TS, including multiple facial angiofibromas, fibrous cephalic plaques (forehead plaques), hypomelanotic macules, ungual fibromas, or shagreen patches (SP). The SP (shagreen is untanned leather with small granulations) is a connective tissue nevus that is considered highly diagnostic of TSC when it has the classic appearance of a large, irregular, firm plaque located on the lower back, appearing in 21 to 83% of patients with TS. The texture of shagreen patches has been likened to “pigskin” or peau d’orange with a pink or skin-colored hue, or prominent, dilated follicular openings. Bongiorno et al, found that 58 of 104 patients with TSC (56%) had at least one connective tissue nevus on the trunk or thighs; of these, 28 of 58 patients (48%) had a solitary lesion, and 30 of 58 patients (52%) had 2 or more lesions. The distribution of lesions was 9% (n = 11), upper back; 29% (n = 35), middle back; 51% (n = 61), lower back; and 11% (n = 13), other locations. All 26 shagreen patches that were analyzed histopathologically had coarse collagen fibers and 24 of 26 stained with Miller elastic stain had decreased elastic fibers. On immunoblot analysis, fibroblasts grown from shagreen patches expressed higher levels of phosphorylated ribosomal protein S6 than paired fibroblasts from normal-appearing skin. (3)
There has been a flurry of reports on the use of topical (and systemic) sirolimus for the cutaneous manifestations of TS. Malissen et al studied 25 patients with TS utilizing a daily application of 1% sirolimus cream — 50% obtained complete clearance of facial angiofibromas within 9 months. Of 7 patients with complete clearance (58%) who were following the maintenance protocol, 6 relapsed within 7 months and 1 was still responding at 1 year. Of 16 patients with facial collagenous plaques, 7 (44%) remained stable at 12 months and 9 (56%) improved after 3 to 9 months of treatment. Only 1 of 5 patients treated for shagreen patches showed improvement at 12 months. Treatment was well tolerated with no serious adverse events. (4)
Vigorous research is being conducted regarding the use of both topical and systemic mTOR inhibitors for the cutaneous and visceral complications of TS. I concur with Nathan et al who do not recommend oral treatment with sirolimus (or everolimus) for patients without concomitant internal disease. For patients with troublesome skin tumors only topical sirolimus is recommended. Topical everolimus may be effective but is still under investigation. (5)
There is no reason to be chagrined by the relative lack of response of lesions like the shagreen patch to topical sirolimus. The manipulation of the mTOR pathway to improve cutanenous and visceral neoplasms that could previously only be treated surgically is miraculous. Refinements to maximize benefit are imminent.
1. Martin KR, et al. The genomic landscape of tuberous sclerosis complex. Nat Commun 2017;8:15816.
2. Islam MP, Roach ES. Tuberous sclerosis complex. Handb Clin Neurol 2015; 132: 97-109.
3. Bongiorno MA, et al. Clinical characteristics of connective tissue nevi in tuberous sclerosis complex with special emphasis on shagreen patches. JAMA Dermatology 2017; 153: 660-5.
4. Malissen N, et al. Long-term treatment of cutaneous manifestations of tuberous sclerosis complex with topical 1% sirolimus cream: A prospective study of 25 patients. J Am Acad Dermatol 2017; May 10 [Epub ahead of print)
5. Nathan N, et al. Improvement of tuberous sclerosis complex skin tumors during long-term treatment with sirolimus. J Am Acad Dermatol 2015; 73: 802-8.
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