Brooke-Spiegler Syndrome: Report of a case of multiple cylindromas and trichoepitheliomas
Published Web Locationhttps://doi.org/10.5070/D39fx4z12m
Brooke-Spiegler syndrome: Report of a case of multiple cylindromas and trichoepitheliomas1. Baylor College of Medicine, Houston, Texas
Sean D Doherty1, Terry L Barrett2, Aaron K Joseph3
Dermatology Online Journal 14 (7): 8
2. Department of Dermatology, The University of Texas, Southwestern Medical School, Dallas, Texas and ProPath, Dallas, Texas
3. Department of Dermatology, The University of Texas, Houston Medical School, Houston, Texas and Private Practice, Mohs Micrographic Surgery, Pasadena, Texas. email@example.com
We report a case of Brooke-Spiegler syndrome, a rare autosomal dominant disorder caused by mutations of the cylindromatosis gene (CYLD) tumor suppressor gene resulting in multiple cylindromas and trichoepitheliomas. Treatment of these patients can involve surgical excision, laser therapy, or topical applications of aspirin derivatives.
Brooke-Spiegler syndrome (BSS) is a rare autosomal dominant disorder with variable expression and penetrance presenting with multiple cylindromas and trichoepitheliomas . The tumors associated with BSS generally appear on the head and neck in early adulthood and progress in both size and number throughout life . We present a case of BSS and discuss treatment options for patients with this condition.
A 49-year-old man presented with a 10-year history of numerous skin-colored papules on the mid-face as well as 3 large pedunculated nodules over the scalp. The scalp lesions had progressively enlarged over the last 10 years. The patient's mother had a history of multiple basal cell carcinomas (BCC), but no family members had any lesions similar to the patient. On examination, three 2-3 cm pink, hairless, pedunculated nodules were present over the scalp and left preauricular area. Additionally, there were clusters of 2-3 mm flesh-colored papules in the left nasolabial fold and the cutaneous upper lip (Fig. 1).
|Figure 1. Three cylindromas over the scalp and left preauricular area and multiple trichoepitheliomas in the nasolabial fold and on the cutaneous upper lip|
A large nodule from the scalp was removed by shave biopsy. Histopathological examination revealed a dermal tumor composed of large lobulated nests of basaloid cells arranged in a jig-saw pattern consistent with a cylindroma (Fig. 2). Additionally, 2 of the smaller papules on the patient's cutaneous upper lip were biopsied and revealed a proliferation of palisading basaloid cells forming small ribbons with a focal trabecular pattern and rare follicular structures consistent with trichoepitheliomas (Fig. 3). Based upon the findings of multiple trichoepitheliomas and multiple cylindromas, the diagnosis of BSS was made.
Brooke-Spiegler syndrome results from mutations or loss of heterozygosity of the cylindromatosis gene (CYLD) located at 16q12-q13 [3, 4, 5, 6]. The cylindromatosis gene is a tumor suppressor gene, and its gene product represses the tumor necrosis factor-α (TNF-α) pathway. Activation of this pathway increases the expression of nuclear factor-κβ (NF-κβ), a transcription factor that regulates a number of anti-apoptotic genes involved in the proliferation of skin appendages. Mutations in the CYLD gene result in increased expression of NF-κβ and lead to apoptotic resistance  and tumors of the folliculosebaceousapocrine unit including cylindromas, trichoepitheliomas, and spiradenomas.
Mutations in this gene have been shown to be the cause of familial cylindromatosis and multiple familial trichoepithelioma. These findings suggest that all three conditions represent phenotypic variations of the same disease . The penetrance of the gene has been estimated to be between 60-100 percent , and affected members of a family may have any of the tumors of the folliculosebaceousapocrine unit mentioned above or other tumors including parotid basal cell adenomas, BCC, milia, or organoid nevi . As mentioned, the patient's mother had a history of multiple BCC, but it is unclear if her tumors were secondary to BSS with low expression.
Additionally, malignant transformation to BCC can occur in trichoepitheliomas . A recent report highlighted the difficulty of treating these BCCs with Mohs micrographic surgery due to the subtle histologic features that distinguish the BCC from the background trichoepithelioma . Coalescing trichoepitheliomas, as can commonly occur on the mid-face, have been successfully treated with an erbium: Yag laser .
Although rare, malignant transformation to cylindrocarcinomas and metastasis can occur in cylindromas . It has been reported that malignant transformation may be more likely when multiple cylindromas are present . Treatment of BSS patients must address the possibility of malignant transformation of the cylindromas and the progressive nature of the disease. These tumors can eventually cover the entire scalp resulting in so called "turban tumors" . Reported treatments of cylindromas include excision, dermabrasion, electrodessication, CO2 laser, cryotherapy, and radiotherapy. Some treatment modalities such as dermabrasion and CO2 laser are associated with high recurrence rates . In view of these undesirable recurrence rates and the risk of malignant transformation of these tumors, wide local excision is the preferred method of treatment . Although not described, Mohs micrographic surgery may be a tissue-sparing alternative to treat these tumors.
The treatments mentioned for cylindromas and trichoepitheliomas do not address the occurrence of new tumors. Since BSS results from a loss of the CYLD gene product's normal inhibition of the TNF-α pathway and increased expression of NF-κβ, normal growth control of the skin appendages may be restored through other pathway inhibitors. These inhibitors, including the aspirin derivative sodium salicylate and prostaglandin A1, have been shown to suppress NF-κβ expression in an in vitro CYLD knockdown cell line. Exposure of cells to sodium salicylate abolished the protective effect of CYLD knockdown on apoptosis . Phase I trials utilizing topical aspirin derivatives to treat cylindromas are currently under way  and may represent an easy treatment to prevent new cylindromas or trichoepitheliomas in these patients by restoring the normal growth control of skin appendages.
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