Brooke-Spiegler syndrome
Joshua Trufant MD, Maria Robinson MD, Rishi Patel MD
Dermatology Online Journal 18 (12): 16

The Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, New York

Abstract

A 50-year-old woman presented with a long history of multiple, flesh-colored papules and nodules on her central face, neck, and upper shoulders, as well as pink papules on her scalp. They were neither pruritic nor tender, but the patient desired treatment for cosmesis. Histopathologic examination of a representative facial lesion was consistent with a trichoepithelioma and an upper forehead papule was consistent with cylindroma. She reported a positive family history of similar lesions.



History


Figure 1 Figure 2

A 50-year-old woman from the Dominican Republic presented to the Charles C. Harris Skin and Cancer Pavilion with a long history of multiple, flesh-colored-to-pink papules and nodules on her scalp, face, neck, and upper shoulders. The lesions first appeared in puberty. They were neither pruritic nor tender, but she desired treatment for cosmetic reasons. All of the lesions were asymptomatic. She reported a family history of similar lesions in her mother and four of her eight siblings who had a similar age of onset. The patient denied a personal or family history of cutaneous or internal malignant conditions. A review of symptoms was negative.


Physical examination

Most prominently on the central face were dozens of 2 to 4 mm, flesh-colored, firm, dome-shaped papules. Her post-auricular scalp, neck, and upper shoulders also were involved but were less densely populated with similar lesions. On her left vertex of the scalp was a 1 cm, sessile, white-pink nodule with no overlying scale. A 5 mm, pedunculated, pink papule was present on her left parietal aspect of the scalp.


Laboratory data

None.


Histopathology

Within the dermis there are aggregates of small uniform epithelial cells rimmed by eosinophilic basement membrane material. Four other biopsies from the patient were reviewed two of which showed a trichoepithelioma and two of which showed the surface of basaloid aggregates consistent with benign adnexal neoplasms.


Discussion

Brooke-Spiegler syndrome (BSS), multiple familial trichoepithelioma (MFT), which also is known as epithelioma adenoides cysticum or Brooke’s disease, and familial cylindromatosis are allelic, dominantly-inherited conditions with overlapping clinical features [1]. All are characterized by the appearance of benign, adnexal neoplasms in late childhood and early adolescence. Clinically, the defining lesions of MFT present as bilateral and symmetrically distributed, flesh-colored papules or small nodules on the face (especially the nose), neck, or chest. Familial cylindromatosis presents with multiple, erythematous nodules that typically arise on the scalp but also on the forehead or pubic area. Multiple cylindromas may coalesce to form a large plaque or so-called turban tumor that may cover the entire scalp and that is associated with alopecia. BSS, first described at the turn of the twentieth century, is a rare, phenotypically heterogeneous disorder that is characterized by neoplasms, along with sporadic spiradenomas, trichoblastomas, parotid basal-cell adenomas, milia, organoid nevi, and basal-cell carcinomas [2, 3, 4]. Malignant adnexal tumors also have, more rarely, been described [5]. The types of lesions can vary within a given family and individual lesions may even exhibit mixed differentiation [6, 7].

A subset of BSS, MFT, and familial cylindromatosis cases have been linked to loss-of-heterozygosity germline mutations in the cylindromatosis (CYLD) gene on chromosome 16q12-13 [8-12]. To date, 68 unique mutations with variable expression and penetrance (both intra- and inter-familial) have been identified in CYLD, which is a putative tumor suppressor gene that codes for a deubiquitinating enzyme with roles in inflammation and cell proliferation [13]. Genotypic heterogeneity has been described as well. MFT has been mapped to a second locus at 9p21; sporadic trichoepitheliomas have been mapped to PTCH (the same gene mutated in nevoid basal-cell carcinoma syndrome); and individuals and families, who lacked CYLD or PTCH mutations, have been described with clinical features of BSS and MFT [13, 14].

Histopathologic findings of trichoepitheliomas include clusters of basaloid germinative cells with keratinizing cystic spaces and superficial follicular differentiation that are surrounded by fibrocytic stroma. Intra-stromal clefts also may be observed [15]. Cylindromas comprise well-circumscribed nodules of basaloid cells in the dermis. The individual nests, which are surrounded by eosinophilic, periodic acid-Schiff-positive, basement-membrane material, are arrayed in a closely packed, jigsaw-like pattern. Ductal structures sometimes can be observed within the nests.

The number of adnexal tumors in BSS typically precludes surgical excision, which is the standard treatment for solitary lesions. Numerous, non-invasive procedures with variable success have been described in case reports. These modalities include dermabrasion, electrosurgery, cryosurgery, ablation with neodymium-doped YAG, erbium:YAG, or carbon dioxide lasers, and photodynamic therapy [16]. Medical treatments have included sodium salicylate and prostaglandin A1, a combination of aspirin and adalimumab, and topical imiquimod [17, 18, 19].

References

1. Bowen S, et al. Mutations in the CYLD gene in Brooke-Spiegler syndrome, familial cylindromatosis, and multiple familial trichoepithelioma: lack of genotype-phenotype correlation. J Invest Dermatol 2005; 124: 919 [PubMed]

2. Brooke H. Epithelioma adenoides cysticum. Br J Dermatol 1892; 4: 269

3. Spiegler H. Uber endothelioma der haut. Arch Derm Syphilol 1899; 50: 163

4. Burrows NP, et al. The clinicopathological features of familial cylindromas and trichoepitheliomas (Brooke-Spiegler syndrome): a report of two families. Clin Exp Dermatol 1992; 17: 332 [PubMed]

5. Kazakov DV, et al. A case of Brooke-Spiegler syndrome with novel germline deep intronic mutation in the CYLD gene leading to intronic exonization, diverse somatic mutations, and unusual histology. Am J Dermatopathol 2009; 31: 664 [PubMed]

6. Weyers W, et al. Spiradenomas in Brooke-Spiegler syndrome. Am J Dermatopathol 1993; 15: 156 [PubMed]

7. Puig L, et al. Brooke-Spiegler syndrome variant: segregation of tumour types with mixed differentiation in two generations. Am J Dermatopathol 1998; 20: 56 [PubMed]

8. Fenske C, et al. Brooke-Spiegler syndrome locus assigned to 16q12-q13. J Invest Dermatol 2000; 114: 1057 [PubMed]

9. Scheinfeld N, et al. Identification of a recurrent mutation in the CYLD gene in Brooke-Spiegler syndrome. Clin Exp Dermatol 2003; 28: 539 [PubMed]

10. Biggs PJ, et al. Familial cylindromatosis (turban tumour syndrome) gene localised to chromosome 16q12-q13: evidence for its role as a tumour suppressor gene. Nat Genet 1995; 11: 441 [PubMed]

11. Bignell GR, et al. Identification of the familial cylindromatosis tumour-suppressor gene. Nat Genet 2000; 25: 160 [PubMed]

12. Young AL, et al. CYLD mutations underlie Brooke-Spiegler, familial cylindromatosis, and multiple familial trichoepithelioma syndromes. Clin Genet 2006; 70: 246 [PubMed]

13. Ponti G, et al. Brooke-Spiegler syndrome: report of two cases not associated with a mutation in the CYLD and PTCH tumor-suppressor genes. J Cutan Pathol 2011; Nov 12 [E-pub ahead of print] [PubMed]

14. Harada H, et al. The gene for multiple familial trichoepithelioma maps to chromosome 9p21. J Invest Dermatol 1996; 107: 41 [PubMed]

15. Bettencourt MS, et al. Trichoepithelioma: a 19-year clinicopathologic re-evaluation. J Cutan Pathol 1999; 26: 398 [PubMed]

16. Rajan N, et al. Familial cylindromatous and Brooke-Spiegler syndrome: a review of current therapeutic approaches and the surgical challenges posed by two affected families. Dermatol Surg 2009; 35: 845 [PubMed]

17. Brummelkamp TR, et al. Loss of the cylindromatosis tumour suppressor inhibits apoptosis by activating NFκ- B. Nature 2003; 424: 738 [PubMed]

18. Fisher GH, Geronemus RG. Treatment of multiple familial trichoepitheliomas with a combination of aspirin and a neutralizing antibody to tumor necrosis factor alpha: a case report and hypothesis of mechanism. Arch Dermatol 2006; 142: 782 [PubMed]

19. LoPiccolo MC, et al. Comparing ablative fractionated resurfacing, photodynamic therapy, and topical imiquimod in the treatment of trichoblastomas of Brooke-Spiegler Syndrome: a case study. Derm Surg 2011; 37: 1047 [PubMed]

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Title:

Brooke-Spiegler syndrome

Journal Issue:

Dermatology Online Journal, 18(12)

Author:

Trufant, Joshua;
Robinson, Maria;
Patel, Rishi

Publication Date:

2012

Publication Info:

Dermatology Online Journal, UC Davis

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