Brooke-Spiegler Syndrome Resident Physician: D. Ryan Skinner DO, PGY-4 Program Director: Daniel S. Hurd DO, FAOCD History
• A 28 year-old female presented to the clinic with multiple facial papules that have been present since around the time of puberty. • She had been previously diagnosed as having “milia”. • There is no family history of similar skin lesions. • She had recently become pregnant and thought that since becoming pregnant she was getting more spots. • She wished to have them “extracted” like her previous dermatologist in North Carolina had done. • On further examination she also had a few small scattered papules on her scalp
Differential Diagnosis
• Multiple facial papules • Brooke-Spiegler syndrome • Multiple familial trichoepitheliomas • Familial cylindromatosis • Cowden syndrome • Birt-Hogg-Dube • Tuberous sclerosis • Rombo syndrome • Bazex syndrome • Muir–Torre syndrome
Brooke-Spiegler Syndrome
• How did I get it ? No one in my family has anything like this… • Is it dangerous? Are these spots cancer, will they turn to cancer? • Are other areas of my body going to be affected? • Other organs? • How much worse are these going to get? • I googled Brooke Spiegler syndrome and the pictures I saw…is that going to be me? • Is my unborn daughter going to get this? • What are the chances? • When will we know if she has it? • If she gets it, how bad will it be…like mine? • Like the pictures on google?? • I felt like these got worse during pregnancy, did I imagine that or do hormones influence these lesions? • Most importantly…how do I get rid of these spots and stop new ones from growing? I HATE them!!! Brooke-Spiegler Syndrome
• Features: • Trichoepithelioma • Cylindroma • Spiradenoma • CYLD mutation on 16q12-q13 • Familial Cylindromatosis • Multiple Familial Trichoepitheliomas • Malignant counterparts • Cylindrocarcinoma • Spiradenocarcinoma • Basal cell carcinoma • Rarely associated • Basal cell adenomas and adenocarcinomas of the parotid glands and minor salivary glands Genetics
• Autosomal Dominant condition • Women affected more severely than men • Variable phenotypical expression • Drastically different presentations within the same family • What causes the second hit that leads to loss of heterozygosity? • UV radiation • Cylindromas occur largely in sun exposed areas • Hormones • Androgen dependent areas of scalp / pubic area • Onset after adrenarche • Follicular neoplasms • One other case reported with worsening of lesions during pregnancy Blake PW, Toro JR. 2009. Update of cylindromatosis gene (CYLD) mutations in Brooke-Spiegler syndrome: novel insights into the role of deubiquitination in cell signaling. Hum. Mutat. 30:1025–1036. 10.1002/humu.21024 Blake PW, Toro JR. 2009. Update of cylindromatosis gene (CYLD) mutations in Brooke-Spiegler syndrome: novel insights into the role of deubiquitination in cell signaling. Hum. Mutat. 30:1025–1036. 10.1002/humu.21024 CYLD
JNK NF-κB CYLD
JNK NF-κB Cell survival through inhibition of apoptosis
Osteoclastognesis and bone Angiogenesis homeostasis.
NF-kB
Immune response Spermatogenesis and Inflammation
Cell differentiation Cell transformation
Proliferation Cell death
JNK
Cell survival Inflammation
Bubici C, Papa S (2014) JNK signalling in cancer: in need of new, smarter therapeutic targets. Br J Pharmacol 171: 24–37 Zhang JY, Selim MA. The role of the c-Jun N-terminal Kinase signaling pathway in skin cancer. Am J Cancer Res. 2012;2:691–698 Treatment
• Characteristic lesions of Brooke-Spiegler are considered benign, medical treatment is not necessary. • Treatment for cosmetic reasons. • Commonly reported treatments • Excision • Electrosurgery • Dermabrasion, • CO2 laser resurfacing, • Cryotherapy • Radiotherapy • Potential for scarring/adverse side effects. Future/Emerging Treatments
• NF-kB inhibitors • Nearly 800 compounds/drugs are inhibitors of NF-kB • ASA, TNF-alpha, cantharidin • Topical Salycylic Acid used on 17 cylindromas • Two showed complete remission • JNK inhibitors • Tanzisertib (CC-930) • Bentamapimod • SP600125 References
1. Carlson, Ryan M., Lori Haddad, and John C. Pui,. "Brooke Spiegler Syndrome with Associated Pegged Teeth." Cutis 82 (2008): 345-49. Web. 9 May 2014. 2. Bowen, Sarah, Melissa Gill, David A. Lee, Galen Fisher, and Roy G. Geronemus. "Mutations in the CYLD gene in Brooke–Spiegler Syndrome, Familial Cylindromatosis, and Multiple Familial Trichoepithelioma: Lack of Genotype–Phenotype Correlation." Journal of Investigative Dermatology 124 (2005): 919- 20. Web. 13 May 2014. 3. Trufant, Joshua; Robinson, Maria; & Patel, Rishi. (2012). Brooke-Spiegler syndrome. Dermatology Online Journal, 18(12). Retrieved from: http://escholarship.org/uc/item/4b04h9p3 4. Scinska, Justyna, Adriana Rakowska, Joanna Czuwara-Ladykowska, Andrzej Mroz, Marcin Lipinski, Anna Nasierowska-Guttmejer, Jolanta Sikorska, Katarzyna Sklinda, Monika Slowinska, Elzbieta Kowalska-Oledzka, Irena Walecka, Jerzy Walecki, and Lidia Rudnicka . "Cylindroma transforming into basal cell carcinoma in a patient with Brooke-Spiegler syndrome." Journal of Dermatological Case Reports 1.1 (2007): 4-9. Web. 16 May 2014. 5. Glodny, Bradley, and Joshua Zeichner. Acneiform Eruptions in Dermatology: A Differential Diagnosis. New York: Springer, 2014. 191-94. Print. 6. Ruiz, Ramon G., Altea E. Martinez, Anna A. Mejias, Juan Corell, and Victor A. De Miquel. "Old Syndromes, New Perspectives: Brooke-Spiegler Syndrome." Journal of the American Academy of Dermatology 64.2 (2011): AB86. Print. 7. Bolognia, Jean L., Joseph L. Jorizzo, and Julie V. Schaffer. Dermatology. Third ed. Vol. 1. N.p.: Saunders Elsevier, 2012. Print. 8. Rathi, Monika, Seema Awasthi, Satish K. Budania, Faiyaz Ahmad, Shyamoli Dutta, and Ashutosh Kumar. "Brooke-Spiegler Syndrome: A Rare Entity." Case Reports in Pathology 2014 (2014). Web. 13 May 2014.