Brooke-SpieglerSyndrome

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

NF-kB

Cell survival through inhibition

of apoptosis

Angiogenesis

Spermatogenesis

Cell differentiation

Immune response and Inflammation

Osteoclastognesis and bone

homeostasis.

Bubici C, Papa S (2014) JNK signalling in cancer: in need of new, smarter therapeutic targets. Br J Pharmacol 171: 24–37

JNK

Cell transformation

Cell death

InflammationCell survival

Proliferation

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

References1. 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/4b04h9p34. Scinska, Justyna, Adriana Rakowska, Joanna Czuwara-Ladykowska, Andrzej Mroz, Marcin Lipinski, Anna Nasierowska-Guttmejer, Jolanta Sikorska, KatarzynaSklinda, 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. <http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3920916/>.9. Uede, Koji, Yuki Yamamato, and Fukumi Furukawa. "Brooke-Spiegler syndrome associated with cylindroma, trichoepithelioma, spiradenoma, and syringoma." The Journal of Dermatology 31 (2004): 32-38. Web. 11 May 2014.10. Oosterkamp, H.M., Neering, H., Nijman, S.M.B., Dirac, A.M.G., Mooi, W.J., Bernards, R. and Brummelkamp, T.R. (2006), An evaluation of the efficacy of topical application of salicylic acid for the treatment of familial cylindromatosis. British Journal of Dermatology, 155: 182–185.11. Johnson, Hillary; Robles, Mirin; Kamino, Hideko; Walters, Ruth F; Lee, Arnold; & Sanchez, Miguel. (2008). Trichoepithelioma. Dermatology Online Journal, 14(10). Retrieved from: http://escholarship.org/uc/item/862492p412. Samaka RM, Bakry OA, Seleit I, Abdelwahed MM, Hassan RA. Multiple familial trichoepithelioma with malignant transformation. Indian J Dermatol2013;58:40913. Bercin, Sami, Ahmet Kutluhan, Ahmet Metin, and Dinc Suren. "Malignant eccrine spiradenoma on the lateral margin of nose as an infrequent localization." Indian Journal of Dermatology 54.2 (2009): 173-175. Print14. Cunha, Rafael A., Caroline B. Batista, Fabricio M. Pinto, Maria C. Issa , Mayra C. Rochael, and Sandra M. Barbosa Duraes. “Cylindroma: Typical presentation of uncommon tumor” Journal of the American Academy of Dermatology , Volume 68 , Issue 4 , AB16015. Smith, Scott A., Anita C. Gilliam, and Paradi Mirmirani. "Familial Cylindromatosis: A Case Report" Journal of the American Osteopathic College of Dermatology 4.1 (2005): 12-14. Print.16. Goette CK, McConnell CA, Fowler MR. “Cylindroma and Eccrine Spiradenoma Coexistent in the Same Lesion” Arch Dermatol. 1982;118(4):273-274.17. Gerretsen AL, van der Putte Sc, Deenstra W, van Vloten WA. “Cutaneous cylindroma with malignant transformation.” Cancer.1993 Sep1;72(5):1618-23.