The Use of Glycopyrrolate in Aquagenic Wrinkling of the Palms Helia Eragi, D.O., Mayha Patel, B.S., MSIV, David Horowitz, D.O., F.A.O.C.D

Journal of the American Osteopathic College of Dermatology PRSRT STD OLUME U.S. POSTAGE Volume 25 2902 North Baltimore Street PAID 2 25 MASON CITY, IA P.O. Box 7525 PERMIT NO. 429 Kirksville, Missouri 63501 Journal of the American Osteopathic College of Dermatology J OURNAL

THE A MERICAN O STEOPATHIC C OLLEGE

OF D ERMATOLOGY

What Dermatologists Need to Know About Interferon- gamma Testing for Tuberculosis 1 ournal of the American Osteopathic J College of Dermatology 2012-2013 OFFICERS

PRESIDENT David L. Grice, D.O., FAOCD

PRESIDENT-ELECT Suzanne Sirota-Rozenberg, D.O., FAOCD

FIRST VICE-PRESIDENT Rick J. Lin, D.O., FAOCD

SECOND VICE-PRESIDENT Alpesh Desai, D.O., FAOCD

THIRD VICE-PRESIDENT Karthik Krishnamurthy, D.O., FAOCD

IMMEDIATE PAST-PRESIDENT Editor-in-Chief Bradley Glick, D.O., FAOCD Karthik Krishnamurthy, DO TRUSTEES Danica Alexander, D.O., FAOCD

Reagan Anderson, D.O., FAOCD

Mark A. Kuriata, D.O., FAOCD

Sponsors: Daniel Ladd, D.O., FAOCD Bayer John P. Minni, D.O., FAOCD Bryan Sands, D.O., FAOCD Global Pathology Laboratory SECRETARY-TREASURER Medicis Jere J. Mammino, D.O., FAOCD EXECUTIVE DIRECTOR Ranbaxy Marsha A. Wise, B.S.

JAOCD Founding Sponsor

AOCD • 2902 N. Baltimore St. • Kirksville, MO 63501 800-449-2623 • FAX: 660-627-2623 www.aocd.org

COPYRIGHT AND PERMISSION: Written permission must be obtained from the Journal of the Ameri- can Osteopathic College of Dermatology for copying or reprinting text of more than half a page, tables or figures. Permissions are normally granted contingent upon similar permission from the author(s), inclusion of acknowledgement of the original source, and a payment of $15 per page, table or figure of reproduced material. Permission fees are waived for authors wishing to reproduce their own articles. Request for permission should be directed to JAOCD c/o AOCD, PO Box 7525, Kirksville, MO 63501.

Print and layout by: The Dimensional Group, Mason City, IA 50401 Copy editing: Julia Layton, Freelance Writing and Editing able of Contents

T Volume 25 JAOCD Editors...... 4 Letter from the Editor-in-Chief...... 5 Letter from the Executive Director...... 6 Letter from the President...... 7 Dermatology Foundation News Release: Vera H. Price, M.D., Receives Dermatology Foundation Lifetime Career Educator Award...... 12

FEATURED ARTICLE Interferon-Gamma-Release Assays: A Guide to Clinical Use in Dermatology Emily Kate Matthews, D.O., Robin Shecter, D.O...... 13

EDITOR'S PICKS Henoch-Schönlein Purpura in an Adult Patient G. Trey Haunson, D.O., Daniel S. Hurd, D.O., F.A.O.C.D...... 16 A Case Report: The Use of Glycopyrrolate in Aquagenic Wrinkling of the Palms Helia Eragi, D.O., Mayha Patel, B.S., MSIV, David Horowitz, D.O., F.A.O.C.D...... 21 An Intertriginous and Flexural Exanthem: Case Report and Drug-Eruption Review Jonathan D. Richey, DO, MHA, Monica Nafsou, DO, Annette LaCasse, DO, FAOCD...... 23

ORIGINAL ARTICLES & CASE REPORTS Zosteriform Lichen Planus Limited to L4 Dermatome of the Right Lower Extremity Donna D. Tran, MSIV, Brent Loftis, DO, Elaine Phuah, DO, Bill V. Way, DO, FAOCD...... 27 Wells’ Syndrome: A Case Report LT Jessica L. Schwartz, MC, USN, CDR Tony S. Clinton, MC, USN...... 29 Familial Koenen tumors (periungual fibromas) without clinical criteria or genetic testing diagnostic for tuberous sclerosis Laurie Lenz, DO, Jacqueline Thomas, DO, Noelle Sanon, DO, Robin Shecter, DO...... 31 Calciphylaxis: Case Report and Literature Review Kristin Regan, D.O., Kate Kleydman, D.O., Cindy Hoffman, D.O...... 34 Klippel-Trénaunay syndrome: A case report and review of the literature Mariel Bird, DO, Michael Centilli, DO, Steven Grekin, DO, FAOCD...... 39 Birt-Hogg-Dubé Syndrome – A Case Report and Review Jennifer Moscoso, Genevieve Midyette, PA-C, David M. Bracciano, D.O., FAOCD...... 43 Treatment of Verruca Vulgaris with Nd: YAG 1064-nm Laser Winifred S. Chu, D.O., M.P.H., Suzanne Sirota-Rozenberg, D.O...... 45 Unusual Seborrheic Keratosis: A Rare Clinical Variant Sanjosh Singh, DO, MPH, Suzanne Rozenberg, DO, FAOCD...... 47 An Interesting Case of Familial Firm Facial Papules: Basal Cell Nevus Syndrome or Multiple Charisse L. McCall, DO, Suzanne Sirota Rozenberg, DO, FAOCD...... 50 Recurrent HSV-associated erythema multiforme: a case report of atypical morphology and distribution Tim A. Galperin, D.O., John P. Minni, D.O., Dwayne D. Montie, D.O...... 56 Extranodal NK/T-cell Lymphoma, Nasal Type Jordan Fabrikant, DO, Donna Tran, DO, Stanley E. Skopit, DO, MSE, FAOCD...... 59 An Unexpected Finding of Sinonasal Melanoma in a Patient Believed to Have Chronic Sinusitis: A Case Report Liza M. Brown, BS, Richard M. Rubenstein, MD, William Smothermon, MD...... 61 Editor-in-Chief Founding Editor Copy Editor Karthik Krishnamurthy, DO Jay Gottlieb, DO Julia Layton, BA, MFA

Associate Editors

Aaron Bruce, DO Michelle Foley, DO Scott Wickless, DO Loveland, CO Ormond Beach, FL Durango, CO

Editorial Board

Brooke Bair, DO Melinda Greenfield, DO Jacksonville, FL Albany, GA

Adriana Ros, DO Clifton, NJ

Sean Stephenson, DO Troy, MI

4 JAOCD EDITORS etter from the Editor-in-Chief L

Karthik Krishnamurthy, DO, FAOCD Editor-in-Chief Dear JAOCD readership,

At the recent Council of Dermatology Editors meeting in Miami during the AAD Annual Meeting, we discussed an important issue that may be familiar to you: spam. In particular, we talked about invitations from obscure online journals that seem to be inundating all of our email accounts at alarming rates.

I’m sure most of us are victims of such unwanted attention from a variety of sources, and as authors, reviewers and readers of the JAOCD, this particular type of spam affects us all. Jeffrey Beall, an academic librarian at the University of Colorado at Denver, has begun cataloguing these questionable journals, and his full report, entitled “Beall’s List of Predatory, Online-Access Publishers,” can be found online at http://www.academia.edu/1151857/Bealls_List_of_Predatory_Open-Access_Publishers. Here is an excerpt of note:

“Predatory, open-access publishers are those that unprofessionally exploit the author-pays model of open-access publishing (Gold OA) for their own profit. Typically, these publishers spam professional email lists, broadly soliciting article submissions for the clear purpose of gaining additional income. Operating essentially as vanity presses, these publishers typically have a low article acceptance threshold, with a false-front or non-existent peer review process. Unlike professional publishing operations, whether subscription-based or ethically-sound open access, these predatory publishers add little value to scholarship, pay little attention to digital preservation, and operate using fly-by-night, unsustainable business models.” -2012 Beall’s List of Predatory, Online-Access Publishers

Of course, the JAOCD is not on this list, and it never will be; however, I want to highlight the dangers of submitting articles to these types of soliciting journals. If the soliciting journal is not immediately recognizable, I advise all potential authors to examine Beall's list prior to submitting articles on which you have worked so hard.

As always, the JAOCD remains of sound academic orientation and invites you to continue submitting your scientific manuscripts (free of charge!).

We appreciate all of your hard work, support, and expertise, and urge you to protect yourselves from falling into these traps.

Warm Regards,

Karthik Krishnamurthy, DO, FAOCD

LETTER FROM THE EDITOR-IN-CHIEF 5 etter from the Executive Director L

Marsha Wise Executive Director, AOCD

Greetings, everyone!

We recently welcomed a new member to the AOCD staff in Kirksville. Look for Jami Johnson’s article of introduction located in the next issue of Dermline.

Our 2013 Midyear Meeting has been completed, and outcome evaluation surveys have been sent to our attendees. By filling out this additional survey, our attendees become eligible to earn up to two additional CME credits. This is a NEW benefit available to members and is another reason we encourage everyone to attend the midyear meetings of the AOCD. Our next midyear meeting in 2014 will be at the Ritz Carlton in Dallas. Dr. Karthik Krishnamurthy is already hard at work planning this meeting.

OMED 2013 On February 2, 2013, I attended the AOA’s pre-OMED meeting in Las Vegas. At this year's meeting, the AOCD will have various events in the Mandalay Bay Hotel, with the primary lectures and exhibits located in the Mandalay Bay Convention Center. Dr. Suzanne Sirota-Rozenberg has planned an exciting line-up of speakers and topics. A preliminary schedule will be in the upcoming issue of Dermline.

AOCD Office Update The AOCD completed our move to the new office. Our post office box (P.O. Box 7525, Kirksville, Missouri, 63501) is our preferred mailing address, and all correspondence should continue to be sent there. All shipments, however, should be sent to our new street address: 2902 N. Baltimore St., Kirksville, MO, 63501. Please be sure to update your records.

ACGME Update The AOA, the Accreditation Council for Graduate Medical Education (ACGME), and the American Association of Colleges of Osteopathic Medicine (AACOM) have entered into an agreement to pursue a single, unified accreditation system for graduate medical education programs in the United States beginning in July 2015.

At the recent AOA Board of Trustees Midyear Meeting held March 3rd to 6th in Maui, it was announced that the much-anticipated Memorandum of Understanding between the ACGME and the AOA would likely be available during the July House of Delegates meeting in Chicago. The AOA met with ACGME during the last week in February, and the two organizations agreed to hold more meetings on the subject of the unified accreditation system.

As developments and details unfold, information can be found at www.osteopathic.org/acgme. There, you can find answers to frequently asked questions, the AOA’s joint press release, a timeline of the issue, and other resources.

All the best, Marsha A. Wise Executive Director, AOCD

6 LETTER FROM THE EXECUTIVE DIRECTOR etter from the President L

David L. Grice, DO, FAOCD President, AOCD

The JAOCD relies on the participation of students, residents, Program Directors, and AOCD members. I believe, though, it is the AOCD dermatology residents who truly drive this journal to its continued success. And those residents will eventually become the leaders of our college.

Our JOACD Editor-in-Chief, Karthik Krishnamurthy, DO, FAOCD, offers a prime example of how members of our college can take advantage of the myriad opportunities for involvement. Besides his duty as editor, Dr. Krishnamurthy is also the AOCD’s Third Vice-President and the Program Chair of the upcoming 2014 Midyear Meeting in Dallas. He also serves on several committees, including as Chair of the Editorial/Public Relations Committee. It wasn’t so long ago that Dr. Krishnamurthy was a resident in New York.

My point is that one can accomplish a lot if the desire to participate is there. At the American Academy of Dermatology Meeting in Miami, a team of dermatology residents from the PCOM/Lehigh Valley Health Network joined the AAD Dermpath Bowl, competing against other allopathic and osteopathic residents from residency programs across the country. These residents, under the direction of Program Director Stephen Purcell, DO, FAOCD, won first place in the competition! Congratulations to Tatyana Goysman, DO, Marie Lewars, DO, Luis Soro, DO, and Christian Oram, DO, for their fantastic performance against some of the top dermatology residents in the United States.

I was also very impressed with the resident presentations at our recent Midyear Meeting in Winter Park, Colorado. There was the talk by Ralph Fiore, II, DO, on iatrogenic infections, and a great case report on lamellar ichthyosis given by Steffany Steinmetz, DO. I also want to congratulate our Koprince Award winners, Aleksandra Brown, DO, Leilani Townsend, DO, Geeta Patel, DO, and Stacy Rosenblum, DO, for their presentations. I am encouraged to see the ever-improving quality of resident talks in general, and I hope that all of our talented presenters will continue speaking as they move forward in their dermatology careers.

So I end this message with a salute to our residents, their program directors and their trainers. May you continue to strive to be experts in the field of dermatology!

David L. Grice, DO, FAOCD President, AOCD

LETTER FROM THE PRESIDENT 7 8 9 BRIEF SUMMARY DRUG InTERACTIonS (see package insert for Full Prescribing Information) Concomitant Topical Medication concomitant topical medication, medicated or abrasive soaps and cleansers, soaps and cosmetics that have a strong drying effect, and products with high concentrations of alcohol, astringents, spices or lime should be used with caution. When used with Ziana® Gel, there may be increased skin irritation. Erythromycin Ziana® Gel should not be used in combination with erythromycin-containing products due to its clindamycin component. In vitro studies have shown antagonism between these two antimicrobials. the clinical significance of this in vitro antagonism is not known. neuromuscular Blocking Agents Think of me clindamycin has been shown to have neuromuscular blocking properties that may enhance the action Rx onlY of other neuromuscular blocking agents. therefore, Ziana® Gel should be used with caution in patients For topical use only receiving such agents.

InDICATIonS AnD USAGE USE In SPECIFIC PoPUlATIonS Ziana® Gel is indicated for the topical treatment of acne vulgaris in patients 12 years or older. Pregnancy pregnancy category c. there are no well-controlled trials in pregnant women treated with Ziana® Gel. ConTRAInDICATIonS Ziana® Gel should be used during pregnancy only if the potential benefit justifies the potential risk to ® ® the fetus. Ziana Gel was tested for maternal and developmental toxicity in new Zealand White rabbits Ziana Gel is contraindicated in patients with regional enteritis, ulcerative colitis, or history of ® antibiotic-associated colitis. with topical doses of 60, 180 and 600 mg/kg/day. Ziana Gel at 600 mg/kg/day (approximately 12 times the recommended clinical dose assuming 100% absorption and based on body surface area WARnInGS AnD PRECAUTIonS comparison) was considered to be the no-observed-adverse-effect level (noael) for maternal and developmental toxicity following dermal administration of Ziana® Gel for two weeks prior to artificial Colitis insemination and continuing until gestation day 18, inclusive. For purposes of comparisons of the animal systemic absorption of clindamycin has been demonstrated following topical use of this product. exposure to human exposure, the recommended clinical dose is defined as 1 g of Ziana® Gel applied Diarrhea, bloody diarrhea, and colitis (including pseudomembranous colitis) have been reported with the daily to a 60 kg person. use of topical clindamycin. When significant diarrhea occurs, Ziana® Gel should be discontinued. Clindamycin severe colitis has occurred following oral or parenteral administration of clindamycin with an onset of up teratology (segment ii) studies using clindamycin were performed orally in rats (up to 600 mg/kg/ to several weeks following cessation of therapy. antiperistaltic agents such as opiates and diphenoxylate day) and mice (up to 100 mg/kg/day) (583 and 49 times amount of clindamycin in the recommended with atropine may prolong and/or worsen severe colitis. severe colitis may result in death. clinical dose based on a body surface area comparison, respectively) or with subcutaneous doses of studies indicate a toxin(s) produced by clostridia is one primary cause of antibiotic-associated colitis. clindamycin up to 180 mg/kg/day (175 and 88 times the amount of clindamycin in the recommended the colitis is usually characterized by severe persistent diarrhea and severe abdominal cramps and may clinical dose based on a body surface area comparison, respectively) revealed no evidence of be associated with the passage of blood and mucus. stool cultures for Clostridium difficile and stool teratogenicity. assay for C. difficile toxin may be helpful diagnostically. Tretinoin Ultraviolet light and Environmental Exposure in oral segment iii studies in rats with tretinoin, decreased survival of neonates and growth retardation Specifically Designed exposure to sunlight, including sunlamps, should be avoided during the use of Ziana® Gel, and patients were observed at doses in excess of 2 mg/kg/day (~ 78 times the recommended clinical dose assuming with sunburn should be advised not to use the product until fully recovered because of heightened 100% absorption and based on body surface area comparison). susceptibility to sunlight as a result of the use of tretinoin. patients who may be required to have With widespread use of any drug, a small number of birth defect reports associated temporally considerable sun exposure due to occupation and those with inherent sensitivity to the sun should with the administration of the drug would be expected by chance alone. thirty cases of temporally exercise particular caution. Daily use of sunscreen products and protective apparel (e.g., a hat) are 1 associated congenital malformations have been reported during two decades of clinical use of another recommended. Weather extremes, such as wind or cold, also may be irritating to patients under formulation of topical tretinoin. although no definite pattern of teratogenicity and no causal association treatment with Ziana® Gel. with in Mind have been established from these cases, 5 of the reports describe the rare birth defect category, Tolerability holoprosencephaly (defects associated with incomplete midline development of the forebrain). the ADVERSE REACTIonS significance of these spontaneous reports in terms of risk to the fetus is not known. Clinical Studies Experience Because clinical trials are conducted under prescribed conditions, adverse reaction rates observed in Dermal tretinoin has been shown to be fetotoxic in rabbits when administered in doses 40 times the the clinical trial may not reflect the rates observed in practice. the adverse reaction information from recommended human clinical dose based on a body surface area comparison. oral tretinoin has been clinical trials does, however, provide a basis for identifying the adverse reactions that appear to be shown to be fetotoxic in rats when administered in doses 78 times the recommended clinical dose based related to drug use for approximating rates. on a body surface area comparison. • Indicated for the topical treatment of acne vulgaris in patients 12 years or older. the safety data presented in table 1 (below) reflects exposure to Ziana® Gel in 1,853 patients with acne nursing Mothers vulgaris. patients were 12 years and older and were treated once daily for 12 weeks. adverse reactions it is not known whether clindamycin is excreted in human milk following use of Ziana® Gel. However, • Suspended crystalline tretinoin in vehicle designed to deliver the active ingredients to the skin.2 that were reported in ≥ 1% of patients treated with Ziana® Gel were compared to adverse reactions in orally and parenterally administered clindamycin has been reported to appear in breast milk. Because patients treated with clindamycin phosphate 1.2% in vehicle gel, tretinoin 0.025% in vehicle gel, and the of the potential for serious adverse reactions in nursing infants, a decision should be made whether to 1 vehicle gel alone: discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the • Hydrogel alcohol-free aqueous base. mother. it is not known whether tretinoin is excreted in human milk. Because many drugs are excreted in Table 1: Adverse Reactions Reported in at least 1% of Patients Treated human milk, caution should be exercised when Ziana® Gel is administered to a nursing woman. with ZIAnA® Gel: 12-Week Studies ZIAnA® Gel Clindamycin Tretinoin Vehicle Pediatric Use ® Important Safety Information for ZIANA Gel n=1853 n=1428 n=846 n=423 safety and effectiveness of Ziana Gel in pediatric patients under the age of 12 have not been • The most commonly reported adverse events were nasopharyngitis, pharyngolaryngeal pain, dry skin, cough, and sinusitis. n (%) n (%) n (%) n (%) established. patients WitH at least one ar 497 (27) 342 (24) 225 (27) 91 (22) clinical trials of Ziana® Gel included patients 12–17 years of age. nasopharyngitis 65 (4) 64 (5) 16 (2) 5 (1) • Diarrhea, bloody diarrhea, and colitis (including pseudomembranous colitis) have been reported with the use of topical Geriatric Use pharyngolaryngeal pain 29 (2) 18 (1) 5 (1) 7 (2) clinical studies of Ziana® Gel did not include sufficient numbers of subjects aged 65 and over to clindamycin. ZIANA Gel should be discontinued if significant diarrhea occurs. Systemic absorption of clindamycin has Dry skin 23 (1) 7 (1) 3 (<1) 0 (0) determine whether they respond differently from younger subjects. cough 19 (1) 21 (2) 9 (1) 2 (1) been demonstrated following topical use of this product. Manufactured for: sinusitis 19 (1) 19 (1) 15 (2) 4 (1) Medicis, the Dermatology company • If a reaction suggesting sensitivity or chemical irritation occurs, use of the medication should be discontinued. note: Formulations used in all treatment arms were in the Ziana® vehicle gel. scottsdale, aZ 85256 • Avoid exposure to sunlight and sunlamps. Patients with sunburn should not use the product. Use with caution in patients cutaneous safety and tolerance evaluations were conducted at each study visit in all of the clinical trials u.s. patents 5,721,275 and 6,387,383 by assessment of erythema, scaling, itching, burning, and stinging: who require considerable sun exposure due to occupation or who are inherently sensitive to the sun. Avoid excessive exposure Ziana is a registered trademark of Medicis pharmaceutical corporation. to the sun, cold, and wind, which can irritate skin. Daily use of sunscreen and protective clothing are recommended. Table 2: ZIAnA® Gel-Treated Patients with local Skin Reactions prescribing information as of october 2008. local Reaction Baseline End of Treatment 300-13B • Keep away from eyes, mouth, angles of nose, and mucous membranes. n=1835 n=1614 n (%) n (%) • This drug is contraindicated in patients with regional enteritis, ulcerative colitis, or history of antibiotic-associated colitis. erythema 636 (35) 416 (26) scaling 237 (13) 280 (17) • Concomitant use of topical medications with a strong drying effect can increase skin irritation. Use with caution. itching 189 (10) 70 (4) Burning 38 (2) 56 (4) To learn more, contact your Medicis, The Dermatology Company representative. stinging 33 (2) 27 (2) at each study visit, application site reactions on a scale of 0 (none), 1 (mild), 2 (moderate), and 3 (severe), and the mean scores were calculated for each of the local skin reactions. in studies 1 and 2, 1277 subjects enrolled with moderate to severe acne, 854 subjects treated with Ziana® Gel and 423 treated with vehicle. analysis over the twelve week period demonstrated that cutaneous irritation scores for erythema, scaling, itching, burning, and stinging peaked at two weeks of therapy, and were slightly higher for the Ziana®-treated group, decreasing thereafter. one open-label 12-month safety study for Ziana® Gel showed a similar adverse reaction profile as seen See reverse side for a Brief Summary of the Full Prescribing Information. in the 12-week studies. eighteen out of 442 subjects (4%) reported gastrointestinal symptoms. References: 1. ZIANA Gel Package Insert. Scottsdale, AZ: Medicis, The Dermatology Company; October 2008. 2. NDA 50-802 for ZIANA Gel; Sections 4.4.4.1 & 4.2.5. 2006. Data on file, Medicis Pharmaceutical Corporation.

ZIANA is a registered trademark of Medicis Pharmaceutical Corporation. ZNA 12-024 06/30/13 10 BRIEF SUMMARY DRUG InTERACTIonS (see package insert for Full Prescribing Information) Concomitant Topical Medication concomitant topical medication, medicated or abrasive soaps and cleansers, soaps and cosmetics that have a strong drying effect, and products with high concentrations of alcohol, astringents, spices or lime should be used with caution. When used with Ziana® Gel, there may be increased skin irritation. Erythromycin Ziana® Gel should not be used in combination with erythromycin-containing products due to its clindamycin component. In vitro studies have shown antagonism between these two antimicrobials. the clinical significance of this in vitro antagonism is not known. neuromuscular Blocking Agents Think of me clindamycin has been shown to have neuromuscular blocking properties that may enhance the action Rx onlY of other neuromuscular blocking agents. therefore, Ziana® Gel should be used with caution in patients For topical use only receiving such agents.

ZIANA is a registered trademark of Medicis Pharmaceutical Corporation. ZNA 12-024 06/30/13 11 Dermatology Foundation News Release

1560 Sherman Avenue, Evanston, IL 60201-4808 Dermatology Voice: (847) 328-2256 Fax: (847) 328-0509 [email protected] Foundation www.dermatologyfoundation.org Shaping the Future of Dermatology For More Information Contact: News Release Chris Boris - Deputy Executive Director

1560 Sherman Avenue, Evanston, IL 60201-4808 Voice: (847) 328-2256 Fax: (847) 328-0509 [email protected] www.dermatologyfoundation.org led to her study of the physical the Year award in 2004 “in rec- and chemical properties of human ognition of her outstanding role hair with the wool chemists at the as a mentor to residents, derma- USDA’s Wool and Mohair Labora- tologists, other physicians, medical For Immediate Release: April 1, 2013 For More Information Contact: tory in Berkeley. Three years later, students, and undergraduates.” Dr. Chris Boris recognizing that her move was per- Price became an Honorary Mem- Deputy Executive Director manent, Dr. Price resumed clinical ber of the AAD in 2010, as well as dermatology at Kaiser-Permanente several international dermatology in San Francisco. She was encour- societies. Described by a mentee aged to continue hair research stud- as “a very skilled and knowledge- Vera H. Price, M.D. ies in addition to patient care, and able clinician and researcher, and Receives Dermatology Foundation Lifetime Career Educator Award established the UCSF Hair and Nail a wonderful mentor,” Dr. Price Deputy Executive Director Clinic in 1970. During this time she has always loved what she does. Vera H. Price, M.D. taught medical students and resi- Of the awards she has received, At its recent annual meeting of membership in Miami Beach, the Dermatology dents and gave lectures about hair. “the DF Lifetime Career Educator In 1991 Dr. Price joined UCSF’s full- Award is the one that makes me Foundation recognized the tremendous contributionVera Vera H. H. Price, Price, M.D., M.D., has madeReceives to the time faculty, establishing the UCSF most humble. My students inspire specialty of dermatology by honoring her with thDermatologye Lifetime Career EducatorFoundation award. The award Hair Research Center and then a me and keep me on my toes. I honors Dr. Price’s distinguished career and the high standard she has set for the next generation one-year Clinical Hair Research Fel- never stop learning from them.” Lifetime Career Educator lowship allowing her to mentor a of teachers in all areas of dermatology. Award The Dermatology Foundation was young dermatologist annually. With established in 1964 and is the lead- Dr. Vera Price, widely recognized hair exAtpert its and recent Professor annual Emer itusmeeting of Dermatology of at one of her early fellows, Dr. Price ing private funding source for skin coauthored the first textbook on University of California, San Francisco (UCSF),membership has devoted her in career Miami of many Beach, decades the to an disease research. It provides fund- Dermatology Foundation recog- scarring alopecia, Cicatricial Alope- ing that helps develop and retain area of dermatology in which there are few educators.nized Followingthe tremendous her residency, contribution Dr. Price came cia: An Approach to Diagnosis and tomorrow’s teachers and research- to the San Francisco area from Canada for “justVera one year.” H. Price, Because M.D., she lacked has madea California to Management. Since this subject is ers in dermatology, enabling the specialty of dermatology by not covered in most residency pro- advancements in patient care. license, she contacted the UCSF Dermatology Departmenthonoring forher a one-yearwith the research Lifetime position. This grams, she devised a plan to fund led to her study of the physical and chemical propertCareeries of Educator human hair award. with the The wool awardchemists at and donate 600 CDs of the books to residents in the U.S. and Canada. the USDA’s Wool and Mohair Laboratory in Berkeley.honors ThreeDr. Price’s years later, distinguished recognizing that her career and the high standard she Dr. Price’s long list of accomplish- move was permanent, Dr. Price resumed clinicalhas dermatology set for the at Kaiser-Permanente next generation in Sanof ments includes the establishment teachers in all areas of dermatology. of two nonprofit patient organiza- Francisco. She was encouraged to continue hair research studies in addition to patient care, and tions, the National Alopecia Areata established the UCSF Hair and Nail Clinic in 1970.Dr. VeraDuring Price, this time widely she taught recognized medical students Foundation (1981), and the Cicatri- hair expert and Professor Emeritus cial Alopecia Research Foundation of Dermatology at University of Page 1 of 2 (2002). Her contribution to hair California, San Francisco (UCSF), research has been significant. Dr. has devoted her career of many Price described several new hair decades to an area of dermatology disorders, was a founding mem- in which there are few educators. ber of the North American Hair Following her residency, Dr. Price Research Society (1991), and pub- came to the San Francisco area lished well over 130 papers. She from Canada for “just one year.” received the AAD’s Gold Triangle Because she lacked a California Award (1999, 2010) in honor of her license, she contacted the UCSF public outreach, and the Women’s Dermatology Department for a Dermatologic Society’s Mentor of one-year research position. This

12 DERMATOLOGY FOUNDATION NEWS RELEASE Interferon-Gamma-Release Assays A Guide to Clinical Use in Dermatology

Emily Kate Matthews, D.O.,* Robin Shecter, D.O.**

*PGY-4 Dermatology Fellow, PBCGME/Columbia Hospital, West Palm Beach, FL **Program Director, PBCGME/Columbia Hospital, West Palm Beach, FL

INTRODUCTION A staggering one-third of the world’s population is thought to have latent tuberculosis, which is defined as the presence of Mycobacterium tuberculosis in the body without signs, symptoms, radiographic, or bacteriologic evidence of active tuberculosis infection.1,2 An estimated 5-10% of patients with latent tuberculosis infection (LTBI) will progress to active tuberculosis without treatment in their lifetime.2 Perhaps even more alarming is the fact that HIV patients have a 7-10% risk of progression to active tuberculosis per year.2 This is especially relevant in the field of dermatology, as many of the new pharmacologic therapies are effectively treating stubborn chronic dermatoses but at the same time categorizing our patients as chronically immunosuppressed (much like those infected with HIV). In all fields of medicine, the goals of testing for LTBI are to identify those patients who are at increased risk for the development of active tuberculosis, thus enabling early treatment.3

Historical Perspectives noted above.4,8 Table 1 shows QFT-GIT Current Concepts Before 2001, the tuberculin skin test interpretation guidelines. (TST) was the only test available to help To date, both QFT-GIT and T-SPOT. in the identification of Mycobacterium The latest IGRA (and perhaps the most useful TB interferon-gamma release assays are tuberculosis.1 In 2001, the CDC introduced from a dermatological perspective) is the approved by the CDC for the detection of the first in vitro blood test for diagnosis of T-SPOT.TB assay, which was approved for Mycobacterium tuberculosis infections.1 It LTBI: QuantiFERON TB.1 Then in 2005, use in 2008.1 In contrast to the QFT-GIT, this is important to remember, however, that the FDA approved QuantiFERON Gold, new assay is performed by selectively isolating IGRAs do not differentiate latent from active which measured the quantity of IFN-gamma peripheral blood mononuclear cells, which tuberculosis. Therefore, in the face of a released from cells after incubation with two has the tremendous benefit of “normalizing” positive IGRA, one must obtain a detailed antigens seen in Mycobacterium tuberculosis: differences in peripheral white blood cells.5 review of clinical symptomatology, CXR and/ ESAT-6 and CFP-10 (early secretory antigenic This added benefit is vitally important in or CT chest, and sputum gram stain/culture target 6 and culture filtrate protein 10, dermatologic testing, as it theoretically x3 to rule out active tuberculosis.1,3 It is respectively).1 These two antigens are present performs better in patients with compromised also dermatologically relevant to realize that in all Mycobacterium tuberculosis strains, immune systems.5 After the white blood both of these approved tests react to other but are also present in several additional cells are incubated with ESAT-6 and CFP-10, atypical mycobacteria due to the overlap of atypical mycobacteria including M. kansasii, ELISpot (enzyme-linked immunospot assay) is mycobacterial antigens, namely M. kansasii, M. marinum, M. flavescens, and M. szulgai, used to detect individual, activated effector T M. marinum, M. flavescens, M. gordonae, and which can cause release of IFN-gamma cells that secrete IFN-gamma (once stimulated M.szulgai.3,9 Therefore, as dermatologists, (and thus false positive QuantiFERON Gold by the antigens).1,9 Each spot represents “the it may also be prudent to do a thorough results).3 footprint” of an individual IFN-gamma- evaluation for the presence of other atypical secreting T cell, and the results are reported as mycobacteria in the presence of a positive In 2007, a third serum assay was approved the number of spots (see Table 2).1,9 IGRA if clinical suspicion for M. tuberculosis for the identification of Mycobacterium is low. tuberculosis called QuantiFERON Gold- in-Tube (QFT-GIT),3 an-ELISA based test. With the use of ELISA (enzyme-linked immunosorbent assay), three antigens QFT-GIT are used: ESAT-6, CFP-10, and TB7. The quantity of IFN-gamma (released in response to these three antigens) is reported in IU/ ml.3 The testing kit for QFT-GIT contains three heparinized tubes: a control tube (“nil, no antigens”), which determines the patient’s baseline level of IFN-gamma production; a tube containing “mitogen,” which is a stimulant of IFN-gamma production

(and serves as a positive control to ensure Interpretation of QFT-GIT: from Cellestis package insert [8] functioning immune status); and a tube containing the three Mycobacterium antigens Table 1 MATTHEWS, SHECTER 13 Apart from the known overlapping IGRA, without known TB risk factors, likely regard to the practice of dermatology. A environmental mycobacterial antigens have encountered unrecognized TB exposure variety of dermatologic disorders pose a associated with the IGRAs, most of the (raising a very important question: Should the serious challenge due to the increased risk confusion in the medical community definition of TB risk be re-evaluated?). of skin testing anergy. This is due to two regarding testing and interpretation has 5. TST, QFT-GIT, and T-SPOT.TB all main factors: intrinsic primary immune come from multiple trials that have studied seem to be affected by decreased CD4+ dysfunction and secondary immunologic the “concordance” of TST with IGRAs. A counts, resulting in false negative TST, false blockade with the use of immunosuppressant patient may have a negative TST and a positive negative QFT-GIT, and higher numbers of medications. A recent cross-sectional IGRA, or vice versa (disconcordance between indeterminate results with T-SPOT.TB.1 study compared TST with QFT-GIT in tests), because TST and IGRAs are not diagnosing LTBI in patients with chronic interchangeable. TST measures delayed-type 6. Pediatric patients less than 5 years of age inflammatory disease (including rheumatoid hypersensitivity 48-72 hours after placement likely have a lack of immunologic maturity arthritis and spondyloarthropathy). This of a PPD, whereas IGRAs measure the cell- and thus may have a decreased IFN-gamma study also included patients who were mediated immune response by quantifying the response, leading to more indeterminate IGRA using immunosuppressive medications IFN-gamma released (once serum is incubated results. Therefore, TST is still recommended (methotrexate, TNF-alpha inhibitors, 1 with the mycobacterial antigens).1 Thus, the for patients younger than age 5. and leflunomide).6 The results showed two tests are measuring different components 7. In any given patient, there is a fluctuation poor concordance between TST and 1 of the immune response. Other factors that in the IFN-gamma response (and subsequent QFT-GIT in this particular population of play a key role in the disconcordance of results quantity measured), possibly enough to cause chronic-inflammatory-disease patients on 6 include: positive IGRA results to become negative, or chronic immunosuppressive medications. Furthermore, the TST results were 1. Prior BCG vaccination can cause false vice versa, with repeat serial testing. Therefore, significantly suppressed in patients taking positive TSTs. BCG vaccination has no effect there are likely yet-to-be-determined immunosuppressant medications (compared on the results of IGRAs.1 contributing immunologic factors playing a role in the results of and disconcordance to those who were not on immunomodulating 2. Prior positive TSTs affect a patient’s 6 between TST and IGRAs. medications). This raises a still-unanswered immune response with subsequent TST question: Why are dermatologists still using 8. False negative TSTs, as well as falsely (called the “boosting” effect). There is no TST, especially since the vast majority of 1 negative/indeterminate IGRAs, are commonly “boosting” effect with IGRAs. patients being screened for LTBI fall into the seen in patients who are immunosuppressed 3. The presence of non-tuberculosis bacteria category of “chronically immunosuppressed” or who are on long-term immunosuppressant (namely M. kansasii, M. marinum, M. or “currently taking an immunosuppressant treatment.1,6 This adds an extra factor to the medication”? flavescens, and M. szulgai) can all cause dermatologist’s use of IGRAs. false positive results in both TST and IGRAs The flip side of this coin is that with QFT-GIT, The CDC has taken into consideration due to the overlap of antigens in atypical there is a higher number of indeterminant 1 countless studies in its current mycobacteria. results, found especially in patients with recommendations regarding the use of 4. A certain percentage of patients who have lower CD4+ counts; in patients receiving IGRAs, but there are several studies that a negative TST and subsequently a positive chemotherapy; in patients who have been are particularly worth mentioning with previously treated with TNF-alpha inhibitors; and in patients who have lymphocytopenia Nil Panel A Panel B Positive Results What secondary to other immunosuppressive control control does it therapy.6 It was also demonstrated by Soborg (ESAT-6) (CFP-10) mean? (PHA) et al. that treatment with corticosteroids increases the risk for an indeterminant QFT- None or only a >20 spots Both the test and 7 few spots the patient's T GIT. cells are working properly There may be a solution for the use of IGRAs >10 spots <20 spots Indeterminant^^ ^^if panel A or in dermatology. A recent rheumatology article B are positive, compared TST with the T-SPOT.TB assay in then results considered precisely the patient population dermatologists positive commonly encounter.5 A variety of otherwise, immunosuppressed rheumatic-disease indeterminant due to decreased patients (including rheumatoid arthritis, response to SLE, vasculitis, scleroderma, sarcoidosis, control PHA from likely polymyalgia rheumatica, dermatomyositis, abnormal T cells polymyositis, and ankylosing spondylitis) on > (or equal) 6 > (or equal) 6 Positive Tuberulosis a vast array of immunosuppressive therapies spots= (+) spots= (+) (latent or active likely) (including corticosteroids, methotrexate,

< (or equal) 5 < (or equal) 5 Negative Tuberculosis azathioprine, rituximab, TNF-alpha inhibitors, spots= (-) spots= (-) (latent or active and cyclophosphamide) were enrolled in this unlikely) study to compare TST with T-SPOT.TB assay if 5, 6 or 7 spots if 5, 6 or 7 spots Borderline/ Due to biological for detection of M. tuberculosis.5 The findings (close to cut-off) (close to cut-off) equivocal and systemic tseteR .snoitairav tseteR suggest three clinically relevant points: and use clinical evaluation. 1. This immunologically complicated patient Table 2 population all had a strong response to the PHA control in T-SPOT.TB, suggesting that 14 INTERFERON-GAMMA-RELEASE ASSAYS A GUIDE TO CLINICAL USE IN DERMATOLOGY these patients showed a sufficient response IGRA PREFERRED to release of IFN-gamma (despite being immunosuppressed).5 HISTORHISTORYY OF BCG VACCINAVACCINATIONTION 2. There were more false negative results with TST, likely due to skin anergy in immunocompromised patients.5 HISTORHISTORYY OF (+) PPD 3. There were more false positive results with T-SPOT.TB assay, which may indicate a HISTORHISTORYY OF CHEMOTHERAPYCHEMOTHERAPY reaction to other atypical mycobacteria (from cross-reacting antigens).5 UNABLE TTOO RETURN FOR PPD ANALYSISANALYSIS With all of the above in mind, one can take a more educated look at the updated CDC TST PREFERRED recommendations for the use of IGRAs. In general, the CDC recommends that “an IGRA CHILDREN <5 (BUTBUT CAN USE BOTH TTOO INCREASE DIAGNOSTICDIAGNOSTIC SENSITIVITY) may be used in place of (but not in addition to) TST in all situations where diagnosing M. tuberculosis infection is needed and relevant.”1 IGRA OR TST CAN BE USED There are, however, several “special situations” delineated by the CDC (see Table 3), and the SCREENING OF HEALTHHEALTH CARE WORKERSWORKERS dermatology field needs further dermatologic, clinical, outcome-based studies that take them RECENT EXPOSURE (TEST ATAT TIME OF EXPOSURE, THEN REPEATREPEAT AT 8-10 WEEKS into account. AFTER EXPOSURE) Regardless of results, if a patient has symptoms of TB (even with a negative IGRA), the IGRA (+) TST AATT THE SAME TIME patient should be treated for latent (or active) 1 tuberculosis. IF INITIAL IGRA IS "INDETERMINANT""INDETERMINANT" (EITHER REPEATREPEAT IGRA OR DO TST

Even with additional clinical studies, and even AT SAME TIME) with access to elaborate laboratory technology, physicians must always remember to stress the IF INITIAL TST IS POSITIVE, AND PATIENT WWANTSANTS importance of a complete history and physical "CONFIRMATION""CONFIRMATION" in diagnosis and treatment. IF EITHER INITIAL TEST IS (-) AND STILL HIGH SUSPICION References 1. Mazurek GH, Jereb J, Vernon A, LoBue Adapted from CDC updated guidelines [1] P, Goldberg S, Castro K. Updated Guidelines for Using Interferon-Gamma- Release Assays to Detect Mycobacterium Tuberculosis Infection Among 9. T-SPOT.TB assay package insert: Oxford tuberculosis infection- United States, Rheumatic Disease Patients on Immunotec. Accessed on 4/19/12 via 2010. CDC MMWR. June 25, 2010. Immunosuppressive Therapy. The www.oxfordimmunoteccom/96-UK. 59;RR-5:1-28. Journal of Rheumatology 2009;36:546- 551. 2. Latent Tuberculosis Infection: A guide for primary healthcare providers. United 6. Gogus F, Gunendi Z, Karakus R, States Department of Health and Human Erdogan Z, Hizel K, Atalay F. Services, CDC; developed in partnership Comparison of tuberculin skin test and with New Jersey Medical School Global QuantiFERON-TB gold in tube test in Tuberculosis Institute 2010. Accessed patients with chronic inflammatory via CDC on 3/29/12. diseases living in a tuberculosis endemic population. Clinical Experimental 3. Pai M, Menzies D. Interferon-gamma- Medicine 2010;10:173-177. release assays for latent tuberculosis infection. UpToDate. Accessed on 7. Soborg B, Ruhwald M, Hetland ML, et 3/19.12 via VA West Palm Beach library. al. Comparison of Screening Procedures for Mycobacterium tuberculosis 4. Miranda C, Tomford JW, Gordon SM. Infection Among Patients with Interferon-gamma-release assays: Better Inflammatory Diseases. The Journal of than tuberculin skin testing? Cleveland Rheumatology 2009;36:1876-1884. Clinic Journal of Medicine. 77;9:606-611. September 2010. 8. QFT-GIT package insert: Cellestis. Accessed on 4/19/12 via www. 5. Behar SM, Shin DS, Maier A, Coblyn J, cellestis.com/IRM/COMPANY/ Helfgott S, Weinblatt ME. Use of showpage.ASPX?CPID=1370. the T-SPOT.TB Assay to Detect Latent

MATTHEWS, SHECTER 15 Henoch-Schönlein Purpura in an Adult Patient

G. Trey Haunson, D.O.,* Daniel S. Hurd, D.O., F.A.O.C.D.**

*PGY-2 resident, LewisGale Hospital Montgomery, Blacksburg, VA

**Program director, LewisGale Hospital Montgomery, Blacksburg, VA

Case Report Our dermatology service was consulted to evaluate a 41-year-old Caucasian male who was admitted with a chief complaint of a “burning rash” on the legs. The patient stated his cutaneous symptoms began about one to two weeks prior to admission, with lesions appearing on the lower legs and then progressing to involve the thighs, buttocks and abdomen. He described associated burning, itching and new-onset lower-extremity swelling. He was previously healthy, his only medicine being a non-steroidal anti- inflammatory agent, nabumetone, which he had taken as needed for several years for chronic low back pain. He denied any recent change in dosage or frequency of use. Prior to admission, the patient was started on 40mg of oral prednisone daily and a 10-day course of oral amoxicillin by his primary care physician. On further questioning, he admitted to experiencing flu-like symptoms consisting of fatigue, body aches, chills and sore throat Figure 1 Bilateral lower extremities with symmetrically-distributed non-blanching three to four weeks prior to admission. He petechiae, palpable purpura and confluent areas of ecchymoses did not experience a cutaneous eruption at that time. He denied any current fever, palms, soles, upper trunk, upper extremities, collection of neutrophils with karyorrhexis chills, abdominal pain, nausea, vomiting, head, neck, mucous membranes and nails surrounding dermal capillaries and post- diarrhea, hematochezia, melena, hematuria or were spared. The differential diagnosis capillary venules. Extravasated erythrocytes, dysuria. He admitted to stable low-back pain at this point included HSP, other forms of fibrin deposits and loss of endothelial cells secondary to arthritis, but denied any new leukocytoclastic vasculitis, and erythema were noted. These findings were consistent arthralgia. He had no past surgical history or multiforme. with a small-vessel leukocytoclastic vasculitis. known allergies. Further examination with DIF revealed Routine labs were unremarkable. A CBC with rings of IgA, C3 and fibrin deposits around On physical examination, vital signs were differential was within normal limits with superficial and mid-dermal capillaries, within normal limits, as they had been the exception of a slightly elevated neutrophil consistent with an IgA-mediated vasculitis. since admission. Examination of the count, which was attributed to the patient lower extremities revealed 1+ non-pitting having taken prednisone. Platelets and The clinical, laboratory and pathologic edema. An impressive dermatitis affecting coagulation studies were within normal limits. findings were consistent with a diagnosis the symmetric bilateral lower legs, thighs, A CMP including liver and renal function of HSP. We recommended completion of buttocks, groin, and lower abdomen was easily tests was within normal limits. A urinalysis the patient’s course of amoxicillin. We also appreciated, consisting of non-blanching revealed no evidence of proteinuria or increased the patient’s dose of prednisone to petechiae, larger areas of palpable purpura microscopic hematuria. Anti-streptolysin O 100mg daily for two weeks with a slow taper and confluent areas of ecchymoses (Figure (ASO) and anti-DNase B titers were negative. over an additional six weeks. The patient 1). Some of the larger purpuric lesions experienced cutaneous flares once to twice Two 4mm punch biopsies were taken contained central hemorrhagic vesicles weekly as the prednisone was tapered down, from the right upper thigh. One was sent and bullae (Figure 2). Some of the lesions but otherwise experienced no adverse effects. for routine processing with H&E staining appeared targetoid and erythema multiforme- A glucose-6-phosphate dehydrogenase and the other for examination with direct like (Figure 3). The lesions were confined (G6PD) level was found to be within normal immunofluorescence (DIF). The epidermis to the lower half of the body, with no lesions limits, and treatment with dapsone was showed mild spongiosis. The dermis was apparent above the level of the umbilicus. The initiated at a dose of 50mg daily. remarkable for a superficial and mid-dermal 16 HENOCH-SCHÖNLEIN PURPURA IN AN ADULT PATIENT The etiology of HSP is unclear, but has been reported to be associated with numerous infections, medications, vaccinations, malignancies, and inherited conditions (Table 1).5 In spite of these many associations, no precipitating cause is ever found in the majority of children and adult patients. Children often present one to two weeks following an upper-respiratory-tract infection. A minority of HSP patients have positive ASO titers, though no causative role for group A β-hemolytic streptococci has been established.3 It is thought that antigens produced through these various processes stimulate the production of immunoglobulins, mostly IgA1. Antigen-antibody complexes are subsequently formed, as in other forms of cutaneous small-vessel vasculitides. IgA1 levels are found to be increased both in circulation and in deposits in vessel walls of the skin, kidneys and GI tract. Immune- complex deposition in vessel walls results in activation of the alternate complement pathway, causing inflammatory cell activation Figure 2 Palpable purpura with central hemorrhagic vesicles and bullae and recruitment and ultimately resulting in vascular damage.6 The role of complement is further supported by reports of HSP in patients with inherited deficiencies of C2 and C4, as these molecules are believed to play a role in the clearance of immune complexes and/or antigens from apoptotic cells.7 Clinically, HSP presents as an acute-onset of the classic tetrad of intermittent palpable purpura on the buttocks and extensor extremities, abdominal pain, arthralgias, and nephritis. Cutaneous lesions begin as macular erythematous papules that may resemble urticaria. They progress to non-blanching petechial pinpoint macules and purpuric papules. Lesions may coalesce into larger ecchymotic areas. Urticaria, hemorrhagic vesicles or bullae, and necrotic foci may be seen. Lesions are symmetrically distributed and commonly involve the buttocks and lower extremities. Rarely, lesions can occur on the upper extremities and face. The trunk is typically spared, but when involved is predictive of renal involvement. Individual lesions typically regress within 10-14 days. Complete cutaneous resolution typically Figure 3 - Targetoid lesions suggestive of erythema multiforme occurs over weeks to months. Lesions tend to fade more quickly with bed rest and may recur At the time of this writing, our patient was delayed-onset renal insufficiency and more frequently with ambulation.1,2 first seen by our service about three months hematuria. ago and has been off of corticosteroids for the Common symptoms to specifically inquire Discussion last six weeks. His cutaneous symptoms are about in the review of systems include colicky being controlled with dapsone, with plans to HSP is most commonly seen in children abdominal pain, nausea, vomiting, melena, increase the dosage as needed and as tolerated. less than 10 years of age, with a peak age of hematochezia, arthralgia, and dependent He still experiences intermittent cutaneous onset of 4-7 years. It is the most common edema. Fever occurs in 20% of adults and flares, but they are declining in frequency form of vasculitis in children. Adults have 40% of children, while 40-60% of patients and severity. He has been referred back to his a much lower incidence of 3-14 per million experience GI symptoms. Abdominal primary care physician with recommendations versus 135-180 per million in children. Peak symptoms occur more commonly in children, for monthly blood work and urinalysis for incidence occurs in the winter and spring, and occasionally complicated by intussusception. 1,2,3,4 the next 12 months to monitor for potential there is a slight male predominance. Abdominal pain is also a significant predictor

HAUNSON, HURD 17 Tables

Table 1: Possible triggers associated with HSP* of nephritis. GI bleeding, if it occurs, is typically self-limited and does not require (Not a comprehensive list) blood transfusions. Rare GI manifestations include intestinal perforation, pancreatitis, Bacterial infections: Medications: pseudomembranous colitis, acute acalculous • Group A beta hemolytic • Non-steroidal anti- cholecystitis, hemorrhagic ascites with streptococci inflammatory agents serositis, and biliary cirrhosis. In one- • Staphylococcus aureus • Angiotensin-converting- fourth of patients, GI symptoms appear • Helicobacter pylori enzyme inhibitors prior to cutaneous lesions, and HSP should • Mycoplasma • Angiotensin II receptor be considered in the differential of an acute antagonists abdomen, especially in children.1,2,5,8 Viral infections: Vancomycin • A non-migratory arthralgia is described in • Hepatitis A, B, E • Cefuroxime greater than 80% of patients, and is more • Herpes simplex • Quinolones commonly seen in adults. Joint pain is most • Parvovirus B19 • Clarithromycin likely the result of periarticular edema rather • Coxsackievirus • Acetaminophen than actual inflammatory arthritis of the • Varicella • Codeine joint space. Typically involved joints include • Adenovirus • Etanercept the ankles, knees, dorsal hands and feet. • Cytomegalovirus • Ranitidine Arthralgias may precede the appearance of • Human immunodeficiency • Streptokinase cutaneous findings and can be incapacitating, virus but are non-destructive and respond to non- Malignancies: steroidal anti-inflammatory agents.1,2,9 Parasites: • Non-small cell lung cancer Renal involvement is common, but usually Toxocara canis Prostate cancer • • mild and self-limited, most often consisting Lymphoma • of microscopic hematuria and minimal Vaccinations: Multiple myeloma • proteinuria. However, gross hematuria can • MMR (Measles, Mumps, occur. Nephritis occurs in 20-50% of children, Rubella) Inherited: and usually occurs within the first three weeks • Pneumococcal • α1-antitrypsin deficiency of disease onset. Adult patients experience • Influenza • Familial Mediterranean fever more frequent and severe renal involvement, • Meningococcal • HLA-DRB1*01 with 10-20% experiencing renal failure versus • Hepatitis B • HLA-B35 1% in children.8 A recent history of infection, pyrexia, purpura involving the trunk, and *Adapted from Sohagia et al.5 elevated erythrocyte sedimentation rate (ESR) are all predictive of renal involvement. Table 2: Nephritis may also be delayed for weeks to months following symptom onset. Differential diagnosis of palpable purpura and plaques* Progression to nephritic syndrome as well as acute crescentic glomerulonephritis and Arthropod bites chronic renal failure is possible.1,2 Morbilliform drug eruptions with hemorrhage in dependent sites Acute scrotal swelling may be the presenting Erythema multiforme manifestation in up to 15% of boys younger Pityriasis lichenoides et varioliformis acuta than 17 years of age with HSP. Ultrasound is useful to differentiate from surgical Infectious emboli (septic vasculitis): emergencies such as testicular torsion or Infective endocarditis incarcerated inguinal hernia. Other rare Neisseria meningococcus in acute meningococcemia manifestations of HSP include involvement of Rickettsiae the central and peripheral nervous systems, pulmonary system, and genitourinary tract.2 Fungi (e.g., Rhizopus) The differential diagnosis includes other Lichenoid capillaritis (pigmented purpura) entities presenting with palpable purpuric Papular urticaria papules and plaques (Table 2). Evidence of Systemic lupus erythematosus medium-sized vessel disease (e.g., livedo Dermatitis herpetiformis reticularis) or widespread lesions (e.g., involving the face) may indicate an underlying Acute hemorrhagic edema of infancy IgA paraproteinemia.2 Idiopathic thrombocytopenic purpura Children who present with palpable purpura, Thrombotic thrombocytopenic purpura typical internal manifestations, and without Atypical cellulitis thrombocytopenia may be diagnosed clinically (Table 3). In atypical cases, such as the adult patient lacking systemic features, a tissue 1 *Adapted from Bolognia biopsy is helpful in confirming the diagnosis.

18 HENOCH-SCHÖNLEIN PURPURA IN AN ADULT PATIENT

Table 3: Diagnostic criteria for HSP*

Required criterion • Palpable purpuric eruption

Additional criteria (at least one is required) • Diffuse abdominal pain • Arthralgia • Nephritis (hematuria or proteinuria) • Histological evidence of IgA deposits in arterioles, capillaries and venules of the skin, kidneys or gastrointestinal tract

*Adapted from Lawee8 Table 2: Differential diagnosis of palpable purpura and plaques*

Arthropod bites Morbilliform drug eruptions with hemorrhage in dependent sites Erythema multiforme Pityriasis lichenoides et varioliformis acuta Infectious emboli (septic vasculitis): Infective endocarditis Neisseria meningococcus in acute meningococcemia Rickettsiae Fungi (e.g., Rhizopus) Lichenoid capillaritis (pigmented purpura) Papular urticaria Systemic lupus erythematosus Dermatitis herpetiformis Acute hemorrhagic edema of infancy Idiopathic thrombocytopenic purpura Thrombotic thrombocytopenic purpura Atypical cellulitis

*Adapted from Bolognia1

Table 3: Diagnostic criteria for HSP* In a case such as ours, cutaneous punch biopsies should be sent for lesional H&E and perilesional DIF. Additional confirmatory Required criterion laboratory studies should include a normal platelet count and coagulation studies to exclude thrombocytopenic processes and • Palpable purpuric eruption coagulopathies, respectively. It is also necessary to perform a urinalysis to evaluate for microscopic hematuria and proteinuria, Additional criteria (at least one is required) and BUN and creatinine levels to evaluate for renal insufficiency. If abdominal pain is present, a normal lipase level makes pancreatitis Diffuse abdominal pain • unlikely. An elevated ESR correlates with more severe renal • Arthralgia involvement. Though not routinely checked, serum IgA levels • Nephritis (hematuria or proteinuria) would be elevated and C3/C4 levels would be depressed. ANA, serum immunoelectrophoresis, ANCA testing, C3 and C4 levels, • Histological evidence of IgA deposits in and genetic typing may be performed if overlap syndromes are arterioles, capillaries and venules of the skin, suspected (Table 4). CBC is typically normal.1 kidneys or gastrointestinal tract Other studies not routinely ordered include abdominal ultrasound if gastrointestinal involvement is suspected and also to evaluate *Adapted from Lawee8 for intussusception. Routine abdominal radiographs are not recommended unless there is clinical suspicion for bowel perforation. A stool guaiac test might reveal an occult GI bleed, but Table 4: Laboratory studies may be of minimal clinical utility in the adult patient and as such is to consider in suspected HSP not routinely performed. Upper gastrointestinal endoscopy may be useful in demonstrating erythema, edema, petechiae, hemorrhage, erosions or ulcerations of the mucosa. Mucosal biopsies, if taken, Required would also show capillary deposition of IgA. Renal biopsy would • Platelet count also show the presence of IgA in the renal glomeruli.2,5 • Coagulation studies Histologically, HSP manifests as leukocytoclastic vasculitis of UA • the small blood vessels (arterioles, capillaries, and post-capillary • BUN and creatinine venules) of the upper to mid-dermis. The typical constellation of findings includes a perivascular infiltrate with neutrophils, Elective neutrophil degeneration (leukocytoclasis) with nuclear dust, • Lipase fibrinoid necrosis of the vessel walls with fibrin deposition, • ESR and extravasated erythrocytes. DIF demonstrates perivascular deposits of IgA, C3 and fibrin in the walls of these vessels. Other • Serum IgA immunoglobulins may be seen to a lesser extent than IgA. • ANA However, intravascular IgA deposits are not specific to HSP and • Serum immunoelectrophoresis may also be seen in venous stasis, erythema nodosum, autoimmune • ANCA connective-tissue diseases, acute hemorrhagic edema of infancy, 10 • C3 and C4 levels Wegener’s granulomatosis, and drug-hypersensitivity reactions. Clinical correlation is therefore required to make the diagnosis. Treatment is mainly supportive, utilizing acetaminophen and nonsteroidal anti-inflammatory agents, as the symptoms of HSP are Table 5: Criteria for nephritic and nephrotic syndromes typically self-limited with spontaneous resolution occurring over weeks to months. More aggressive management depends largely Nephritic Syndrome on the severity of renal involvement, which is more commonly • Required seen in adult patients. Controversy exists surrounding the use of o Hematuria (usually with dysmorphic RBCs) more aggressive therapy, including systemic corticosteroids and/ o Urinary sediment with RBC casts or cytotoxic agents (such as cyclophosphamide, cyclosporine or • Additional Features azathioprine), in patients with severe renal vasculitis in order to 9,11 o Mild to moderate proteinuria (< 3g in 24 hours) prevent progression to chronic renal failure and hypertension. o Edema Systemic corticosteroids are also effective in treating the arthralgia o Hypertension and abdominal pain associated with HSP as well as reducing the o Elevated serum creatinine duration of cutaneous involvement; however, they do not prevent 12 o Oliguria (< 400 mL in 24 hours) recurrences of new lesions. Dosing is typically 1-2mg/kg of prednisone or methylprednisolone daily for two weeks with a slow taper. Children treated with prednisone for a course of two to four Nephrotic Syndrome weeks have exhibited more rapid resolution of skin lesions, renal • Proteinuria ( > 3.5 g in 24 hours) disease, and arthralgia as well as improvement of abdominal pain; Hypoalbuminemia • however, the risk of developing nephritis over a follow-up period of Edema • six to 12 months was not reduced.12,13 Dapsone and colchicine have • Hyperlipidemia been reported to decrease the duration of cutaneous lesions.14,15 • Lipiduria Factor XIII infusions have been shown to improve arthralgias and • Hypercoagulability gastrointestinal bleeding.16 Several small case series have suggested beneficial effects of plasmapheresis, aminocaproic acid, and HAUNSON, HURD 19 Table 6 – Predictors of significant chronic renal disease (Adapted from Sohagia5) Gastroenterology Research and Practice. Predictors of significant chronic renal disease 2010; Article ID 597648:1-7. 6. Kawana S, Shen GH, et al. Membrane attack complex of complement in Pyrexia Henoch-Schönlein purpura skin and Arterial hypertension nephritis. Arch Dermatol Res. 1990; Purpura above the waist 282:183-7. Hematuria or anemia at onset 7. Stefansson TV, Kolka R, et al. Increased High creatinine levels at onset frequency of C4B*Q0 Alleles in patients Presenting with nephritic or nephrotic syndrome with Henoch-Schönlein purpura. Scand Proteinuria >1g/day J Immunol. 2005; 61:274-8. Elevated ESR 8. Lawee D. Atypical clinical course of Renal biopsy showing high percentages of sclerotic Henoch-Schönlein purpura. Canadian glomeruli, interstitial fibrosis and fibrinoid sclerosis Family Physician. 2008; 54:1117-20. Persistent purpura 9. Blanco R, Martinez-Taboada VM, et Progressively increased proteinuria during follow-up al. Henoch-Schönlein purpura in adulthood and childhood: two different expressions of the same syndrome. Arthritis Rheum. 1997; 40:859-64. 10. Magro CM, Crowson AN. The intravenous immunoglobulin.17,18,19 have more severe long-term complications. cutaneous neutrophilic vascular injury The prognosis depends mainly on the Outcomes are typically favorable for both syndromes: a review. Semin Diagn extent of renal involvement and its course, children and adult patients. Complete Pathol. 2001; 18:47-58. recovery is expected in 94% of children and which may be delayed in appearance. The 11. Kawasaki Y, Suzuki J, Suzuki H. 89% of adults. One-third of patients have factors that portend a poorer prognosis have Efficacy of methylprednisolone and relapses, which are milder and shorter in been discussed, and the need for continual urokinase pulse therapy combined duration, for several months.5 Five percent follow-up and laboratory monitoring even in with or without cyclophosphamide in to 10% of patients experience cutaneous the absence of initial internal involvement is severe Henoch-Schönlein nephritis: a recurrences.20 Renal involvement determines again restated. clinical and histopathological study. long-term prognosis. Two percent of patients Our patient was an adult male with a Nephrol Dial Transplant. 2004; 19:858- will develop chronic renal impairment, and cutaneous eruption typical for HSP; however, 64. this risk is 10-fold greater in patients who typical systemic signs and symptoms of HSP present with nephritic or nephrotic syndrome were lacking, necessitating a skin biopsy for 12. Ronkainen J, Koskimies O, et al. Early (Table 5). Adults are also more likely than confirmation of the diagnosis. Our patient prednisone therapy in Henoch- children to develop significant chronic renal continues to lack any detectable sign of renal Schönlein purpura: a randomized, disease, especially if they experience pyrexia, involvement, but will need to be followed double-blind, placebo-controlled trial. J arterial hypertension, purpura above the waist, to monitor for delayed-onset nephritis. Of Pediatr. 2006; 149:241-7. hematuria/anemia at onset, high creatinine interest, our patient did have a possible recent 13. Huber AM, King J, et al. A randomized, levels at disease onset, proteinuria >1g/day, history of upper respiratory infection and was placebo-controlled trial of prednisone in an elevated ESR, renal biopsy showing high on chronic NSAID therapy, both counted as early Henoch-Schönlein purpura. BMC percentages of sclerotic glomeruli, interstitial possible triggers for HSP. Med. 2004; 2:7. fibrosis and fibrinoid sclerosis, persistent purpura, and/or progressively increased 14. Iqbal H, Evans A. Dapsone therapy for proteinuria during follow-up (Table 6). References Henoch-Schönlein purpura: a case series. Arch Dis Child. 2005; 90:985-6. Urinary abnormalities may persist for two 1. Bolognia JL, Jorizzo JL, et al. to five years in patients who develop acute Dermatology. 2nd edition. Elsevier; 15. Saulsbury FT. Henoch-Schönlein nephritis. When HSP presents with more 2008. purpura in children: report of 100 than just microscopic hematuria, only 72% of patients and review of the literature. 2. Habif TP. Clinical Dermatology: A cases proceed to complete recovery. Evidence Medicine (Baltimore). 1999; 78:395-409. color guide to diagnosis and therapy. 5th of renal disease may reappear after apparent edition. Elsevier; 2010. 16. Fukui H, Kamitsuji H, et al. Clinical complete recovery, so long-term follow-up is evaluation of a pasteurized factor XIII necessary. Monthly urinalysis for at least 12 3. Gonzalez-Gay MA, Garcia-Porrua C. concentrate administration in Henoch- months is recommended.9,21,22,23 Children and Systemic vasculitides. Best Pract Res Schönlein purpura. Japanese Pediatric young adults with a history of HSP may also Clin Rheumatol. 2002; 16:833-45. Group. Thromb Res. 1989; 56:667-75. be at increased risk for pregnancy-induced 4. Watts RA, Lane S, Scott DG. What 17. Hattori M, Ito K, et al. Plasmapheresis hypertension and/or proteinuria, and should is known about the epidemiology of the 2 as the sole therapy for rapidly progressive be counseled and evaluated accordingly. vasculitides? Best Pract Res Clin Henoch-Schönlein purpura nephritis in Conclusion Rheumatol. 2005; 19:191-207. children. Am J Kidney Dis. 1999; HSP is typically a vasculitis of childhood 5. Sohagia AB, Gunturu SG, et al. Henoch- 33:427-33. with an excellent prognosis; however, it rarely Schönlein purpura - a case report and 18. Prandota J, Pankow-Prandota L, Kotecki occurs in adults, and in those cases it can review of the literature. L. Impaired activation of the fibrinolytic

20 HENOCH-SCHÖNLEIN PURPURA IN AN ADULT PATIENT system in children with Henoch- Schönlein purpura: beneficial effect of A Case Report: hydrocortisone plus sigma-aminocaproic acid therapy on disappearance rate of The Use of Glycopyrrolate in Aquagenic cutaneous vasculitis and fibrinolysis. Wrinkling of the Palms Am J Ther. 2001; 8:11-19. 19. Rostoker G, Desvaux-Belghiti D, et al. High-dose immunoglobulin therapy Helia Eragi, D.O.,* Mayha Patel, B.S., MSIV,** David Horowitz, D.O., F.A.O.C.D.*** for severe IgA nephropathy and Henoch- * PGY3, Second-year Dermatology Resident, Pacific Hospital Long Beach/Western University, Long Schönlein purpura. Ann Intern Med. Beach, CA 1994; 120:476-84. ** Fourth-year Medical Student, Western University of Health Sciences, Pomona, CA 20. Fiorentino DF. Cutaneous vasculitis. J Am Acad Dermatol. 2003; 48:311-40. *** Dermatology Residency Program Director, Pacific Hospital of Long Beach/Western University, 21. Meiller MJL, Cavallasca JA, et al. Long Beach, CA

Henoch-Schönlein purpura in adults. Clinics. 2008; 63(2):273-6. INTRODUCTION 22. Pillebout E, Thervet E, et al. Henoch- Aquagenic wrinkling of the palms (AWP), also referred to as transient reactive Schönlein purpura in adults: outcome papulotranslucent acrokeratoderma, is a rare condition that mainly affects adolescents and prognostic factors. J Am Soc and young women. It often occurs after just three minutes of immersion in water Nephrol. 2002; 13: 1271–1278. in patients with cystic fibrosis or those who are carriers of the cystic fibrosis gene.1 23. Tancrede-Bohin E, Ochonisky S, et al. Normally, wrinkling of the palmar skin is seen after an average of 11 minutes of Schönlein-Henoch purpura in immersion in water. AWP has also been linked to COX-2 inhibitor use. We present a adult patients: predictive factors for IgA case of persistent, painful aquagenic wrinkling of the palms in a young female with no glomerulonephritis in a retrospective history of cystic fibrosis. study of 57 cases. Arch Dermatol. 1997; 133:438-42.

Figures 1-2: Initial patient presentation

CASE REPORT A 13-year-old female presented with a history erythematous macules and wrinkling of the of painful aquagenic wrinkling and edema of palms and digits (Figures 1-2). The patient’s the palms that began when she was younger, palms were also hyperhidrotic and slightly as intermittent episodes with exposure to tender to palpation. water, and thereafter became a chronic problem. She described her lesions as non- F i g u r e s 1 - 2 : I n i t i a l p a t i e n t p r e s e n t a t i o n pruritic, edematous and painful, and denied The patient was treated with glycopyrrolate involvement of her soles. Review of systems 1mg PO BID for one month and had improved was negative for diarrhea, acholic stools, significantly when seen for follow-up. There pneumonia, wheezing, palmar hyperhidrosis, was a 75% decrease in erythema, swelling and nasal polyps, poor growth, and pancreatic pain. insufficiency. Family history was negative for cystic fibrosis (CF) and excessive palmar Figures 3-4: Post-treatment demonstrates wrinkling. The patient denied any use of marked reduction in wrinkling, swelling and cyclooxygenase (COX-2) inhibitors such as pain. rofecoxib, celecoxib or aspirin. Discussion On physical exam, the patient had erythema Aquagenic wrinkling of the palms (AWP) is and swelling of palmar hands with small a rare condition that mainly affects young women. It presents with exaggerated wrinkling

ERAGI, PATEL, HOROWITZ 21 ducts, causing AWP. In the literature, there have been approximately 100 reported cases of associations between CF and AWP.2 Other contemporary theories for AWP include a weakness of the eccrine-duct wall, defective stratum-corneum barrier function, or occlusion of the eccrine-duct ostia.2 Drug-induced cases of AWP are known to be caused by the use of aspirin and rofecoxib.4 The most recent speculation regarding mechanism is COX-2 inhibition. COX-2 inhibition prevents the down-regulation of many renal water- and sodium-transport proteins also in keratinocytes. Therefore, this protein, when inhibited by aspirin and rofecoxib, leads to an increase in the sodium retention of these cells, causing increased water retention and wrinkling of the palms.4 Histological studies show a hyperkeratotic, dilated eccrine ostia and a hyperkeratotic stratum corneum. In addition, an aberrant aquaporin-5 expression is seen.5 The association of AWP with cystic fibrosis, and cyclooxygenase-2 inhibitors, suggests that exposure of the skin to abnormally high concentrations of salt may play a role in AWP’s pathogenesis. It is important to recognize this association. In a patient with a CF gene mutation, there might be a lower threshold for developing AWP when taking certain medications such as aspirin or rofecoxib. In addition, in children and adolescents with forms of CF that might have previously gone unnoticed, recognition of this cutaneous manifestation may be the only sign of an underlying mutation. Patients presenting with AWP should be offered screening for both CF and the carrier state.6 Treatment Treatment for AWP is aimed at decreasing the hyperkeratosis and providing a water barrier to prevent exposure. Some patients have reported improvement with 12% Figures 3-4: Post-treatment demonstrates ammonium lactate creams, petroleum jelly and glycopyrrolate 1mg PO daily. of the palms with sharply demarcated small, a salt imbalance in the skin cells, which Other treatments include iontophoresis, white-to-translucent papules following brief results in increased water retention within antihistamines and acetic acid, but these immersion in water.1 Patients may experience these cells. The high salt concentration in have been shown to have only limited effects. pain, edema, discomfort, tingling, numbness, the epidermis, as seen in CF patients, causes Using 20% aluminum chloride applied pruritus or a burning sensation during an an increase in the water-binding capacity of nightly to the palms results in the most episode.1 In most cases, the palmar skin keratin. Another proposed theory links the effective, rapid improvement of symptoms.7 returns to normal within a few hours after etiology of AWP to an abnormal regulation Glycopyrrolate has also been shown to have exposure to water. Plantar involvement of the of a cell-membrane water-channel protein a significant effect on AWP. It works as hands is not observed in AWP; however, the in the CFTR gene called aquaporin 5.3 an anticholinergic drug, reducing certain soles of the feet may be involved. Other recent theories explain AWP in CF as secretions in different organs in the body. The clinical findings associated with AWP originating from a dysfunction of the specific Oral glycopyrrolate tablets are very safe, and were first described in 1974 by R.B. Elliot, protein channel TRPV4 produced in human by blocking the actions of acetylcholine can who observed excessive skin wrinkling upon keratinocytes. The function of this protein help to reduce the stimulation of sweat glands exposure to water in children with cystic channel is to regulate the effect of cell-volume in the hands. fibrosis (CF). The majority of reported cases swelling due to osmosis. In persons with CF, Genetic testing was not recommended in of AWP have been associated with cystic the activation of the TRPV4-channel protein our patient due to the negative family history fibrosis, a mutation in the CFTR gene.2 in keratinocytes is impaired, which leads of CF and lack of associated symptoms. There are several theories for the etiology to the inability of the cells to monitor the However, with the diagnosis of AWP, the of AWP. One theory states it is caused by normal influx of water through the eccrine clinician should always further investigate the 22 A CASE REPORT: THE USE OF GLYCOPYRROLATE IN AQUAGENIC WRINKLING OF THE PALMS patient’s family history and possible symptoms of CF, in addition to any medications used. An Intertriginous and Flexural Exanthem: Had there been a positive history and physical of a possible CF gene mutation, genetic testing Case Report and Drug-Eruption Review and counseling would have been discussed and highly recommended. Jonathan D. Richey, DO, MHA,* Monica Nafsou, DO,** Annette LaCasse, DO, FAOCD***

References *Dermatology Resident, 2nd Year, Pontiac/Botsford Hospital Dermatology Residency Program, 1. Halsey MA, Johnston RB Jr, Shenefelt Farmington Hills, MI PD. A 16-year-old with white plaques on the palms. Aquagenic wrinkling of **Intern, St. Joseph Mercy Hospital, Pontiac, MI the palms (AWP). Arch Dermatol. 2011 May; 147(5):609-14. ***Program Director, Pontiac/Botsford Hospital Dermatology Residency Program, Farmington Hills, MI 2. Gild R, Clay CD. Aquagenic wrinkling of the palms in a cystic fibrosis carrier. Australas J Dermatol. 2008 Feb; 49(1):19-20. 3. Kabashima K, Shimauchi T, Kobayashi M, et al. Aberrant aquaporin 5 expression in the sweat gland in aquagenic wrinkling of the palms. J Am Acad Dermatol. 2008 Aug; 59(1):28-32. 4. Carder KR, Weston WL. Rofecoxib- induced instant aquagenic wrinkling of the palms. Pediatr Dermatol 2002 Aug; 19(4):353-5. 5. Davis LS, Woody CM. Idiopathic aquagenic wrinkling of the palms. Pediatr Dermatol. 2004 Mar; 21(2):180. 6. Stewart LC, Doe SJ, Bourke SJ, Leech S. Aquagenic palmar wrinkling as a presenting feature of cystic fibrosis gene dysfunction. Clin Exp Dermatol. 2009 Dec; 34(8):647-9. 7. Vale R, Adam DN. Aquagenic wrinkling of the palms in sisters. J Dermatol. 2011 Oct 20(10):1346-8138.

Figure 1

History A 44-year-old Caucasian male with a history Laboratory examination revealed only a stable of lower-extremity osteomyelitis was treated normocytic anemia and a mild hyponatremia. with ampicillin-sulbactam and vancomycin. The patient had no prior medical history Ampicillin with sulbactam and vancomycin and a 20 pack-year history of smoking. On were both stopped. The patient was instructed the eighth day of treatment with antibiotics, to apply betamethasone to erythematous areas the patient developed a “rash.” The patient and to alternate silver sulfadiazine cream described the lesions as “very painful,” the with cool compresses of Burow’s solution worst areas being the right axilla and sacral (aluminum acetate dissolved in water) to area. bullous erosive areas. The patient was given analgesics for pain control and anti-histamines Symmetric, pink-to-erythematous, erosive for mild pruritus. On day 2, the patient had plaques and flaccid bullae were found on his reddening of the involved areas and epidermal buttocks (Figure 1). The right axillae, deltoid, sloughing (Figures 3 & 4). No other areas chest and back had a morbilliform eruption became involved, and mucocutaneous and and multiple 6-8 mm erythematous, well- palmar or plantar involvement was absent. circumscribed plaques (Figure 2). The patient At the end of the 2nd day, progression of the had no systemic symptoms, and his vital signs lesions stopped, and the patient went on to were stable. make a complete recovery.

RICHEY, NAFSOU, LACASSE 23 Discussion No deaths have been attributed to fixed identify patients with this syndrome. Since it The differential diagnosis for a rash as drug eruptions. Widespread lesions may appears following a long latency (2–8 weeks) described includes such entities as: initially mimic toxic epidermal necrolysis, after initiation of the culprit drug, and it has a but they have a benign clinical course.1 2 prolonged course after cessation of the culprit 1. Acute generalized exanthematous Localized hyperpigmentation is a common drug, the symptoms are often not recognized pustulosis (AGEP) complication; pain, infection, and, rarely, as drug-related. The diagnosis, then, is made 2. Fixed drug eruption (FDE) hypopigmentation also may occur. by exclusion. 3. Hypersensitivity syndrome (HSS), also known as “drug rash Although the exact mechanism is unknown, General awareness of HSS is important due with eosinophilia and systemic research suggests a cell-mediated cytotoxic to the severity and life-threatening potential symptoms” (DRESS) process.8 The process may involve an of this type of drug reaction, as the reported 4. Serum sickness-like reaction antibody-dependent, cell-mediated cytotoxic mortality rate is around 10%. 5. Systemic drug-related intertriginous response.3 CD8+ effector/memory T cells and flexural exanthem (SDRIFE), play an important role in reactivation of The lack of consensus regarding the definition also known as “baboon syndrome” lesions with re-exposure to the offending of HSS has practical implications impeding in some reviews1,2 drug.4,5 The offending drug is thought to the development of better diagnostic tests and function as a hapten that preferentially treatment methods. Nevertheless, great strides Acute generalized exanthematous pustulosis binds to basal keratinocytes, leading to an have been made to elucidate the natural Acute generalized exanthematous pustulosis inflammatory response.6 Through liberation history and pathogenesis of HSS, and so far (AGEP) typically presents initially with an of cytokines such as tumor necrosis factor- it can be concluded that HSS is characterized edematous erythrodermic eruption in the alpha, keratinocytes may locally up-regulate by: drug-induced immunological background, body folds or on the face, with subsequent expression of the intercellular adhesion later onset than other drug reactions, longer dissemination of primarily non-follicular, molecule-1 (ICAM1).7 The up-regulated duration than common “drug rashes,” sterile pustules. The eruption is associated ICAM1 has been shown to help T cells (CD4 multiorgan involvement, lymphocyte with high fever and leukocytosis with and CD8) migrate to the site of an insult.8,9 activation, eosinophilia, and herpes virus high neutrophil count. Pustules resolve reactivation. spontaneously within a few days and are The newly arriving and residential CD8 typically followed by a characteristic pinpoint cells likely perpetuate tissue damage by their Serum sickness-like reaction desquamation. The whole episode lasts up to production of the inflammatory cytokines Serum sickness-like reaction refers to an 15 days. interferon-gamma and tumor necrosis factor- immune-complex disease following parenteral alpha. Changes in cell-surface markers allow injections of therapeutic sera. The immune The estimated incidence is one to five cases vascular endothelium to select CD4 cells for complexes consist of antigen and IgG, usually per million per year. Occurring at any age, migration into active lesions. These regulatory with antigen excess (type III reaction). As males and females are equally affected. More CD4 cells likely produce interleukin 10, which the amount of antibody formed increases, than 90% of the AGEP cases are drug-induced, has been shown to help suppress immune phagocytic mononuclear cells eliminate with antibacterial medications being the most function, resulting in a resting lesion.3 As the the antigen slowly. The immune complexes frequent triggers. In a minority of cases, viral inflammatory response dissipates, cause intravascular complement activation infections have been suspected. interleukin-15 expression from keratinocytes and subsequent immune complex–induced is thought to help ensure the survival of necrotizing angiitis, which is responsible This is a self-limited disease with a favorable CD8 cells, helping them fulfill their effector- for the diverse clinical symptoms of this prognosis, although secondary infection memory phenotypes. Thus, when re-exposure syndrome. Eventually, the circulating might pose danger to patients in poor general to the drug occurs, a more rapid response complexes shift to antibody in excess of condition, in which mortality can reach 5%. develops in the exact locations of any prior antigen, and the clinical signs subside. lesions.3 Fixed drug eruption Initial onset is after one to three weeks, but it Fixed drug eruption (FDE) is a drug- Hypersensitivity syndrome (DRESS) may be as soon as two to four days after induced disorder clinically distinguishable Hypersensitivity syndrome (HSS), also known secondary exposure. Over 70 percent of by its localized, often acral or mucosal, as drug rash with eosinophilia and systemic patients with serum sickness manifest asymmetric, frequently pigmented, round- symptoms (DRESS), can often lead to lethal urticaria, often preceded by pruritus and oval lesions. These lesions normally resolve organ involvement such as fulminant hepatitis erythema. Urticarial lesions are persistent, with hyperpigmentation and typically recur and must be diagnosed rapidly. In 1950, lasting a few days, and are sometimes tender at the same site with re-exposure to the phenytoin was first reported in association or painful with bruising, unlike classical offending drug. Fixed drug eruptions have with the constellation of symptoms that urticaria. Characteristically, a serpiginous, been reported in patients as young as 1.5 years now characterizes HSS. The “phenotypic” erythematous and purpuric eruption and as old as 87 years. diversity of this syndrome hampers the develops on the hands and feet at the borders development of accepted diagnostic criteria. of palmar and plantar skin, from the dorsa The prevalence of drug eruptions has been Its main clinical features, which include rash, of the extremities (Wallace’s line). Systemic reported to range from 2-5% for inpatients fever and internal organ involvement, could features might include fever, joint pain and and greater than 1% for outpatients.10 Fixed be attributed to a wide range of other causes swelling, lymphadenopathy, and occasionally drug eruptions may account for as much as such as infectious diseases, neoplastic diseases, proteinuria, nephritis or endocarditis, with 16-21% of all cutaneous drug eruptions. The collagen vascular disorders and also adverse eosinophilia. In minor forms, fever, urticaria actual frequency may be higher than current drug reactions. In addition, asymptomatic and transitory joint tenderness may be the estimates, owing to the availability of a systemic involvement such as eosinophilia only manifestations. variety of over-the-counter medications and and atypical lymphocytes are often missed. nutritional supplements that are known to Also, the clinical features of this syndrome Serum sickness-like reactions may be elicit fixed drug eruptions. are not all present simultaneously. Thus, produced by exposure to drugs such as long-term follow-up is needed to accurately penicillin, hydantoins, aminosalicylic acid,

24 AN INTERTRIGINOUS AND FLEXURAL EXANTHEM: CASE REPORT AND DRUG-ERUPTION REVIEW Figure 2 Figure 3 streptomycin, thiazides, sulfonamides, that are frequently stimulated mechanically. of avoiding the precipitating allergens as well streptokinase, tamoxifen, oral contraceptives, Mechanically stimulated skin exhibits as providing symptomatic relief and wound anti-influenza vaccine, and anti-snake venom enhanced expression of intercellular adhesion care. Medium-to-high-potency topical or serum. Other causes of serum sickness- molecules on the keratinocytes, contributing systemic glucocorticoids may hasten recovery. like syndrome include radiocontrast media; to the accumulation of drug-activated infections (a serum sickness-like syndrome lymphocytes there. Summary occurs in about 20 to 30 percent of patients Our patient’s bullous intertriginous with hepatitis B infection); and rarely, foods. The diagnostic criteria for SDRIFE include2: eruption had a short onset, no serious organ 1. exposure to a systemically involvement, and complete resolution after The diagnosis is mainly based on the time lag administered drug cessation of offending medication, leading between initiating the offending agent and 2. sharply demarcated erythema of the us to the conclusion that he had SDRIFE. the appearance of the symptoms, the clinical gluteal/perianal area and/ or Although no biopsy was performed due manifestations, and the absence of other V-shaped erythema of the inguinal/ to the patient’s lack of systemic symptoms immunological or infectious causes. Prompt perigenital area and signs and the classic clinical picture, discontinuation of the offending agent and 3. involvement of at least one other histopathologic examination would have supportive care are the mainstays of treatment. intertriginous/flexural fold contributed to our report, as there is little Aspirin and antihistamines may relieve the 4. symmetry of affected areas data on this matter. Some authors indicate symptoms. In case of severe symptoms, a short 5. absence of systemic symptoms and that the lesions demonstrate a non-specific course of high-dose corticosteroids may be signs dermatitis, while others have seen findings warranted. However, symptoms are usually consistent with a toxic epidermal necrolysis self-limited, lasting for five to 28 days and SDRIFE is self-limited, and treatment consists (subepidermal bulla with confluent necrosis resolving without sequelae. Avoidance of the offending agent is important.

Systemic drug-related intertriginous and flexural exanthem (“baboon syndrome”) The term “baboon syndrome” was originally introduced in 1984 to describe a mild systemic cutaneous reaction after oral exposure to type IV allergens, such as nickel, mercury or drugs.1 Recently, it has been proposed to replace this term by the acronym SDRIFE (systemic drug-related intertriginous and flexural exanthem).2 One hundred cases between 1984 and 2004 have been documented, with amoxicillin being the most common drug causing SDRIFE, followed by cephalosporins.

SDRIFE describes a special form of systemic contact dermatitis that occurs after systemically administered drugs. The proposed pathophysiology of SDRIFE is most likely a T cell-mediated reaction. The intertriginous and flexural areas are sites Figure 4

RICHEY, NAFSOU, LACASSE 25 of the overlying epidermis, and perivascular literature. Drug Saf. 2007;30(5):379-407. infiltrate of lymphocytes which, if present 16,17 11. Lee AY. Fixed drug eruptions. Incidence, at all, is usually sparse). As further recognition, and avoidance. Am J Clin information is gathered on the histopathologic Dermatol. 2000 Sep-Oct;1(5):277-85. and immunologic findings in the skin biopsy of a patient with SDRIFE, dermatopathologists 12. Baird BJ, De Villez RL. Widespread will become important players in helping bullous fixed drug eruption mimicking recognize this severe-appearing eruption as toxic epidermal necrolysis. Int J a reaction to medications. Dermatologists Dermatol. 1988 Apr;27(3):170-4. who are familiar with classic presentations 13. Pellicano R, Ciavarella G, Lomuto of common drug-induced reactions will be M, Di Giorgio G. Genetic susceptibility essential contributors to the medical team to fixed drug eruption: evidence for a caring for patients. link with HLA-B22. J Am Acad Dermatol. 1994 Jan;30(1):52-4. 14. Pellicano R, Lomuto M, Ciavarella G, Di Giorgio G, Gasparini P. Fixed drug References eruptions with feprazone are linked 1. Handisurya A, et al. SDRIFE (baboon to HLA-B22. J Am Acad Dermatol. 1997 syndrome) induced by penicillin. Clin May;36(5 Pt 1):782-4. Exp Dermatol. 2009;34:355-7. 15. Bolognia JL, Jorizzo JL, Rapini RP. 2. Hausermann P, et al. Baboon syndrome Dermatology. London: Mosby; c2003. resulting from systemic drugs: is there Fixed drug eruptions; p. 344-5. strife between SDRIFE and allergic 16. Sánchez-Morillas L, Reaño contact dermatitis syndrome? Martos M, Rodríguez Mosquera M, Contact Dermatitis. Iglesias Cadarso C, González Sánchez L, 2004;51:297–310. Domínguez Lázaro AR. Non-specific 3. Teraki Y, Shiohara T. IFN-gamma- dermatitis. Allergol Immunopathol producing effector CD8+ T cells and (Madrid). 2004 Jan-Feb;32(1):43-5. IL-10-producing regulatory 17. Weedon D. Skin Pathology. 3rd ed. CD4+ T cells in fixed drug eruption. J London: Churchill Livingstone; c2009. Allergy Clin Immunol. Chapter 6, Toxic Epidermal Necrolysis. 2003 Sep;112(3):609-15. 4. Mizukawa Y, Shiohara T. Fixed drug eruption: a prototypic disorder mediated by effector memory T cells. Curr Allergy Asthma Rep. 2009 Jan;9(1):71-7. 5. Shiohara T. Fixed drug eruption: pathogenesis and diagnostic tests. Curr Opin Allergy Clin Immunol. 2009 Aug;9(4):316-21. 6. Weedon D. Skin Pathology. 2nd ed. London: Churchill Livingstone; c2002. The lichenoid reaction pattern (‘interface dermatitis’); p. 42-43. 7. Smoller BR, Luster AD, Krane JF, et al. Fixed drug eruptions: evidence for a cytokine-mediated process. J Cutan Pathol. 1991 Feb;18(1):13-9. 8. Hindsen M, Christensen OB, Gruic V, Lofberg H. Fixed drug eruption: an immunohistochemical investigation of the acute and healing phase. Br J Dermatol. 1987 Mar;116(3):351-60. 9. Shiohara T, Nickoloff BJ, Sagawa Y, Gomi T, Nagashima M. Fixed drug eruption. Expression of epidermal keratinocyte intercellular adhesion molecule-1 (ICAM-1). Arch Dermatol. 1989 Oct;125(10):1371-6. 10. Krahenbuhl-Melcher A, Schlienger R, Lampert M, Haschke M, Drewe J, Krahenbuhl S. Drug-related problems in hospitals: a review of the recent 26 AN INTERTRIGINOUS AND FLEXURAL EXANTHEM: CASE REPORT AND DRUG-ERUPTION REVIEW Zosteriform Lichen Planus Limited to L4 Dermatome of the Right Lower Extremity

Donna D. Tran, MSIV,* Brent Loftis, DO,** Elaine Phuah, DO,*** Bill V. Way, DO, FAOCD****

*4th year medical student, University of North Texas Health Science Center, Fort Worth, TX **3rd year resident, Northeast Regional Medical Center Texas Division, Dermatology Institute, Duncanville, TX ***2nd year Internal Medicine resident, Plaza Medical Hospital, Fort Worth, TX ****Dermatology Residency Program Director, Northeast Regional Medical Center Texas Division, Dermatology Institute, Duncanville, TX

Report of a Case

An 18-year-old female presented to our transparent, and adherent scale may be epidermal-dermal junction, hyperkeratosis, dermatology clinic with a three-month history present atop some lesions. Fine, whitish focal areas of wedge-shaped hypergranulosis, of pruritic lesions extending from the right puncta or reticulated networks known as and elongation of rete ridges that resemble a upper thigh to lower leg in a linear pattern. Wickham’s striae is present over the surface sawtooth pattern. Multiple apoptotic cells or The patient was otherwise healthy and had no of many papules. Symmetric involvement colloid-hyaline (Civatte) bodies are present significant past medical history. She denied of the flexor surfaces of the wrist, arms, and at the dermal-epidermal junction. The previous or concomitant history of herpes lower extremities is common. Oral mucous differential diagnosis of linear LP includes zoster infection or trauma at the site of the membranes and the genitalia may also be lichen striatus,2 linear verrucous epidermal involved skin. Prior dermatologic history affected. Lichen planus tends to be pruritic, nevus,3 and linear psoriasis. was significant for lichen simplex chronicus although some patients are completely Linear LP commonly presents secondary involving the forehead and submental asymptomatic. to trauma (koebnerization)4 or on the site a r e a . P a t i e n t ’ s o n l y m e d i c a t i o n w a s a n o r a l LP may exhibit numerous variations in pattern of healed herpes zoster, an example of the h control pill. and are generally categorized according to Wolf’s isotopic response.5-7 In extremely Physical examination of the skin revealed the configuration of lesions, morphology, rare cases, linear LP presents in a segmental multiple violaceous and polygonal papules or the site of involvement. Variants of LP fashion corresponding to one dermatome with Wickham’s striae along the L4 include annular, linear, hypertrophic, atrophic, and is termed zosteriform LP. Zosteriform dermatome of the right lower extremity vesiculobullous, erosive and ulcerative, or linear distributions appear de novo on (Figures 1-3). The mucous membrane, hair, follicular, actinic, and pigmentosus.1 previously normal, non-traumatized skin, as and nails were spared. Sections of the punch Linear LP refers to LP with a unilateral, in our patient. Although case reports of de biopsy showed an irregularly acanthotic linear distribution. Histopathologically, linear novo zosteriform LP have been reported,8-10 epidermis with a dense lichenoid band of LP is identical to LP. Key features include this entity is controversial. Happle argued that lymphocytes and histiocytes in the superficial band-like infiltrate of lymphocytes at the in most reported cases of zosteriform lichen dermis and abutting the dermoepidermal junction. There were occasional melanophages in the papillary dermis and occasional dyskeratotic keratinocytes in the epidermis. There was overlying compact orthokeratosis and foci of wedge-shaped hypergranulosis (Figures 4-5). Serology for hepatitis C antibody was negative. Hepatitis B serology was reactive for hepatitis B surface antibody. Based on the clinical and histopathological findings, a diagnosis of zosteriform lichen planus was made. The patient was treated with topical triamcinolone acetonide (0.1% twice daily) for three months and subsequently switched to clobetasol propionate ointment (0.05% twice daily). Her itching improved, and her lesions are controlled. A regular follow-up with our clinic was suggested to see the course of the disease. She is followed by her primary care physician for the positive hepatitis B serology.

Discussion Lichen planus (LP) is a relatively common skin disease of unknown etiology characterized by erythematous to violaceous, flat-topped, polygonal papules. A thin, Figures 1: Linear papules of lichen planus over right thigh and calf TRAN, LOFTIS, PHUAH, WAY 27 2. Herd KM, McLaren KM, Aldridge RD. Linear lichen planus and lichen striatus—opposite ends of spectrum. Clin Exp Dermatol. 1993 Jul;18(4):335-7. 3. Brownstein MH, Silverstein L, Lefing W. Lichenoid epidermal nevus: “linear lichen planus” J Am Acad Dermatol. 1989;20:913-915. 4. Boyd AS, Neldner KH. The isomorphic response of Koebner. Int J Dermatol 1990;29:401-410. 5. Braun RP, Barua D, Masouve I. Zosteriform lichen planus after herpes zoster, Dermatolog 1998;197:87-88. 6. Shemer A, Weiss G, Trau H. Wolf’s isotopic response: a case of zosteriform lichen planus on the site of healed herpes zoster. J Eur Acad Dermatol Venereol. 2001 Sep;15(5):445-7. 7. Turel A, Ozturkcan S, Sahin MT, Turkdogan P. Wolf’s isotopic response: a case of zosteriform lichen planus. J Figures 1: Linear papules of lichen planus over right thigh and calf Dermatol. 2002 June;29(6):339-42. 8. Harder MK, Kasha EE. Pruritic planus, the lesions appeared to follow the lines Our patient’s lesions and pruritus are currently zosteriform eruption: Zosteriform lichen of Blaschko.11,12 controlled with topical corticosteroids. She planus. Arch Dermatol. 1990 In our patient, the distribution of lesions will continue to follow up in our dermatology May;126(5):665-668. followed the L4 dermatome. The patient clinic for her skin lesions as well as with denied history of herpes zoster infection, and her primary care physician for the positive 9. Lutz ME, Perniciaro C, Lim KK. lesions did not occur on any previous site of hepatitis B serology. Zosteriform lichen planus without trauma. The linear eruption seemed to follow evidence of herpes simplex virus or a true dermatome rather than the lines of varicella zoster virus by polymerase Blaschko on the lower extremity. Interestingly, References chain reaction. Report of two cases. Acta reports of LP associated with hepatitis C 1. Bolognia J, Jorizzo J, Rapini R. Derm Venereol 1997;77(6):491-492. nd infection, chronic active hepatitis, and Dermatology. 2 Edition. Mosby; 2008. 10. Fink-Puches R, Hofmann-Wellenhof 13 primary biliary cirrhosis have been reported. 159-170 p. R, Smolle J. Zosteriform lichen planus.

Figure 3: Linear papules of lichen planus Figures 4: Histopathology of lesional skin Figures 5: Histopathology of lesional skin over right thigh (close-up)

28 ZOSTERIFORM LICHEN PLANUS LIMITED TO L4 DERMATOME OF THE RIGHT LOWER EXTREMITY Dermatology. 1996;192(4):375-377. 11. Happle R. Zosteriform lichen planus: Is it zosteriform? Dermatology. Wells’ Syndrome: A Case Report 1996;192(4)385-6. 12. Long CC, Finlay AY. Multiple linear lichen planus in the lines of Blaschko. Br LT Jessica L. Schwartz, MC, USN,* CDR Tony S. Clinton, MC, USN** J Dermatol. 1996 Aug;135(2):275-6. *General Medical Officer, United States Navy, Kinser Group Aid 13. Cribier B, Garnier C, Laustriat D, Station, Camp Kinser, Okinawa, Japan Heid E. Lichen planus and Hepatitis C virus infection: an epidemiologic study. J **Dermatology Department Head, United States Naval Hospital, Am Acad Dermatol. 1994;31:1070-2. Okinawa, Japan

INTRODUCTION Wells’ syndrome, or eosinophilic cellulitis, is a hypersensitivity reaction of unknown etiology. It is typically described as an acute, recurrent, pruritic skin reaction. While the etiology is unknown, this syndrome has been linked to a variety of allergic stimuli and arthropod bites,1 as well as cutaneous viral and fungal infections, parasitic infestations, and medication-hypersensitivity reactions.2 Familial cases have been described as well. About eighty cases have been reported in the literature.3 The syndrome has an excellent prognosis.

Case Description A 17-month-old girl was referred to the dermatology clinic by her primary care manager for pruritic skin lesions of a few months’ duration that would resolve and then return. Her parents stated that the child had itchy, round lesions that appeared on her bilateral forearms, hands, plantar feet, no such symptoms. There were no pets in and legs over the past month that would the household. The lesions did not respond appear abruptly (Figure 1). Blistering was to various courses of oral trimethoprim/ observed with some of the lesions (Figure 2). sulfamethoxazole, topical mupirocin, The lesions would resolve and then appear permethrin treatment for presumptive elsewhere, with random intervals of time scabies, chlorhexidine washes or oral between outbreaks. Some lesions appeared in antihistamine treatment. Skin bacterial areas where the mother stated she witnessed cultures were negative. Initial complete blood the child being bitten by mosquitoes a few counts (CBC) were unremarkable. The last hours earlier, while others had no clear CBC showed elevated band neutrophils but association to anything and appeared in no leukocytosis. Punch biopsy of a lesion clothing-covered areas. The mother also revealed compact orthokeratosis overlying an reported the child had recurrent unexplained epidermis containing numerous eosinophils fevers for the last two to three months, and a dermis with eosinophilic infiltrate with which preceded skin symptoms. The child’s scattered flame figures (Figures 3 and 4). history was otherwise unremarkable, and The patient’s blood work never revealed any she appeared healthy. No household family hypereosinophilia. members shared similar symptoms. The mother reported sleeping in the same bed Discussion as the child a few times before the lesions The clinical presentation along with were noted in the morning. The mother had histopathology led to a diagnosis of

SCHWARTZ, CLINTON 29 papulovesicular, bullous, papulonodular, and fixed drug eruption-like.8 The most common presentation in children is the classic plaque type, while adults most frequently exhibit erythematous annular lesions.8 While uncommon, systemic symptoms such as malaise and arthralgia can occur, and fever is even less common.

While the etiology is unclear, this hypersensitivity reaction is most commonly associated with a variety of allergic stimuli and arthropod reactions.1 In the spectrum of hypersensitivity disorders, Wells’ syndrome represents the benign cutaneous end, while hypereosinophilic syndrome represents the multiple-organ-system-dysfunction end. Histopathology may overlap between the two syndromes, but Wells’ syndrome lacks the persistent blood eosinophilia and multiorgan involvement.6

Differential diagnosis includes allergic and contact dermatitis, drug reaction, granuloma annulare, candidiasis, Churg-Strauss syndrome, bullous arthropod bite reaction, and cellulitis. The history of spontaneous lesion eruption in multiple areas (including some clothing-covered areas), inconsistent blistering of lesions, lack of lesions in family members, and failure to respond to antihistamine treatment suggested this was a diagnosis other than an arthropod- bite reaction. Of the differentials, cellulitis is the most likely diagnosis to be confused for Wells’ syndrome, as clearly demarcated erythematous indurated lesions can occur in both cases. However, cellulitic infections will rapidly expand in 24 hours and are more likely to be associated with systemic symptoms such as fever, chills, and malaise. Wells’ syndrome lesions are more typically pruritic than painful and tender. Wells’ syndrome should be considered in the setting of negative bacterial skin cultures and lack of response to antibiotic treatment. Clinicians should consider obtaining a CBC to check for eosinophilia, although it is not present in all stages of disease and is only present 50% of 4 Wells’ syndrome, or eosinophilic cellulitis. Clinically, most cases present with pruritic, the time. Biopsy is necessary for diagnosis. Childhood cases are rare and may be erythematous, edematous plaques that Histology demonstrates a dense infiltration associated with more severe blistering.4 appear over a few days and resolve in two of eosinophils and histiocytes in the dermis A PubMed search revealed a review of 27 to eight weeks. As the lesions resolve, they in the acute stage, widespread degranulation pediatric cases from 1979 to 2005, and a may indurate and discolor.7 Lesions most known as “flame figures” in the subacute stage, and phagocytic histiocytes and few eosinophils search of cases from 2005 to 2012 revealed commonly present on the limbs, followed by 7 10 additional pediatric cases cited in the the trunk, arms, and face. Lesions typically in the resolving stage. Flame figures are not literature.5 This is a benign condition heal without scarring, although atrophy and specific to Wells’ syndrome and can be seen in not usually associated with systemic hyperpigmentation can persist.4 Recurrence biopsies of eczema, herpes gestationis, scabies, prurigo nodularis, and Trichophytron rubrum manifestations, although a few cases have typically occurs over several years, with a 6 been linked to leukemia, myeloproliferative mean relapse rate of four times in adults and infection. and lymphoproliferative disorders, and other three times in children.8 Seven clinical variants underlying nonhematologic malignancies.6 have been identified to include plaque- The time course of Wells’ syndrome is type, annular granuloma-like, urticarial, variable, as is the response to treatment. Lesions will heal without treatment,

30 WELLS’ SYNDROME: A CASE REPORT although reasons to treat include persistent lesions, patient comfort, and prevention of a Familial Koenen tumors (periungual secondary bacterial infection. Most localized disease is treated with topical corticosteroids. fibromas) without clinical criteria or Isolated cases of successful treatment with tacrolimus, colchicine, antimalarial drugs, genetic testing diagnostic for tuberous and immunosuppressive agents have been described in the literature.9 The mainstay sclerosis of treatment remains oral corticosteroids, which have been shown to decrease the duration of symptoms in cases of widespread Laurie Lenz, DO,* Jacqueline Thomas, DO,** Noelle Sanon, DO,*** or persistent disease, alone or in combination Robin Shecter, DO**** with dapsone.8 Antihistamines are often given nd to reduce pruritus. The patient’s parents opted *2 Year Dermatology Resident, Palm Beach Centre for Graduate Medical Education, not to use oral steroid treatment as the lesions West Palm Beach, FL had lessened and the child appeared more ** Dermatologist, The Skin Institute, Ft. Lauderdale, FL nd comfortable. As of this writing, the patient was ***2 Year Internal Medicine Resident, Palm Beach Centre for Graduate Medical lost to follow-up. Education, West Palm Beach, FL ****Program Director, Dermatology Residency, Palm Beach Centre for Graduate Medical Education, West Palm Beach, FL References 1. Gandhi RK, et al. Wells Syndrome (eosinophilic cellulitis) a clinical imitator of bacterial cellulitis. J Clinical Aesthetic INTRODUCTION Dermatol. 2011; 4(7):55-57. Periungual fibromas (Koenen tumors) present as flesh-colored or red papules arising 2. Hussein W, et al. Punch Biopsy in Wells from the proximal nail matrix. They usually lead to a longitudinal groove in the nail Syndrome. Southern Med J. 2009; plate and may be painful. A periungual fibroma is one of the major clinical criteria for 102(7):775. the diagnosis of tuberous sclerosis (TS) and, along with facial angiofibromas, is often considered pathognomonic of the disease.1 In some cases, Koenen tumors may be the 3. Cashin B, Allan N, Kang C. Wells only clinical manifestation of TS at the time of diagnosis.2,3 There are no reports in Syndrome. West J Emerg Med. 2010; the literature to date of familial inheritance of Koenen tumors without the presence of 11(1):95-96. multisystem disease. 4. Katoulis A, et al. Idiopathic bullous We present a case of a mother and daughter with multiple Koenen tumors, no clinical eosinophilic cellulitis (Wells’ Syndrome). evidence of systemic disease, and negative genetic testing for the TSC1 and TSC2 gene Clin Exp Dermatol. 2009; 34(7):e375- mutations. 376. 5. Gilliam AE, et al. Bullous “Cellulitis” Case Report with Eosinophilia: Case Report and A 15-year-old girl presented with a skin-colored to reddish, painful periungual tumor on the Review of Wells’ Syndrome in left second finger (Figure 1). The tumor began to develop one to two years prior and had been Childhood. Peds. 2005; 116:e149-155. increasing in size. The patient attempted treatment with over-the-counter wart remover and 6. Carlesimo M, et al. Wells Syndrome physical removal with nail files and clippers without success. She was otherwise healthy with no with Multiorgan Involvement Mimicking history of cardiac, renal, or neurologic disease. She was of normal intelligence. Hypereosinophlic Syndrome. Cas Rep Dermatol. 2009; 1:44-48 The minor was accompanied by her 42-year- old mother, who reported multiple similar 7. Steffen, C. George Crichton Wells periungual tumors on both her fingers and eosinophilic cellulitis (Wells Syndrome). her toes but was otherwise healthy (Figures Am J of Dermatopathology. 2002; 2 and 3). The patient’s 11-year-old brother 24(2):164-165. and maternal grandmother were unaffected 8. Caputo R, Marzano A, Vezzoli P, by these tumors, and further family history Lunardon L. Wells Syndrome in Adults was negative. Physical exam of the patient and and Children. Arch Dermatol. 2006; mother revealed no hypomelanotic macules, 142:1157-1161. facial angiofibromas, shagreen patches, dental 9. Ohtsuka, T. Oral tacrolimus treatment pits, or gingival hamartomas. Excisional for refractory eosinophilic cellulitis. Clin biopsy was performed, and histology Exp Dermatol. 2009; 34(8):e597-598. was consistent with fibroma, showing orthokeratosis and dense fibrotic tissue with atypical stellate fibroblasts. Molecular genetic Figure 1: Left second finger of 15-yr-old analysis for gene mutations of the TSC1 and female with periungual tumo TSC2 genes was performed and was negative.

LENZ, THOMAS, SANON, SHEETER 31 multiple acral fibromas, mostly located in the subungual region, in a patient with familial retinoblastoma. This report hypothesized that multiple cutaneous fibromas may be a clinical marker of inheritable disorders with germ-line mutations of tumor suppressor genes, citing TS, neurofibromatosis, multiple endocrine neoplasia type 1, Li-Fraumeni syndrome and familial retinoblastoma as examples.8

It is possible that these patients represent the very mildest clinical manifestation of TS, considering the extreme variability in clinical severity associated with the disease. This patient and her mother may be in the 20-25% of people affected by TS in whom Figure 2: Patient’s 42 year-old mother with periungual tumors of the right second finger current genetic testing is negative. Cardiac, and left fourth finger neurologic, and renal manifestations of TS typically present in infancy or childhood, and pulmonary manifestations present in the second to third decade, but this is variable.5 The individuals we present here may not have yet developed the clinical manifestations of the hamartomatous growths that affect the brain, kidneys, lungs, and heart. Alternatively, this mother and daughter may represent a unique case of familial Koenen tumors without the association of any systemic involvement. Only time can elucidate this. In cases like this one, patients should be followed closely for clinical manifestations of systemic involvement so that early treatment can be initiated.

Acknowledgements The authors are indebted to Eduardo Weiss, MD, for his support in this manuscript. References: 1. Mazaira M, del Pozo Losada J, Figure 3: Patient’s mother with periungual tumors of the left great toe and fourth toe Fernandez-Jorge B, Fernandez- Torres R, Martinez W, Fonseca E. Shave Discussion and phenolization of periungual in questionable cases, prenatal diagnosis, and Tuberous sclerosis is a genetic disease fibromas, Koenen’s tumors, in a patient for screening family members of affected inherited in an autosomal-dominant manner; with tuberous sclerosis. Dermatol Surg individuals. however, in up to 75% of affected individuals it 2008;34:111-113. We present a unique case of familial is due to a spontaneous mutation.4 The genes development of multiple Koenen tumors responsible for tuberous sclerosis are TSC1 2. Webb DW, Clarke A, Fryer A, Osborne without apparent multisystem involvement or and TSC2, tumor suppressor genes, located on JP. The cutaneous features of tuberous TS diagnosis. Sporadic appearance of Koenen chromosome 9 and 16, respectively. Mutations sclerosis: a population study. Br J of tumors can occur, and acquired digital in these genes lead to hamartomatous growths Dermatol 1996;135:1-5. fibromas are clinically and histologically affecting the brain, skin, eyes, kidneys, heart, similar but are usually solitary and likely lungs, and bones. The expression of these gene 3. Quist SR, Franke I, Sutter C, Bartram trauma-induced.6 Literature review revealed defects and the clinical severity that results is CR, Gollnick HP, Leverkus M. two cases of multiple acral and periungual highly variable among patients, even among Periungual fibroma (Koenen tumors) tumors without TS association. In the patients within the same family.4 Diagnosis is as isolated sign of tuberous sclerosis first, Moulin et al. described a 70-year- typically made with clinical criteria set forth complex with tuberous sclerosis complex old woman, her 50-year-old son, and his by the Diagnostic Criteria Committee of 1 germline mutation. J Am Acad 27-year-old daughter all presenting with the National Tuberous Sclerosis Association Dermatol 2010;62:159-61. multiple mucinous fibrokeratomas on their (USA). Table 1 is provided to list the required palms and fingers, without the presence of diagnostic criteria for TS.5 Genetic testing 4. Berlin AL, Billick RC. Use of CO2 a multisystem familial disease.7 Although is now available and identifies mutations laser in the treatment of periungual they resembled Koenen tumors of TS, they in the TSC1 or TSC2 gene in 75-80% of fibromas associated with tuberous differed in both location and histologic affected individuals.5 This test is most useful sclerosis. Dermatol Surg 2002;28:434-6. appearance. Dereure et al. described a case of 32 FAMILIAL KOENEN TUMORS (PERIUNGUAL FIBROMAS) WITHOUT CLINICAL CRITERIA OR GENETIC TESTING DIAGNOSTIC FOR TUBEROUS SCLEROSIS Table 1: Diagnostic Criteria for Tuberous Sclerosis 5. Franz DN. Tuberous Sclerosis. Medscape [Internet]. Updated: 2010, Major Features Nov 1 [cited 2012, June 1]. Available Facial angiofibromas or forehead plaque from: http://emedicine.medscape.com/ Non-traumatic ungula or periungual fibroma article Hypomelanotic macules (more than three) 6. Satter EK. Acquired Digital Shagreen patch (connective-tissue nevus) Fibrokeratoma. Medscape [Internet]. Multiple retinal nodular hamartomas Updated: 2011, Jul 11 [cited 2012, Cortical tuber June 1]. Available from: http:// Subependymal nodule emedicine.medscape.com/article Subependymal giant-cell astrocytoma 7. Moulin G, Balme B, Thomas L. Familial Cardiac rhabdomyoma, single or multiple multiple acral mucinous Lymphangiomyomatosis fibrokeratomas. J Am Acad Dermatol Renal angiomyolipoma 1998;38:999-1001. 8. Dereure O, Savoy D, Doz F, Junien Minor Features C, Guilhon JJ. Multiple acral fibromas Multiple randomly distributed pits in dental enamel in a patient with familial retinoblastoma: Hamartomatous rectal polyps a cutaneous marker of tumour- suppressor gene germline mutation? Br J Bone cysts Dermatol 2000;143:856-9. Cerebral white-matter migration lines Gingival fibromas Non-renal hamartoma Retinal achromic patch “Confetti” skin lesions Multiple renal cysts

Criteria Definite TSC: Either 2 major features or 1 major and 2 minor features Probable TSC: One major and one minor feature Possible TSC: Either 1 major feature or 2 or more minor features

LENZ, THOMAS, SANON, SHEETER 33 Calciphylaxis: Case Report and Literature Review

Kristin Regan, D.O.,* Kate Kleydman, D.O.,** Cindy Hoffman, D.O.*** *Intern, PGY-1, Nassau University Medical Center, East Meadow, New York **Dermatology Resident, PGY-4, St. Barnabas Hospital, Bronx, New York ***Program Director, Dermatology Residency, St. Barnabas Hospital, Bronx, New York

Abstract Calciphylaxis is a rare but often lethal vasculopathic disorder that has a high predilection for patients with renal disease. It is most commonly recognized by the rapid progression of cutaneous ischemia and necrosis due to calcification, intimal fibroplasias, and pannicular thrombosis of arterioles.1,2 Commonly referred to as “metastatic calcification,” calciphylaxis has been attributed to the imbalance between serum calcium levels and phosphate levels.1 This imbalance has been largely associated with renal failure; more recently, it has been associated with hyperparathyroidism, diabetes mellitus, female sex, obesity, warfarin use, protein C and S deficiency, and a high phosphate level, as well.2,3 Additionally, a considerable number of patients with calciphylaxis have normal serum calcium levels or minimal to no renal impairment, suggesting an obscure causative factor to this condition. Evidence supporting the mechanism behind calciphylaxis is weak.1 Figure 1: Necrotic ulcers with black eschars and scattered hemorrhagic bullae of the lower We hope to shed light on its pathogenesis, extremity. risk factors, and other variables that may be implicated in its development and diabetes mellitus complicated by end-stage A 4-mm punch biopsy of the left lower calf progression. Referencing these factors renal disease, and she was on dialysis. The was obtained, revealing subcutaneous calcium would open up additional discussions patient was taking aspirin, ipratropium, deposits with panniculitis and fat necrosis. on future therapies for prevention and vitamin B and C complex, folate, senna, Seldom, areas of calcification within the resolution of this often devastating disease metoprolol, hydralazine, esomeprazole, media of small- and medium-sized arterioles process. isosorbide mononitrate, metformin, lactulose, with intimal hyperplasia and fibrosis were and sevelamer hydrochloride. She denied also noted (Figures 3 and 4). The patient was Case Report alcohol and drug use. Her family history was diagnosed with calciphylaxis on the basis of A 61-year-old Hispanic female presented negative for any significant dermatologic clinical history, physical exam, and laboratory to the emergency department with altered disease or autoimmune disorders. and histological findings. mental status. According to the patient’s family, she was noted to have lesions on Physical exam revealed necrotic plaques with Treatment was initiated with intravenous her bilateral lower extremities that began induration and bullae of the lower extremities, sodium thiosulfate after each dialysis. Daily to appear two weeks prior. The lesions were bilaterally. The area was surrounded by livedo- wound care was introduced with application initially red in color but changed to a black like or retiform-like purpura (Figures 1 and 2) of mupirocin ointment, lidocaine ointment discoloration over the past “few weeks.” She and scattered hemorrhagic bullae with large, 5% and mometasone furoate ointment 0.1% had seen a doctor weeks prior and was told violaceous borders on the right and left thighs to sites of necrotic tissue. The patient also that she had cellulitis. She completed a one- with areas of necrosis. All sites were tender to underwent pain management. Unfortunately, week course of vancomycin. Blistering of the palpation. Laboratory analysis was significant due to progressive renal failure, the patient area and eschar formation was noted three for hyperparathyroidism (PTH 438.7 pg/mL) expired several weeks after her hospital days prior to her admission to the hospital. with elevated serum calcium and phosphorous admission. levels, 8.0mg/dL and 7.9mg/dL, respectively. Her past medical history was significant for Coagulation parameters were normal. Historical Perspectives on Calciphylaxis hypertension, congestive heart failure and The first-ever mention of the occurrence 34 CALCIPHYLAXIS: CASE REPORT AND LITERATURE REVIEW disease severity.7 A female predilection for development of lesions has been attributed to the gender’s tendency to deposit fat in various sites where the condition manifests.1,6,7 Furthermore, several published records show that Caucasian females have a greater predilection for the disease than do African American females.5,9

In order to accurately diagnose this condition, one must have a high index of suspicion, as there are several differential diagnoses for necrotic ulcers.2,8 The typical presentation is a uremic patient with a characteristic necrotic lesion with abnormalities in laboratory values. Commonly, patients have hyperphosphatemia, increased serum calcium-to-phosphate level, moderately elevated serum parathyroid hormone, and a normal to slight increase in serum calcium levels.10,35 Additional studies do not aid in the diagnosis of this condition but may be warranted depending on other presentations of the disease.

Figure 2: Violaceous, reticulated plaques and retiform-like purpura surrounding a Histological Profile of Calciphylaxis necrotic ulcer on the lower extremity. The early stages of calciphylaxis include collagenous degeneration with erythrocytic 11 of calciphylaxis was by Bryant and White described the development of these lesions extravasation. Microcalcifications in small in 1898 as a subsequent effect of uremia. as “uremic small-artery disease characteristic to medium-sized venules are often evident, Nearly 70 years later, Selye et al. coined of skin necrosis and acral gangrene due to as well as fine granular stippling of the the term “calciphylaxis” for more-acute medial calcification and intimal hyperplasia vascular media. In addition to microvascular local calcification and related it to a local in arteries of subcutaneous tissues” of the calcifications, the most consistent features hypersensitivity reaction in a rodent model extremities.7 This served as additional are acute and chronic panniculitis in a after exposure to various sensitizing agents. He evidence of the intricate relationship between septal pattern as well as slight to moderate referred to agents such as dihydrotachysterol, end-stage renal disease, the administration inflammation. The dispersed infiltrate is vitamin D2, vitamin D3, and parathyroid of appropriate hemodialysis, and the usually neutrophils, lymphocytes, and rare hormone as “calcifiers.” Although a noble consequence of subcutaneous calcification. eosinophils. In the early-phase lesions, attempt at explaining this condition, he later neutrophils and lymphocytes can be revoked his initial hypothesis and suggested Clinical Presentations of Calciphylaxis seen within the dermis along with a deep instead that it was extensive calcification of Several case reports have shown the clinical perivascular infiltrate. Of note, there have soft tissues due to high doses of vitamin D.3,4 rarity that surrounds the diagnosis of been studies that have seen minimal to no 11-13 Subsequently, Selye et al. defined calciphylaxis calciphylaxis as well as the severity of the inflammation and solely calcific venules. as it was reported in humans as a syndrome condition clinically. The majority of patients primarily seen in uremic patients.4,5 Further seen with clinical evidence of calciphylaxis In late lesions, endovascular endothelial evidence by Gipstein et al. strengthened Selye’s have received a kidney transplant or are proliferation and intimal fibrosis in cutaneous observations by thoroughly demonstrating undergoing dialysis. The development of blood vessels are seen, but these findings are that tissue calcification occurs with severely lesions begins as painful, symmetrical, not very common. Many cases also show uremic patients undergoing hemodialysis. violaceous discolorations of the skin that the concomitant presence of micro-thrombi He noted that both initiation and progression evolve into well-demarcated, non-healing as well as thrombosis of larger venules. In of necrotic lesions were largely related ulcers.3 Most commonly, lesions on the one case studied by Essary et al., marked to uncontrolled levels of calcium and shoulders, trunk, buttocks, and thighs have endovascular proliferation with luminal phosphate. In the event that subcutaneous, a poor prognosis due to the propensity for a occlusion and partial re-canalization was seen necrotic lesions developed, a therapeutic larger degree of necrotic tissue. Chan et al. in addition to dermoepidermal separation and parathyroidectomy was performed, were able to confirm that patients undergoing epidermal devitalization. On a histological demonstrating the importance of calcium dialysis who developed proximal lesions level, the most consistent finding is still balance.6 The benefits of a therapeutic were more likely to die than those with distal intravascular calcium deposits within small parathyroidectomy in relationship to uremic lesions.8 and medium-sized venules and arterioles with calcification were further explored and or without necrosis using the confirmatory 11 encouraged in 1995 by Hafner et al. In that An extensive review of the literature reveals von Kossa stain. It is important to recognize case, out of 100 patients diagnosed with end- difficulty in making a distinct relationship that many conditions can mimic the histologic stage renal failure, 58 patients underwent between age of onset and outcome of findings associated with calciphylaxis, and therapeutic parathyroidectomy, and of those, disease. In many cases, age of onset ranged many diseases can stimulate the production of 38 patients survived; in the control group, from 6 months to 83 years, with a mean age subcutaneous findings. As described by many only 13 of the 37 patients survived. Hafner of about 49 years, without correlation to other clinicians, peripheral vascular disease,

REGAN, KLEYDMAN, HOFFMAN 35 cytochemical factors, receptor activator of nuclear factor-KB [RANK], RANK ligand, and osteoprotegerin. These also appear to regulate extraskeletal mineralization and could have a potential role in calciphylaxis.1,13 In a study by Luo et al., a specific matrix protein called mineral-binding ECM protein (Mgp) was shown to be a potential factor in arterial calcification. Shown in a mouse model, those animals that lacked this gene died within two months as a result of arterial calcification as well as inappropriate calcification of various cartilages. This revealed that to prevent calcification in soft tissues, there must be an inhibitory signal.15 This is a potential avenue of study to possibly correlate subcutaneous- tissue calcification with a potential causative mechanism, leading to a modality behind calciphylaxis.

However, there are other causative factors that could increase the expression of RANK ligand, in turn causing a decrease of the expression Figure 3: Dermatohistopathology revealed calcification within the media of small- of osteoprotegerin. These factors include and medium-sized arterioles with intimal hyperplasia and fibrosis (H&E, original but are not limited to parathyroid hormone, magnification 4x). corticosteroids, aluminum, liver disease, and various other forms of inflammation.13,15 Osteoprotegerin (OPG) is a protein that inhibits osteoclast formation and has a significant relationship to bone density and prevention of calcification in inappropriate areas of the body. Bucay et al. demonstrated that mice deficient in this protein exhibited a decrease in total bone density and high incidence of fractures. Unexpectedly, they also noted that mice deficient in this protein exhibited medial calcification of the aorta and renal arteries.16 This suggests a crucial role for OPG in calcification, once again showing the importance of gene regulation in extraosseous calcification, leading to a potential correlation with calciphylaxis.

By far the most common disease associated with calciphylaxis is end-stage renal disease, a correlation that has increased in frequency in the last decade. In a retrospective study performed by Mazhar et al., patients diagnosed with calciphylaxis and end-stage Figure 4: Dermatohistopathology revealed calcification of the subcutis (H&E, original renal disease over a 10-year period were magnification 40x). observed and treated according to study designs. They collectively reviewed the risk atheroembolus syndrome, septic emboli, process.3 Although poorly understood, there factors for calciphylaxis and determined that oxalosis, protein C or S deficiency, Coumadin are a number of associated diseases and female gender, low serum albumin, elevated necrosis, lupus antiphospholipid syndrome biological triggers that play a convincing serum phosphate, and higher serum alkaline and other calcifying disorders are convincing role in this condition.14 As stated previously, phosphatase levels were all significant. They mimickers.4,7,10,11 Hence, clinical assessments the first mention of human subcutaneous also determined that patients who developed as well as other pertinent laboratory values are calcification was in relation to vascular calciphylaxis during their time in dialysis essential in making this diagnosis. calcification secondary to renal failure.1,4,5 had an eightfold increase in risk of death. It More recently, there has been work in was also determined that the increased risk Pathogenesis of Calciphylaxis: The Old and bone and cardiovascular diseases that associated with female gender was due to its New Evidence has shown a reliable relationship with relatively large proportion of adipose tissue Determining the pathogenesis of calciphylaxis calcification.13 Several very crucial parts of compared to males due to hypoperfusion has been a challenging and speculative bone mineralization are the molecular and of the skin. Similarly, persons with more

36 CALCIPHYLAXIS: CASE REPORT AND LITERATURE REVIEW abundant adipose tissue are also at increased of any clinician would be to decrease the lowers the parathyroid hormone levels and risk, leading to an association between obesity calcium-phosphate product. When there aids in the restoration of normal calcium-to- and subcutaneous calcification.9 is an absence of hyperparathyroidism, this phosphorous homeostasis, helping to reduce sodium thiosulfate can be a very adequate the risk factors for calciphylaxis. Hafner et One metal, aluminum, has been an unlikely adjunct to therapy. It is an inorganic salt that al. demonstrated that 38 of their 58 patients culprit in the formation of calciphylaxis, enhances and may restore endothelial-cell who underwent a parathyroidectomy had a backed by several pieces of supporting function through antioxidant effect. Often, prolonged survival compared to those that did evidence.1,13 Aluminum is renally cleared from 25g of sodium thiosulfate is given with dialysis not undergo the surgery.7 This treatment is still the body, and toxic levels of aluminum are three times per week, especially when Class controversial to some practicing physicians as often not reached without pre-existing renal II calcimimetics or bisphosphonates are of it also comes with side effects. Moreover, not insufficiency.1 Weenig et al. demonstrated no avail. In a small case study, Ackermann et all patients are candidates for this operation, that aluminum levels greater than 25ng/ml al. noted a marked decrease in livedo as well and a proper medical evaluation must be are much more common in calciphylaxis as normalization of calcium and phosphate performed prior to this treatment. A larger patients. To parallel this finding, aluminum, levels. In that case, almost six weeks prior to and more focused series looking at patients which is found to be deposited in the bone, the beginning of treatment, those lesions were treated with parathyroidectomy is required, as is directly related to the severity of arterial well healed, and within two more weeks the current reports are anecdotal. calcification and acts directly on osteoblasts.1,13 patient was taken off therapy without relapse Furthermore, the severity of bone aluminum for several months.18 While sodium thiosulfate More recently, a focused approach that deposition is directly proportional to the has been shown to reduce the level of rebound addresses hypercalcemia, hyperphosphatemia, extent of arterial calcification in patients following dialysis sessions, it cannot be fully and hyperparathyroidism has been implicated. who are undergoing dialysis.13 Since it is ascertained which part of the treatment, Weenig et al. proposed a combination therapy unclear whether or not aluminum itself is dialysis or sodium thiosulfate, played the that addressed the pathologic components of related to dialysis, it is safe to assume that greater role in the resolution of lesions. calciphylaxis, which are vascular thrombosis renal impairment is the leading cause of the and the cutaneous ischemia related to it. accumulation of the metal. Another adequate second-line agent, By treating the vascular complications with cinacalcet hydrochloride, has been utilized thrombolytic agents and anticoagulation Although there are many intricate pathways in multiple cases as well.7,14,17 Cinacalcet medications as well as hyperbaric oxygen that seem to be involved in the pathogenesis hydrochloride, a calcimimetic that lowers therapy, there may be a way to decrease the of calciphylaxis, not one has been solely the levels of parathyroid hormone in regions of cutaneous ischemia. In addition, implicated. Therefore, it is important to patients receiving dialysis, may be utilized Weenig suggests the use of whirlpool therapy take into consideration all the various data carefully. According to Robinson et al., 30 rather than manual debridement, which is available but always consider the most mg of cinacalcet hydrochloride every day can far more painful and requires downtime. common causes when suspecting this successfully treat the symptoms of patients Although these are all valid options, it is condition. with calciphylaxis. After treatment with important to involve the necessary additional cinacalcet hydrochloride for several weeks, medical services as well: Endocrinology, Past, Present and Future in Treatment patients reported less pain in the area, and nephrology and dermatology are all key Calciphylaxis is a condition that the parathyroid level continued to decline players in the treatment of these patients.13 dermatologists are often called in to diagnose. progressively. There was also progressive re- When it comes to treatment options, it epithelization of the wound area, and after Conclusion is difficult to take into consideration the five months of consistent therapy, ulcerations The condition of calciphylaxis can no longer multitude of co-morbidities associated with markedly improved. Cinacalcet hydrochloride be avoided as an important area of study. the condition as well as prescribe one adequate is generally well-tolerated, and the most While it is extremely rare, it is a potentially treatment. More commonly, nephrology, frequently reported side effects were nausea life-threatening condition, often related to internal medicine, surgery, and dermatology and vomiting. During this treatment measure, dialysis. Understanding the key cutaneous must come together to treat this condition. calcium levels were adequately monitored to findings and course of this disease is essential. assess for the risk of hypocalcemia. Since it is The progressive nature of the disease has It is often a therapeutic challenge to balance a class II calcimimetic, it targets the calcium- encouraged countless physicians to devote the symptoms of this condition with its sensing receptor of the parathyroid gland’s more time to uncovering its often indolent internal manifestations, which more often chief cells. It induces a conformational change course. Since the first case in 1898, significant than not are related to dialysis. There has not that increases the sensitivity to circulating headway has been made in developing a more been any optimal treatment for calciphylaxis calcium. It has the additional use of treating case-by-case approach to therapy, although determined, but many explored modalities secondary hyperparathyroidism.17 In view larger patient populations must be studied. have been partially therapeutic. There has of the results demonstrated by Robinson et Hopefully, there will be further investigation been experimentation with low-dose tissue al., there could be some promise in treating into the particular cause and treatment of plasminogen activator, parathyroidectomy, calciphylaxis patients medically. this devastating condition, which deserves hyperbaric oxygen, wound debridement, significant physician attention and care. intravenous sodium thiosulfate, low- The most successful surgical treatment so molecular-weight heparin, and zero-calcium far has been parathyroidectomy, which References: dialysate.17 has not only reduced most of the external 1. Weenig R, Sewell L. Calciphylaxis: manifestations of the disease but also provided Natural history, risk factor analysis, and By far and for many years, the first-line prolonged survival.7,17 For some, it has outcome. Journal of American Academy treatment for calciphylaxis has been sodium been a treatment of choice for those who of Dermatology. 2006(April 2007): p. thiosulfate. When calciphylaxis is related have an unknown etiology associated with 569-79. to end-stage renal disease, the major aim hyperparathyroidism. A parathyroidectomy

REGAN, KLEYDMAN, HOFFMAN 37 2. Doctoroff A, Purcell S. Protracted matrix GLA protein. Nature. 1997. Calciphylaxis Part I. Cutis, 2003. 71: p. 386(6620): p. 78-81. 43-475. 16. Bucay N. Osteoprotegerin-deficient mice 3. Mathur R, Shortland JR. Calciphylaxis. develop early onset osteoporosis and Post Graduate Medicine Reviews. 2000. arterial calcification. Genes and 77: p. 557-561. Development. 1998. 12: p. 1260-1268. 4. Selye H, Gentile G, Prioreschi P. 17. Robinson M, Augustine J. Cinacalcet for Cutaneous Molt Induced by the Treatment of Calciphylaxis. Archives Calciphylaxis in the Rat. Science. 1961. of Dermatology. 2007. 143(Feb 2007): p. 134(3493): p. 1876-1877. 3. 5. Nigwekar S, Wolf M. Calciphylaxis from 18. Ackerman F, Levy A, Sodium Thiosulfate Nonuremic Causes: A Systematic as First-Line Treatment for Calciphylaxis Review. Clinical Journal of American Archives of Dermatology. 2007. Society of Nephrologists, 2008. 3. 143(October): p. 1. 6. Gipstein RM, et al. Calciphylaxis in Man: A Syndrome of Tissue Necrosis and Vascular Calcification in 11 Patients With Chronic Renal Failure. Arch Intern Med. 1976. 136(11): p. 1273-1280. 7. Hafner J, et al. Uremic small-artery disease with medial calcification and intimal hyperplasia (so-called calciphylaxis): A complication of chronic renal failure and benefit from parathyroidectomy. Journal of the American Academy of Dermatology. 1995. 33(6): p. 954-962. 8. Chan YL, et al. The vascular lesions associated with skin necrosis in renal disease. British Journal of Dermatology, 1983. 109(1): p. 85-96. 9. Mazhar AR, et al. Risk factors and mortality associated with calciphylaxis in end-stage renal disease. Kidney Int. 2001. 60(1): p. 324-332. 10. Fischer AH, Morris DJ. Pathogenesis of calciphylaxis: Study of three cases with literature review. Human Pathology. 1995. 26(10): p. 1055-1064. 11. Essary L, Wick M. Cutaneous Calciphylaxis. American Society for Clinical Pathology. 2000. 113: p. 280-287. 12. Nikko AP, Dunningan M, Cockerell CJ. Calciphylaxis with Histologic Changes of Pseudoxanthoma Elasticum. The American Journal of Dermatopathology. 1996. 18(4): p. 396- 399. 13. Weenig RH. Pathogenesis of calciphylaxis: Hans Selye to nuclear factor [kappa]-B. Journal of the American Academy of Dermatology. 2008. 58(3): p. 458-471. 14. Schliep S, Schuler G. Successful treatment of calciphylaxis with pamidronate. European Journal of Dermatology. 2008. 18(5): p. 554=556. 15. Luo G, et al. Spontaneous calcification of arteries and cartilage in mice lacking

38 CALCIPHYLAXIS: CASE REPORT AND LITERATURE REVIEW Klippel-Trénaunay syndrome: A case report and review of the literature

Mariel Bird, DO,* Michael Centilli, DO,** Steven Grekin, DO, FAOCD*** *PGY-2 Resident, Oakwood Southshore Department of Dermatology, Trenton, MI **PGY-1 Intern, Pontiac Osteopathic Hospital, Pontiac, MI ***Program Director, Oakwood Southshore Department of Dermatology, Trenton, MI

Abstract Klippel-Trénaunay syndrome (KTS) is a rare congenital malformation characterized by the triad of capillary malformations, atypical varicose veins, and hypertrophy of bone and/or soft tissue typically affecting one extremity. The extent of clinical involvement varies on an individual basis, and significant morbidity can accompany the disease. The exact etiology of KTS remains largely unknown, but may be related to inappropriate angiogenesis. We present a case of KTS occurring in a 73-year-old Caucasian female and discuss clinical features, diagnosis and management.

Case Presentation pitting edema of the right lower extremity slightly elevated D-dimer level (0.89 mcg/mL were evident (Figure 1). Examination of the fibrinogen equivalent units). Fibrinogen and A 73-year-old Caucasian female presented left lower extremity was benign and did not coagulation assays were within the normal to the clinic with an ulcer on her right foot, reveal findings similar to those of the right limits, as were kidney and liver functions. A present for approximately one month. She lower extremity. A large, erythematous and chest radiograph displayed hyperinflation described it as exquisitely painful and noted violaceous cutaneous hemangioma with of the lungs in the absence of infiltrates, and occasional hemorrhage with the presence multiple palpable varicosities encompassed the a recommended CT scan of the chest was of serous crust. Additionally, she had back, crossing the midline in an asymmetric refused. Venous ultrasound of the right lower increased edema localized to her right lower pattern (Figures 2 and 3). extremity visualized multiple superficial extremity. She had experienced multiple varicosities with minimal calcification, and episodes of similar symptoms in the past for The findings of a cutaneous capillary there was no evidence of acute deep venous which she was treated with oral antibiotic malformation, venous varicosities, and thrombosis. Arterial Doppler ultrasound of therapy. Review of systems was negative for hypertrophy of a single limb were consistent the right lower extremity was also performed, constitutional symptoms. with a diagnosis of Klippel-Trénaunay displaying triphasic waveforms in all arteries syndrome. A venous ultrasound of the Her past medical history was significant for except for the anterior tibial artery, which lower extremity was offered to assess for emphysema, hypertension, atrial fibrillation, exhibited a biphasic waveform. At this time deep venous thrombosis, but the patient phlebitis, and deep venous thrombosis. the vascular surgeon determined that our refused. Topical lidocaine ointment, topical Current medications included atenolol, patient was not a candidate for surgical garamycin ointment and oral cephalexin lisinopril, warfarin and lidocaine ointment. intervention. were prescribed for treatment. By the 10-day She was allergic to multiple medications follow-up appointment, her condition had After a three-day hospitalization, our patient’s including bacitracin, amoxicillin, clindamycin progressed, developing 2+ edema, increasing ulceration had significantly improved, and and sulfa drugs. No other family members pain, and necrotic crust. After a thorough her fever and leukocytosis had resolved. She were similarly affected. discussion with the patient, a vascular surgery elected not to pursue any further testing to Physical examination revealed a 10 mm consultation was requested, and she was evaluate the extent of her disease, and we ulceration with hemorrhagic crust on admitted to the hospital for IV antibiotic determined that she was not an appropriate th the dorsal right 4 metatarsal. The lesion therapy. candidate for invasive therapy secondary to was located within an erythematous and her multiple medical comorbidities. Daily Upon admittance to the hospital, the violaceous plaque spanning the digits and compression therapy with 30-40 mmHg patient’s vitals were stable but did show a lateral aspect of the foot. A thick, adherent pantyhose was recommended, and she was low grade fever of 100.1 degrees Fahrenheit white scale was also present on the surface (37.8 C). Laboratory testing revealed a of the plaque. In addition, soft tissue and mild leukocytosis (11.1 x 10^3 mL) and a bony hypertrophy of the right foot and 1+ BIRD, CENTILLI, GREKIN 39 color and span large amounts of skin over the affected limb with poorly demarcated borders. Patients affected by blotchy/segmental stains tend to exhibit the other symptoms of KTS, such as hypertrophy and varicosities, at a later point in life than those with geographic stains.5,6 It is important to clinically classify the capillary malformation of patients, as Maari and Frieden were able to correlate geographic stains with an increased presence of lymphatic malformations and risk of complications. As the patient matures, the geographic stains are prone to bleeding and may develop lymphatic macrocysts known as blebs. The presence of lymphatic hypoplasia with abnormal drainage increases the probability of cellulitis and gram-negative bacteremia in these patients. Geographic stains may actually represent a combined lymphatic-capillary/venous malformation. A higher rate of presentation of these lesions at birth than the segmental stains may help identify infants and children that need to be more closely monitored for complications.6 Venous varicosities are present in 72% of cases of KTS.3 They may be recognized in early infancy but typically do not become prominent until the child becomes ambulatory or spends more time in the upright position. Varicose veins in KTS are most commonly located below the knee but may also present on the thigh and in the pelvic region.2,5,6 Persistence of the embryonic lateral marginal vein spanning the full length of the lateral limb is observed in 56% of patients.3,5 Local consumption of coagulation factors secondary to venous stasis leads to microthrombi that bind calcium and form a palpable phebolith. A large number of patients have recurrent instructed to continue her anticoagulation the triad of KTS, lymphatic malformations bleeding in the subsynovial vascular plexus therapy with warfarin. After two months, the and deep venous anomalies including venous within the knee joint and may present with ulceration had completely resolved and our incompetence, aneurysmal dilatation, loss of knee motion, swelling or morning patient was doing extremely well with her hypoplasia, and aplasia are also associated stiffness from knee arthropathy.4 therapy. Long-term follow-up with our patient with the disease.2 was discontinued due to relocation. A wide spectrum of deep venous anomalies The most common manifestation of KTS is occurs and may impact internal organs the capillary malformation or port-wine stain, such as the liver, kidney, gastrointestinal 2,3 which occurs in 98% of patients. This is 3,5,7 Discussion tract, heart and lungs. In patients with typically noted at birth and most frequently extensive vascular malformations of the Klippel-Trénaunay syndrome was first 5 involves a single lower extremity. Ipsilateral lower limb that extend to the trunk, there described in 1900 by the French physicians involvement of both the upper and lower is a three-fold greater likelihood of visceral Klippel and Trénaunay and was termed extremities is found in about 10% to 15% of anomalies. Absence of lesions on the trunk “naevus vasculosus osteohypertrophicus.”1 cases, and rarely, contralateral extremities does not exclude visceral involvement, and KTS is a rare congenital malformation 5 are affected. They can be further classified patients may present with pain, hemorrhage, characterized by the triad of capillary as having either a “geographic” or “blotchy/ genital lymphedema, or gross hematuria. malformations, atypical varicose veins, 5,6 segmental” pattern. The geographic Recurrent or unresolved pulmonary embolism and hypertrophy of bone and/or soft tissue stains have confluent, well-defined borders (PE) can lead to chronic thromboembolic typically affecting one extremity. All three throughout the extent of the lesion and pulmonary hypertension. In the absence of features of KTS need not be present to confer typically display an intensely saturated, red-to- PE, pulmonary arterial hypertension (PAH) the diagnosis; the occurrence of two of violaceous color. The most common location may occur from small-vessel abnormalities these features is sufficient.2,3 The incidence for geographic stains is laterally along the that lead to endothelial dysfunction and is reported as <1:10,000, and the condition thigh, knee and lower leg. Conversely, the 4 4 activation. affects and females equally. In addition to blotchy/segmental stains are pink to red in

40 KLIPPEL-TRÉNAUNAY SYNDROME: A CASE REPORT AND REVIEW OF THE LITERATURE Hypertrophy of the bones or soft tissue (3D-MR) venography may be most useful Cellulitis is a common problem, especially in of an affected limb is the most variable to assess the musculoskeletal extent of the patients with a geometric-pattern capillary cardinal feature of KTS and occurs in 67% malformation, characterize bone-density malformation and associated lymphatic of patients.3 Hypertrophy of the soft tissue changes, study limb dissymmetry and abnormalities.6,16 Prophylactic antibiotics are leads to an increase in the limb girth, while thoracic or pelvic involvement, and verify necessary for patients with recurrent episodes hypertrophy of the osseous structures leads the presence and patency of the deep venous or persistent ulcers after bacterial culture to an increase in limb length.8 The type and system. However, there is radiation exposure and antibiogram.4 The administration of location of vascular malformations have been and contrast administration. Indirect low-molecular-weight heparin in patients shown to influence soft-tissue hypertrophy, magnetic resonance venography provides with localized intravascular coagulation and therefore clinical presentation is widely precise volumetric extent while also depicting and the clinical presence of pheboliths not variable and the rate of progression is anatomy and patency. Given the young age only decreases thrombosis risk by reduction difficult to predict. Extent of the vascular at which these patients might present and the of D-dimer levels and normalization of malformation lesion is the single independent need for sequential follow-up and therapeutic fibrinogen levels, but also provides pain relief.4 risk factor for leg-length discrepancies, planning, indirect magnetic resonance Of note, pain is a prevalent morbidity factor regardless of the type or depth of the lesion.2-5,8 venography is now the most suitable imaging in KTS and affects up to 88% of patients, Common complications associated with leg- technique.4,15 with chronic venous insufficiency as the most length discrepancies include vertebral scoliosis Lymphoscintigraphy with radionuclide tracers frequent cause. Cellulitis, thrombophlebitis, 7 Extensive vascular and gait abnormalities. may be utilized in those individuals with DVT, vascular calcifications, growing pains, malformations, especially when situated significant girth discrepancy to determine the intraosseous vascular malformations, arthritis, deeply in soft tissue, may cause reactive and neuropathic pain have also been identified presence of abnormal lymphatic drainage and changes in bone including demineralization 13 as common etiologies of pain. Sporadic 4 assess the risk of infection. Bone vascularity leading to pathologic fractures. and regional blood flow can also be evaluated use of analgesics and non-steroidal anti- Etiology with scintigraphy.7 inflammatory drugs may be effective, but treatment should be directed to the underlying The etiology of KTS remains largely unknown. Bone-involvement evaluation should include cause of the pain.16 Recent findings in several case studies suggest annual clinical and radiologic measurements Common procedures to reduce superficial a genetic component to the disease, with the of limb length with plain radiographs varicosities include venous stripping, possibility of several genes contributing to the starting after age 2 until skeletal maturity ligation, endovascular laser ablation, and pathogenesis in different patients. Somatic is reached.4 Yearly evaluation will provide sclerotherapy.7,16 Foam sclerosants are mutations in angiogenic factors that are insight into the rate of progression and can recommended over traditional ethanol-based critical during embryonic development may aide in determining the timing of leg-length sclerosants, which may be too aggressive lead to an inappropriate angiogenesis and equalization procedures.2 in large lesions.4,7,14,16 Despite a nearly 50% production of vascular malformations.3,10-12 A baseline D-dimer, fibrinogen, coagulation recurrence rate of varicosities following Diagnosis and Imaging assay and platelet count should be measured. invasive procedures, patients reported an Evaluation is best performed with a variety Elevated D-dimer levels are highly specific for overall clinical improvement and decrease in 16 of noninvasive imaging techniques.13 Initial venous malformations, and fibrinogen levels symptoms. are usually low. Platelet count may be slightly evaluation of the extremities should include Port-wine stains may be a cosmetic concern reduced. Local intravascular coagulation an arterial and venous Doppler ultrasound. for patients, and pulsed dye laser is currently (LIC) favors the production of thrombi. The In addition to providing hemodynamic the first-line therapy. Generally, several continuous formation of thrombi consumes information, this is non-invasive and treatment sessions are needed, and the coagulation factors, which can then favor economical. A greater than 50% change in response is worse for acral sites than in facial bleeding, and activation of disseminated arterial dynamics is a significant predictor of lesions, perhaps due to gravitational effects on intravascular coagulation can occur. Patients future limb-length discrepancies. A Doppler capillary pressure. Laser treatment of venous with KTS are known to be at a higher risk for examination of arterial blood flow should malformations is limited to superficial lesions PE and PAH, and a recent study revealed that be conducted in children > 1 year of age or may be combined with sclerotherapy. The statistically significant PAH correlated with with extensive malformations of the lower most commonly used laser for this is the long- 4 levels of D-dimer when compared to a healthy limb. Changed vascular dynamics warrant pulsed neodymium-doped yttrium aluminum control population. All patients with extensive evaluation with arterial/venous angiography. garnet (Nd:YAG) 1064nm.4 Although invasive, these studies provide a slow-flow vascular malformations should be referred for an echocardiogram to exclude the Orthopedic surgical intervention is indicated more detailed picture of anatomy. presence of PAH.15 for projected leg-length discrepancies of Magnetic resonance imaging (MRI) 2,4,7 Treatment greater than 2.0 cm. Although the most is the study of choice for soft-tissue suitable age is around 11 years, determining evaluation, but also allows visualization Patients with KTS are best initially evaluated the appropriate timing of intervention is of vascular malformations and lymphatic and treated in a center with an experienced crucial in achieving limbs of similar length 4,5,7 15 abnormalities. The development of a knee multidisciplinary team. Day-to-day at skeletal maturity, further emphasizing the flexion contracture is an urgent indication for treatment of low-flow vascular malformations need for yearly radiographs of the limbs. an MRI, even in young children. Irreversible leading to edema can be treated with Procedures aim at either halting limb growth 4,5 knee arthropathy occurs from a chronic compression garments. Lymphedema may or elongating bone.4 In minor cases of leg- synovial inflammatory response and erosion be treated with manual technique combined length discrepancy, shoe lifts or heel inserts of local articular cartilage and bone if surgical with exercise and pneumatic compression may be instituted to avoid developing gait 4 4,6 intervention does not occur early. garments up to 50-60 mmHg. abnormalities and scoliosis.2,7 The current Multidetector computed tomography (MDCT) Medical treatment is directed toward approach for knee arthropathy is synovectomy. and three-dimensional magnetic resonance symptom relief and preventing complications. Vascular surgery should be consulted when BIRD, CENTILLI, GREKIN 41 intense hemorrhage, refractory pain, recurrent and review of the literature. Cutis. 2009 infection, necrosis, and/or physical deformity May;83(5):255-62. are present, as partial amputation of the 4 9. Funayama E, Sasaki S, Oyama A, affected limb may be necessary. Furukawa H, Hayashi T, Yamamoto Y. How do the type and location of a Conclusion vascular malformation influence growth in Klippel-Trénaunay syndrome? Plast KTS is a rare congenital vascular Reconstr Surg. 2011 Jan;127(1):340-6. malformation that requires complex 10. Servelle M. Klippel and Trenaunay’s evaluation and therapeutic planning due to syndrome. 768 operated cases. Ann Surg. its wide range of involvement. Early detection 1985;201:365-373. of clinical manifestations and intervention at the appropriate juncture may minimize the 11. Baskerville PA, Ackroyd JS, Browse NL. morbidity associated with KTS and lead to a The etiology of Klippel Trénaunay significant improvement in quality of life. The syndrome. Ann Surg. 1985;202:624-627. psychological effects that KTS can have on the 12. Aelvoet GE, Jorens PG, Roelen LM. affected individual should not be dismissed. Genetic aspects of the Klippel-Trénaunay Treatment strategies must be individualized syndrome. Br J Dermatol. 1992;126:603- to address the needs and expectations of each 607. patient. This is best accomplished with a multidisciplinary team. 13. Berry SA, Peterson C, Mize W, Bloom K, Zachary C, Blasco P, Hunter D. Klippel-Trénaunay syndrome. Am J Med References: Genet. 1998 Oct 2;79(4):319-26. 1. Klippel M, Trénaunay P. Du nauvus 14. Redondo P, Bastarrika G, Sierra A, variqueux osteohypertrophique. Arch Martínez-Cuesta A, Cabrera J. Efficacy General Med (Paris). 1900; 185:641-672. and safety of microfoam sclerotherapy 2. Jacob AG, Driscoll DJ, Shaughnessy in a patient with Klippel-Trénaunay WJ, et al. Klippel-Trénaunay syndrome: syndrome and a patent foramen ovale. spectrum and management. Mayo Clin Arch Dermatol. 2009 Oct;145(10):1147- Proc. 1998;73:28-36. 51. 3. Timur AA, Driscoll DJ, Wang Q. 15. Bastarrika G, Redondo P, Sierra A, et Biomedicine and diseases: the Klippel- al. New techniques for the evaluation Trénaunay syndrome, vascular anomalies and therapeutic planning of patients and vascular morphogenesis. Cell Mol with Klippel-Trénaunay syndrome. J Am Life Sci. 2005 Jul;62(13):1434-47. Acad Dermatol. 2007;56(2):242-249. 4. Redondo P, Aguado L, Martinez-Cuesta 16. Lee A, Driscoll D, Gloviczki P, Clay A. Diagnosis and Management of R, Shaughnessy W, Stans A. Evaluation extensive vascular malformations of the and management of pain in patients lower limb. J Am Acad Dermatol with Klippel-Trénaunay syndrome: a 2011;65:893-906. review. Pediatrics. 2005;115(3):744-749. 5. Garzon MC, Huang JT, Enjolras O, Frieden IJ. Vascular malformations. Part II: associated syndromes. J Am Acad Dermatol. 2007 Apr;56(4):541-64. 6. Maari C, Frieden IJ. Klippel-Trénaunay syndrome: the importance of “geographic stains” in identifying lymphatic disease and risk of complications. J Am Acad Dermatol. 2004 Sep;51(3):391-8. 7. Kihiczak GG, Meine JG, Schwartz RA, Janniger CK. Klippel-Trénaunay syndrome: a multisystem disorder possibly resulting from a pathogenic gene for vascular and tissue overgrowth. Int J Dermatol. 2006 Aug;45(8):883-90. 8. Gober-Wilcox JK, Gardner DL, Joste NE, Clericuzio CL, Zlotoff B. Limb hyperplasia: case report of an unusual variant of Klippel-Trénaunay syndrome

42 KLIPPEL-TRÉNAUNAY SYNDROME: A CASE REPORT AND REVIEW OF THE LITERATURE Birt-Hogg-Dubé Syndrome – A Case Report and Review

Jennifer Moscoso,* Genevieve Midyette, PA-C,** David M. Bracciano, D.O., FAOCD***

*OMS-III, Georgia Campus – Philadelphia College of Osteopathic Medicine, Suwanee, GA ** Bracciano Dermatology, University Park, FL ***Bracciano Dermatology, University Park, FL

Case Report A 48-year-old Caucasian male presented to the dermatologist with a 10-year history of “white bumps” on his face and neck. The patient history included hypothyroidism, a pituitary tumor, and a family history of renal carcinoma of unknown type. Physical examination revealed numerous small, flesh-colored white papules on his face, neck, and chest (Figures 1 and 2). Shave biopsy of one of his lesions revealed findings consistent with a fibrofolliculoma. The pathology showed a hair follicle with thin extension of epithelium extending into the surrounding fibromyxoid stroma (Figure 3). The patient was diagnosed with Birt-Hogg- increase in the risk for renal tumors and a Dubé syndrome (BHD) and was referred 50-fold increase in the risk of pneumothorax to a cancer center for a full work-up. CT in BHD-affected individuals, adjusted for age. scans of the chest, abdomen, and pelvis as The cutaneous manifestations of BHD tend well as a colonoscopy were obtained. The to appear in the third or fourth decade of results were unremarkable. Further biopsies life. Fibrofolliculomas and trichodiscomas are were performed, which showed evidence clinically indistinguishable and require biopsy of a fibrofolliculoma and an acrochordon. for differentiation. They present as 1 mm He was referred for genetic testing and to 5 mm, smooth, skin-colored to grayish- counseling for his syndrome. If a mutation white papules usually located on the face, is not identified, then it will not be neck, and upper trunk.3 Birt et al. described necessary to refer his son for genetic testing. these tumors as “abnormal hair follicles However, because BHD is an autosomal- with epithelial strands extending out from dominant genodermatosis, his son should the infundibulum of the hair follicle into a be aware of the likelihood of development hyperplastic mantle of specialized fibrous of this disease in the future regardless tissue.”1 It is commonly thought that these of whether a gene is identified or not. benign tumors may be part of a morphological spectrum and are two presentations of the same lesions.5,6 Figure 1 Discussion Drs. Birt, Hogg, and Dubé first described Kidney neoplasms associated with BHD 4,6 BHD in 1977. They studied a family whose are usually multiple and bilateral, and members were affected with numerous they typically occur earlier than sporadic 5,6 small, white and skin-colored, dome- tumors. The most common renal neoplasm shaped papules found on the face, neck, and associated with BHD is chromophobe renal chest.1 These benign hair-follicle tumors, carcinoma. Chromophobe renal carcinomas termed “fibrofolliculomas,” appeared after are uncommon and locally invasive, 5,7 the age of 25. They discovered that this and they rarely metastasize. A mixed genodermatosis was characterized by a histologic pattern of chromophobe cancer triad of fibrofolliculomas, trichodiscomas, and oncocytoma is a typical feature of BHD- 6 and acrochordons and was inherited in an associated renal cancer. At one time, BHD autosomal-dominant fashion.1 Since the was also associated with an increased risk 2 original report, several cases of BHD have of colorectal polyps and cancers; however, been described, but its incidence is yet recent studies do not indicate an increased risk 2,4 to be established. Birt et al. made no for their development. mention of associated kidney, pulmonary, Pulmonary cysts associated with BHD are or gastrointestinal risks in their original usually located basally in the lungs, and report. Since then, several studies have their histology has been shown to be Figure 2 shown that affected individuals may consistent with emphysematous changes.6 be at risk for developing renal neoplasms, Pneumothorax associated with BHD is multiple pulmonary cysts, and spontaneous typically secondary to ruptured pulmonary pneumothorax.2-4 In the largest single study cysts and does not occur spontaneously.5 to date, Zbar et al. found almost a seven-fold Recurrent episodes of spontaneous MOSCOSO, MIDYETTE, BRACCIANO 43 pneumothorax are more common than single the angiofibromas associated with tuberous episodes in patients with BHD.6 While the sclerosis may have overlapping features with risk of spontaneous pneumothorax decreases the fibrofolliculomas in BHD.6 BHD may be with age, the risk of developing renal tumors associated with familial renal carcinomas and increases with age.7 spontaneous pneumothorax; therefore, it is A co-occurrence of various malignant and recommended that patients with BHD and benign tumors can occur in BHD. These can their relatives undergo screening tests such include deforming lipomas, collagenomas, and as CT or MRI, as they may lack cutaneous oral fibromas. Other abnormalities such as manifestations and may be asymptomatic. internal carotid-artery aplasia and congenital Once a family-specific mutation is identified, cystic lung soft-tissue masses have been genetic testing in asymptomatic at-risk reported.3,6 However, no studies have proven a relatives may also be appropriate for early Figure 3 causal relationship. detection. FLCN-mutation databases and patient support groups have been established The BHD gene locus was originally mapped to for this syndrome. Unfortunately, there are chromosome 17p12q11.2 by linkage analysis currently no established guidelines regarding References in 2001 by Khoo et al. and was later confirmed 1. Birt AR, Hogg GR, Dube WJ. surveillance methods for associated risks by multiple studies. Numerous truncating Hereditary multiple fibrofolliculomas in BHD. In 2009, Menk et al., on behalf of germline mutations have been reported in the with trichodiscomas and acrochordons. the European BHD Consortium, proposed BHD gene, and it is now possible to screen Archives of Dermatology. diagnostic criteria for BHD (Table 1) and for these pathogenic mutations.6 Eventually 1977;113:1674-1677. suggested annual renal MRI as the best named “folliculin” (FLCN), this gene was 2. Leter EM, Koopmans AK, Gille JJ, et available surveillance due to its high sensitivity found in a variety of normal tissues, including al. Birt-Hogg-Dube syndrome: clinical and avoidance of radiation exposure. As kidney, lung, and skin.5 Its function remains and genetic studies of 20 families. we gain more knowledge and a better unknown, but it is hypothesized to be a Journal of Investigative Dermatology. understanding of BHD, improved guidelines tumor-suppressor gene.3,5 2008;128:45-49. and methods of surveillance can eventually be 3. Toro JR, Glenn G, Duray P, et al. Birt- It is important to consider tuberous sclerosis established. in the differential diagnosis for BHD, as Hogg-Dube Syndrome: A Novel Marker of Kidney Neoplasia. Archives of Dermatology. 1999;135:1195-1202. Table 1. Diagnostic Criteria for Birt-Hogg-Dubé Syndrome* 4. Zbar B, Alvord WG, Glenn G, et al. Risk of renal and colonic neoplasms Patients should fulfill one major or two minor criteria for diagnosis. and spontaneous pneumothorax in the Birt-Hogg-Dube syndrome. Cancer Epidemiology, Biomarkers & Prevention. 2002;11:393-400. Major Criteria 5. Adley BP, Smith ND, Nayar R, et al. • At least five fibrofolliculomas or trichodiscomas, at least Birt-Hogg-Dube syndrome: one of which is histologically confirmed, of adult onset clinicopathologic findings and (see note below) genetic alterations. Archives of Pathology & Laboratory Medicine. • Pathogenic FLCN germline mutation 2006;130:1865-1870. 6. Menko FH, van Steensel MA, Giraud S, et al. Birt-Hogg-Dube syndrome: Minor Criteria diagnosis and management. The Lancet • Multiple lung cysts: bilateral, basally located lung cysts with Oncology. 2009;10:1199-1206. 7. Habiff, TP. Clinical Dermatology. 5th no other apparent cause, with or without spontaneous primary Edition. Elsevier, 2010. pneumothorax 8. Khoo SK, Bradley M, Wong FK, et • Renal cancer: early onset (<50 years) or multifocal or bilateral al. Birt-Hogg-Dube syndrome: mapping renal cancer, or renal cancer of mixed chromophobe and of a novel hereditary neoplasia gene to chromosome 17p12-q11.2. Oncogene. oncocytic histology 2001;20:5239-5242. • A first-degree relative with BHD 9. Elder, DE. Lever’s Histopathology of the Skin. 9th Edition. Lippincott Williams & Wilkins, 2005. Note: Fibrofolliculomas and trichodiscomas may be two presentations of the same lesion.

*Adapted from Menko et al.6

44 KLIPPEL-TRÉNAUNAY SYNDROME: A CASE REPORT AND REVIEW OF THE LITERATURE Treatment of Verruca Vulgaris with Nd: YAG 1064-nm Laser

Winifred S. Chu, D.O., M.P.H.,* Suzanne Sirota-Rozenberg, D.O.**

*PGY-II Dermatology Resident, St. John’s Episcopal Hospital, Far Rockaway, NY **Program Director, Dermatology Department, St. John’s Episcopal Hospital, Far Rockaway, NY

Figure 1. Finger with wart before (left) and after (right) laser treatment.

Case presentation A 39-year-old, healthy Caucasian female Discussion excision, and laser therapy. Immunotherapy presented to the dermatology office with a Verruca vulgaris is caused by HPV infection is aimed at eliciting an immune response to non-itchy, painless bump on her finger that (subtypes 1, 2, 4, 27, 57, and 63) and occurs HPV, which may be achieved by applying had been increasing in size for the past few mostly in children and young adults. They a topical irritant such as salicylic acid, months. Physical examination revealed a are usually asymptomatic and are transmitted cantharidin, trichloroacetic acid, podophyllum 2 mm, flesh-colored, firm, hyperkeratotic, via skin-to-skin contact. Trauma and resin, 5-fluorouracil, or tretinoin over the verrucous papule with disruption of normal maceration may facilitate initial epidermal wart. These compounds can also be used in skin markings and display of small black inoculation, and spreading may subsequently combination or with a destructive method.3,4 dots on the right middle finger, close to the occur by autoinoculation.1 Common warts Cryotherapy is one of the most commonly nail. A clinical diagnosis of verruca vulgaris often present as well-demarcated, rough, hard used first-line treatments for verruca vulgaris. was made, and the patient received multiple nodules or plaques with irregular surfaces. The wart is frozen with a thaw time of 30 to treatment sessions using liquid nitrogen for Diagnosis of verrucae is based upon clinical 45 seconds to produce a blister in one to two wart destruction. However, she reported no appearance. Spontaneous remission of warts days. A sustained 10-second freeze with a improvement at her follow-up visits, and the occurs in up to two-thirds of patients within spray gun has been found to be more effective wart remained the same size. Subsequently, two years; hence, observation is an option for than simply freezing to obtain a 2 mm to 3 the patient was prescribed topical treatments all patients.2 However, since recurrence of mm halo around the wart. The ideal frequency including imiquimod 5% cream, sinecatechins verrucae is common, early intervention may of treatment is every two to three weeks, as 15% ointment, and imiquimod 3.75% cream, be preferred to prevent wart spreading. the old blister desquamates. Complications but they did not significantly decrease the size of cryotherapy include hypopigmentation, of the wart. At her tenth visit to our office, Treatment of verruca involves two approaches: scarring, and rarely, damage to the digital the patient began to receive Nd:YAG 1064-nm destruction of the wart and induction of nerves from freezing too deeply on the side of laser therapy for wart treatment at two-week local immune reaction with immunotherapy. the digit when treating a periungual wart.1 intervals. After the completion of the fourth Destructive methods are most commonly laser treatment, the wart was completely used as initial therapy, and they include Immunotherapy may also be used for resolved (Fig. 1). cryosurgery, electrocautery, curettage, treatment of verruca vulgaris. Antiviral effect

CHU, SIROTA-ROZENBERG 45 Figure 2. Nd:YAG 1064nm Laser. can be achieved with bleomycin and interferon Conclusion 7. Sloan K, Haberman H, Lynde CW. alpha-2b, but they are reserved for recalcitrant We have demonstrated the success of utilizing Carbon dioxide laser-treatment of warts. Imiquimod 5% cream may be used to Nd:YAG 1064-nm laser in treating a verruca resistant verrucae vulgaris: retrospective induce local production of antiviral cytokines that had failed to respond to standard analysis. J Cutan Med Surg. 1998; in the skin.3 Intralesional immunotherapy treatment. Dermatologists should consider 2(3):142-5. with skin test antigens (e.g., mumps, Candida, using this laser therapy early in the course of 8. Cantatore JL, Kriegel DA. Laser surgery: or Trichophyton antigens) and HPV vaccine treating resistant warts since it is well-tolerated 5 an approach to the pediatric patient. J have demonstrated success in treating warts. by patients, and it provides timely, significant Am Acad Dermatol 2004;50:165-184. Lesions that have failed to respond to routine results that help to bring disease remission. office modalities are often successfully treated with laser therapy such as carbon dioxide or References 6,7 pulsed dye laser. Nd:YAG 1064-nm laser has 1. James WD, Berger TG, Elston DM. also been reported to be successful in treating Andrew’s Diseases of the Skin: Clinical verruca and has received FDA clearance for Dermatology, 10th Ed. Philadelphia: WB this indication (Fig. 2). Saunders, 2000:403-407.

The Nd:YAG 1064-nm laser treatment 2. Bourke JF, Berth-Jones J, Hutchinson involves the delivery of laser light irradiation PE. Cryotherapy of common viral warts at wavelength 1064 nm, which allows deeper at intervals of 1, 2 and 3 weeks. Br J penetration into thicker tissue compared to Dermatol 1995;132:433. shorter-wavelength lasers without direct skin 3. Bunney MH, Nolan MW, Williams DA. or verruca contact. This laser is also used for An assessment of methods of treating treating vascular and pigmented lesions, hair viral warts by comparative treatment removal, skin rejuvenation, onychomycosis trials based on a standard design. Br J and many other aesthetic and medical Dermatol 1976;94:667. treatments.8 A minimum of one to two 4. Focht DR, Spicer C, Fairchok MP. treatment sessions is needed, with sessions The efficacy of duct tape vs. placebo spaced two to three weeks apart. Treatment in the treatment of verruca vulgaris (the sessions usually begin using a focused lens common wart). Arch Pediatr Adolesc with a 2-mm spot under the settings of 1.5- Med 2002;156:971. ms pulse duration and energy mode of 8 or 9 (fluence of 255 J/cm² to 287 J/cm²). A Zimmer 5. Johnson SM, Roberson PK, Horn TD. cooler is used upon the end of the laser Intralesional injection of mumps treatment. In the case of our patient, a total of or Candida skin test antigens: a novel two passes over the wart was applied with each immunotherapy for warts. Arch treatment session, and the patient tolerated Dermatol 2003;20:268. the treatment very well. Upon the end of the 6. Ross BS, Levine VJ, Nehal K, et al. fourth treatment session, the patient’s wart Pulsed dye laser treatment of warts: an had completely resolved. update. Dermatol Surg 1999;25:377.

46 TREATMENT OF VERRUCA VULGARIS WITH ND: YAG 1064-NM LASER Unusual Seborrheic Keratosis: A Rare Clinical Variant

Sanjosh Singh, DO, MPH,* Suzanne Rozenberg, DO, FAOCD**

*Dermatology Resident, PGY-3, Touro University - St. John’s Episcopal Hospital, Far Rockaway, NY **Dermatology Residency Program Director, St. John’s Episcopal Hospital, Far Rockaway, NY

Abstract Seborrheic keratosis is a benign skin tumor that can occur on almost any site of the body, with the exception of the palms and soles. Linear and dermatomal distribution is rare and may be associated with fibroepithelioma of Pinkus. We report a case of a 36-year- old woman who presented with itchy brownish papules and plaques on the left lower extremity with linear distribution for 10 years. Diagnosis was confirmed histologically as seborrheic keratosis. This case presents as a rare clinical variant with only four other reported cases in the current literature.

Figures 1- 3: Tan brown papules and plaques on the left lower extremity with a solitary erythematous, atrophic plaque at biopsy site. Case Report A 36-year-old woman presented with a A biopsy was performed, and the surface, rarely more than 3 cm in diameter. 10-year history of itchy brownish papules histopathology showed hyperkeratosis and They are located mostly on the chest and back, and plaques in a linear distribution on the acanthosis with basaloid appearance and true but also commonly involve the scalp, face, anterior left lower extremity. Lesions gradually and pseudo horn cysts in the epidermis. This neck and extremities, sparing the palms and increased in size and number over time. is consistent with seborrheic keratosis.1 soles. Occasionally, genital lesions are seen. Patient denied history of underlying disease, The lesions appear to increase with age, and and family history was non-contributory. Discussion: although the pathogenesis is unknown, they She stated that the lesions were treated Seborrheic keratoses are common, benign skin are thought to develop from the proliferation with cryotherapy one year prior, providing tumors and usually present as multiple oval, of keratinocytes of the epidermis.2,3 temporary relief although some lesions slightly raised, light brown to black, sharply recurred. demarcated papules or plaques with a scaly SINGH, ROZENBERG 47 Typical lesions of the trunk are much more common in white persons; however, the “dermatosis papulosa nigra” variant of the central face is common in African Americans and Asians.2,3 The lesions are usually asymptomatic, but can be itchy.2,3 The lesions tend to be self-limited, and the appearance of new lesions may continue for a few years.2,3 There have been no reports of malignant changes. Differential diagnosis includes linear verrucous epidermal nevus, lichen striatus, verruca plana and verruca vulgaris.

Linear verrucous epidermal nevi are verrucous, skin-colored, dirty gray or brown papules, which coalesce to form a serpiginous plaque. The age of onset is generally at birth, but it also may develop within the first 10 years of life. They follow the lines of Blaschko. Rarely, keratinocytic and adnexal malignancies occur in the epidermal nevi.2

Lichen striatus presents as small, 1 mm to 3 mm papules that are erythematous and slightly scaly. They coalesce to form a band 1 cm to 3 cm wide, either continuous or interrupted, that over a few weeks progresses down the extremity or around the trunk, following the lines of Blaschko. Most frequently, it appears before age 6, but young adults, and more uncommonly older adults, may also be affected. Ten percent or fewer of cases occur on the face. Nail involvement can occur, such as nail-plate thinning, longitudinal ridging, splitting, and nail-bed hyperkeratosis. All lesions, including nail dystrophy, spontaneously resolve without scarring, although hypopigmentation may persist for several years.2

Verruca plana, or flat warts, are most often caused by HPV-3, 10, 28 and 41. Children and young adults are primarily affected. Flat warts present most typically as 2 mm to 4 mm, flat- topped papules that are slightly erythematous or brown on pale skin and hyperpigmented on darker skin. They are generally multiple and grouped, most commonly occurring on the face, neck, dorsa of the hands, wrists, elbows or knees. Flat warts have the tendency to Koebnerize, forming linear, slightly raised, papular lesions. In men who shave their beards and in women who shave their legs, numerous flat warts may develop as a result of autoinoculation. Of all clinical HPV infections, flat warts have the highest rate of spontaneous remission.2

Verruca vulgaris, also known as common warts, occurs largely between the ages of 5 and 20, with only 15% occurring after the age of 35. HPV-1, 2, 4, 27, 57 and 63 cause Figures 4-6: Histology images showing hyperkeratosis and acanthosis with true and common warts. Common warts can occur pseudo horn cysts in the epidermis. anywhere on the skin but commonly arise on the hands, favoring the fingers and palms. They grow in size for weeks to months and

48 UNUSUAL SEBORRHEIC KERATOSIS: A RARE CLINICAL VARIANT usually present as elevated, rounded papules Pattern on the Back of Elderly Patient. with a rough verrucous surface. Periungual Arch Dermatol, 1998; Mar 134(3):382-3 warts are more common in nail blisters and may be confluent, involving the proximal and lateral folds. Common warts usually resolve spontaneously.2

In current literature, one 44-year-old female patient has been described as having multiple fibroepithelial basal-cell carcinomas (FEBCC) associated with seborrheic keratosis, distributed in a neviform fashion on the left side of the body.4 Differential diagnosis included Bazex-Dupré-Christol and Rombo syndromes and nevoid basal-cell carcinoma syndrome. There is one report of distribution along skin cleavage lines on the lower back and waist of a 65-year-old-woman,5 and another more recent report of 16-year-old female with linear and dermatomal seborrheic keratosis on the right side of the lower chest without underlying disease.6 Raindrop pattern on the back of elderly patients has also been described.7

This case presents as a rare clinical variant of seborrheic keratosis, and although the patient did not report underlying disease, clinicians should be aware of the potential risk of associated BCC. In our office, the patient was treated with cryotherapy; however, further work-up and biopsies may be warranted. Unfortunately, she was lost to follow-up.

References: 1. Rapini RP. Practical Dermatopathology. 1st Ed. Philadelphia, PA: Elsevier Inc., 2005. pg.132 2. James WD, Berger TG, Elston DM. Andrews’ Diseases of the Skin Clinical Dermatology. 10th Ed. Philadelphia, PA: Elsevier Inc Publisher, 2006. pg.637-8 3. Wolff K, Johnson RA. Fitzpatrick’s Color Atlas and Synopsis of Clinical Dermatology. 6th Ed. McGraw-Hill Professional Publisher, 2009. pg.215 4. Rodriguez RA, Neto CF. Multiple Fibroepithelial Basal Cell Carcinoma of Pinkus Associated with Seborrheic Keratosis in a Nevoid Distribution. Journal of Dermatology, 2000; May 27(5):341-5 5. Li X, Zhu W. A Case of Seborrheic Keratosis Distributed Along Skin Cleavage Lines. Journal of Dermatology, 1998; April 25(4):272-4 6. Darjani A, Ramezanpour A. Seborrheic Keratosis: A Rare Clinical Appearance. The Internet Journal of Dermatology, 2000 Volume 1 Number 2 7. Hefferan P, Khavari A. Raindrop Seborrheic Keratosis, A Distribution

SINGH, ROZENBERG 49 An Interesting Case of Familial Firm Facial Papules: Basal Cell Nevus Syndrome or Multiple Hereditary Infundibulocystic Basal Cell Carcinoma?

Charisse L. McCall, DO,* Suzanne Sirota Rozenberg, DO, FAOCD**

*Second-year Dermatology Resident, St. John’s Episcopal Hospital, Far Rockaway, NY **Program Director, Dermatology Residency, St. John’s Episcopal Hospital, Far Rockaway, NY

Abstract: Multiple facial papules concentrated in the nasolabial folds are an important clue to an underlying genodermatosis and should initiate a thorough work-up. Basal-cell nevus syndrome (BCNS), or Gorlin’s syndrome, is an autosomal-dominantly inherited disorder with a mutation in the PTCH gene that predisposes to tumor formation. Patients classically have multiple basal-cell carcinomas, odontogenic keratocysts of the jaw, palmoplantar pits, calcification of the falx cerebri, medulloblastomas, and skeletal anomalies. Multiple hereditary infundibulocystic basal-cell carcinoma (MHIBCC) and generalized basaloid follicular hamartoma syndrome (GBFHS) are newly described syndromes that are also linked to a PTCH gene defect, but they have milder presentations. We describe a patient who meets the current criteria for BCNS, but due to her relatively indolent course we believe her condition is more likely to fit the diagnosis of MHIBCC. The following is a review of the differential diagnoses for multiple facial papules and a summary of current treatment options.

CASE A 55-year-old white female presented to the office complaining of an irritated lesion at the left nasal ala and a cyst on the right upper arm that continually became infected despite repeated incision and drainage. Her medical history included anxiety and ovarian cysts. She was taking no medications and reported an allergy to penicillin. On exam, there was a flesh-colored nodule with a central punctum at the right upper posterior arm, which was later excised and found to be an epidermoid cyst. There was a crusted pearly papule at the left nasal ala which was biopsied and found to be a nodular basal-cell carcinoma. Incidentally, the patient was noted to have multiple firm, flesh-colored, 1 mm to 3 mm facial papules, especially concentrated in the nasolabial folds (see Figure 1). When the patient was questioned about the lesions, she Figure 1: Note the multiple flesh-colored papules, predominantly in the nasolabial folds. said they had been present for many years and The wound at the left nasal ala represents the biopsy site, which proved to be a nodular did not think they were of concern. Several of BCC. the facial papules were periodically biopsied, referred to Mohs surgery for treatment of the ribs or vertebral abnormalities. We plan to and the diagnosis of infundibulocystic basal- nodular basal-cell carcinoma of the left nasal treat the multiple infundibulocystic BCC cell carcinoma was elucidated. The patient ala. The patient was referred to genetics to test with Levulan photodynamic therapy, which was also noted to have scattered small palmar for PTCH, PTEN and BHD genes. is emerging as a promising treatment for this pits on exam (see Figure 2). condition. As of this report, the patient has been Family history included a mother with temporarily lost to follow-up. When infundibulocystic basal-cell carcinoma and contacted she informed us that she needs to basal-cell hamartomas. The patient’s brother BASAL CELL NEVUS SYNDROME put her medical care on hold in order to tend had a history of BCC and a brain tumor of to her 16-year-old niece, who has developed Basal-cell nevus syndrome (BCNS) is also unknown type diagnosed at age 40. Another four brain tumors. The largest of the tumors referred to as nevoid basal-cell carcinoma brother had frontal bossing and multiple was resected and found to be glioblastoma on syndrome (NBCCS), Gorlin syndrome and facial papules, many of which were shown to pathologic examination. To further solidify Gorlin-Goltz syndrome. It is an autosomal- be basal-cell carcinoma. The patient was sent our diagnosis we would like to obtain a skull dominantly inherited disease linked to a for a panorex of the jaw, which was negative X-ray to look for calcification of the falx gene defect in the sonic hedgehog signaling for odontogenic keratocysts. She was also cerebri and a chest X-ray to check for bifid pathway that predisposes patients to 50 AN INTERESTING CASE OF FAMILIAL FIRM FACIAL PAPULES: BASAL CELL NEVUS SYNDROME OR MULTIPLE HEREDITARY INFUNDIBULO- CYSTIC BASAL CELL CARCINOMA? Figure 3: Infundibulocystic BCC. Note the well-circumscribed aggregate of basaloid buds and cords in the upper dermis with peripheral palisading, scant stroma with clefting, and infundibular cystic structures filled with cornified cells. (Photomicrograph provided by the courtesy of Dr. Paul Chu, Dermpath Diagnostics, Port Chester, NY.) developmental abnormalities and neoplasm is almost complete penetrance of the PTCH1 established. The literature reports anywhere formation.1,2 A family with basal-cell mutation, but expression is widely variable. from 8% to 90% of BCNS patients developing carcinomas, jaw cysts and bifid ribs was first Inactivation of the gene has been proposed BCCs before age 40, sometimes before age described to have this syndrome by Doctors to be caused by a “two-hit” hypothesis, the 10, with fair-skinned patients generally first occurring in the germline and the second developing the tumors at an earlier age and Gorlin and Goltz in 1960. It appears, however, 3 to date back to the Dynastic Period (3000- occurring postnatally. A few cases of NBCCS in higher numbers. Previous criteria for 2575 BC), as shown by two Egyptian skeletons have been shown to be caused by mutations BCNS have differed, with some sources listing in the PTCH2 gene on chromosome 1p32 “multiple BCCs or a BCC before age 20” as discovered to have the characteristic bony 3 changes of Gorlin syndrome.1 The syndrome and the suppressor of fused (SUFU) gene on a major criterion, and others listing “greater chromosome 10q24-q25. PTCH1, PTCH2 than five BCCs in a lifetime or a BCC before is now thought to affect 1 in 40,000 to 57,000 2 people.2 and SUFU are all tumor-suppressor genes of age 30” as a criterion. the Hedgehog (Hh) signaling pathway and In 2005, the first international colloquium regulate the production of growth-promoting on basal-cell nevus syndrome was held at the transcription factors.2,4 Etiology and Pathogenesis A defect in PTCH Saint Louis University School of Medicine. leads to increased smoothened activity, which An inactivating mutation in the patched or The following guidelines were proposed after leads to increased Gli activity and finally a literature review and roundtable discussion PTCH1 gene located on chromosome 9q22.3 causes uninhibited cell-cycle progression.5 has been shown to be responsible for most between 15 experts in the field: A patient cases of Gorlin syndrome. About 70% of must either (1) meet one major criterion and have molecular confirmation; (2) meet two these mutations are gene rearrangements Clinical Presentation that lead to truncated protein formation.2 major criterion; or (3) meet one major and PTCH1 mutations are autosomal-dominantly Basal-cell carcinomas (BCC) arise in nearly two minor criteria (see Table 1). inherited in most cases, but 35% to 50% of all BCNS cases, but the frequency and age cases are thought to be new mutations.3 There of onset of the tumors have not been fully MCCALL, ROZENBERG 51 Table 1: Diagnostic Criteria for Basal-Cell Nevus Syndrome1,2

Major Criteria Minor Criteria

(1) BCC prior to age 20 or excessive number of (1) rib anomalies (classically bifid ribs) BCCs out of proportion to sun exposure and skin type (2) odontogenic keratocyst of the jaw prior to age (2) other skeletal abnormalities (vertebral 20 anomalies, kyphoscoliosis, short 4th metacarpals, polydactyly, frontal bossing) (3) palmar or plantar pitting (3) macrocephaly (4) lamellar calcification of the falx cerebri (4) cleft lip or palate (5) medulloblastoma (typically desmoplastic) (5) ovarian or cardiac fibroma (6) first-degree relative with BCNS (6) lymphomesenteric cysts (7) ocular abnormalities (strabismus, hypertelorism, congenital cataracts, glaucoma, coloboma) It has been shown that approximately 90% of Histologically, the lesions are well- basaloid follicular hamartomas (BFH). BCNS patients develop keratocysts of the jaw circumscribed aggregates of basaloid buds Histologic features include follicular-based, (usually by age 40); approximately 70% have and cords in a radial and anastomosing vertically oriented columns of squamoid lamellar calcification of the falx cerebri (less pattern located in the upper dermis. cells with buds and cords of basal cells at the frequently of the tentorium cerebelli and bony Sometimes necrosis, peripheral palisading, periphery. The basaloid cells are uniform, bridging of the sella turcica); and about 70% and cystic structures containing melanized small cells surrounded by scant fibrous have abnormal skull configuration including and cornified cells can be seen. IBCC can stroma with clefting.6 Low mitotic rate, frontal, biparietal, or temporal bossing and be differentiated from trichoepithelioma, lack of necrosis, less than 10% of nuclei large calvaria.3 a benign follicular neoplasm, by the scant staining positively for PCNA, and less than stroma consisting of wiry collagen bundles 5% staining for Ki-67 markers prove that Other reported features not listed in the and few fibrocytes arranged in a compact BFH has a low proliferative capacity and thus criteria above include coarse facies, multiple fashion. See the photomicrograph from benign nature.3,6 nevi, benign dermal cysts, chalazion, ovarian Palmoplantar pits have the above case presentation in Figure 3. In cysts in females, and hypogonadotrophic been show to represent malformed eccrine contrast, trichoepithelioma has abundant and 6 hypogonadism in males.3 ducts on histology. Inheritance appears to densely fibrous stroma. Gorlin’s syndrome be autosomal-dominant and, again, related and MHIBCC are pathogenically similar in to the PTCH gene, but with a lesser degree of 3 Histopathology that the inheritance of MHIBCC seems to be dysfunction than MIBCC and BCNS. autosomal-dominant and linked to the PTCH Basal-cell carcinomas associated with BCNS gene.3 cannot be differentiated from those in the Multiple Hereditary Trichoepithelioma general population. The most common types Generalized Basaloid Follicular Hamartoma (MHT) are the solid and superficial types. Other types Syndrome (GBFHS) Trichoepithelioma (TE) is a benign follicular of BCC may be seen less often. Odontogenic Basaloid follicular hamartoma is a benign neoplasm that is usually solitary and keratocysts typically have a thin, corrugated, tumor of abnormal follicular differentiation. sporadic. MHT is a disorder presenting with stratified squamous epithelial lining with a Most patients present with one isolated multiple TE: 2 mm to 8 mm flesh-colored surrounding thick, fibrous capsule. Varying lesion, but a rare multiple familial form has papules on the face, predominantly in the degrees of keratinization can be noted.3 6 been described. The clinical presentation nasolabial folds. The histopathology of of GBFHS is variable, but the classic triad trichoepithelioma consists of aggregates of of findings consists of milium-like lesions, DIFFERENTIAL DIAGNOSIS basaloid cells, often difficult to distinguish comedone-like lesions, and 1 mm to 2 mm from BCC, IBCC or BFH. TE is characterized Multiple Hereditary Infundibulocystic Basal- hyperpigmented papules that resemble by groups of basaloid cells that look similar Cell Carcinoma (MHIBCC) seborrheic keratosis, acrochordons or to hair bulbs. The tumor islands have dermatosis papulosa nigra. Lesions usually MHIBCC is a newly described syndrome in peripheral palisading and multiple horn start on the cheeks in early childhood and which patients present with pearly papules on cysts seated in an inflammatory fibrous then spread to the scalp, ears, neck, shoulders, the face, most densely concentrated within stroma. Abortive hair shafts and follicles are chest, axillae and upper arms. Patients may the nasolabial folds. On histology, the lesions sometimes present. Features that differentiate also have hypotrichosis of the scalp along are found to be infundibulocystic basal-cell TE from BCC include circumscription of with pinpoint, slightly hyperpigmented carcinoma (IBCC), a more indolent form of the lesion, antler-like branching of basaloid palmoplantar pits.3 BCC which tends to grow very slowly and cells and an epithelial tract that consists of rarely ulcerates. Upon biopsy the papules are shown to be multiple layers of basal cells. Inheritance is

52 AN INTERESTING CASE OF FAMILIAL FIRM FACIAL PAPULES: BASAL CELL NEVUS SYNDROME OR MULTIPLE HEREDITARY INFUNDIBULO- CYSTIC BASAL CELL CARCINOMA? autosomal-dominant and linked to a mutation on the nasolabial folds, cheeks and chin in to have just a 6% recurrence rate at 36 months. at chromosome 9p21 on the PTCH gene.3 early childhood. The lesions are clinically A five-year recurrence rate of 14% was found Two additional syndromes with multiple characterized as flesh-colored to pink, in nBCC patients who took part in a phase III TE and autosomal-dominant inheritance of telangiectatic papules. They may also be found study of MAL-PDT.9 For comparison, a review a chromosome 9p21 mutation are Brooke- periungually, on the scalp and oral mucosa. of available studies by Thissen, Neumann, Spiegler syndrome and Rombo syndrome. Histology shows dilated blood vessels in a and Schouten showed a five year cumulative Brooke-Spiegler syndrome is characterized fibrous stroma with many stellate fibroblasts. recurrence rate of 5.7% to 18.8% with by multiple trichoepitheliomas, along with Other skin findings include ash leaf macules electrodessication and curettage and 3.2% to cylindromas of the nasolabial folds, nose, and shagreen patches. Associated systemic 8.0% with surgical excision.10 Overall, MAL- upper lip, forehead and scalp. Lesions findings are CNS tumors, seizures, mental PDT is recommended as a first-line treatment usually appear at puberty and slowly increase retardation, schizophrenia, autism, ADHD, for both sBCC and nBCC lesions, with in number over time. There is no known retinal phakomas, cardiac rhabdomyomas supporting evidence for long-term efficacy.9 association with internal disease. Rombo and aneurysms. The defect has been localized Several smaller open-label studies tested syndrome consists of multiple TE, milia, basal- to the TSC2 gene on chromosome 9q34 and the efficacy of 5-aminolevulinic acid cell carcinoma, vermiculate atrophoderma, 16p13. Inheritance is classically autosomal- photodynamic therapy (ALA-PDT) on hypertrichosis, and peripheral vasodilation.7 dominant, but 50% to 70% of cases are now primary sBCC lesions, showing initial thought to be caused by new mutations.7 Other Syndromes with Firm Facial Papules clearance rates between 90% and 100%. ALA-PDT studies report variable efficacy The physical exam finding of multiple in the treatment of nBCC, ranging from facial papules can be associated with many Treatment 61% to 92% clearance rates. Varying rates genodermatoses and should trigger the Electrodessication and curettage, cryotherapy, of clearance are likely due to inconsistency clinician to begin a detailed work-up. surgical excision and Mohs micrographic of lesion preparation with curettage and Histopathologic diagnosis of the papules is surgery are the conventional treatment different light sources used (blue, red or key to narrowing the search. The following options for basal-cell carcinomas. These laser). Although MAL and ALA have not syndromes were initially considered but have treatments, however, are often impractical been compared directly in clinical studies, it become low on the list of differential diagnoses in Gorlin syndrome due to the extent is known that ALA has poorer penetration for our patient due to the knowledge that the of disease and concerns about scarring, into nBCC lesions as compared to MAL. papules are infundibulocystic and nodular especially with the predilection for facial MAL has a decreased charge and an increased BCCs. involvement. Non-surgical techniques such lipophilicity, which aids in the delivery of Cowden syndrome is caused by an as topical 5-flourouracil or topical imiquimod sufficient photosensitizer to the full depth of autosomal-dominantly inherited mutation may be used to cover larger areas of tumor the lesion. To facilitate penetration, nBCC of the tumor suppressor gene PTEN on involvement, but several weeks of treatment lesions larger than 2 mm may be debulked chromosome 10q23. Characteristic findings are necessary, which decreases patient before treatment, with re-treatment if include multiple benign tumors called compliance, and control rates are low for necessary.9 Systemic photosensitization with trichilemmomas that appear around the nodular lesions.4 the use of an intralesional optical fiber or laser mouth, nose, ears and neck around age 30 Over the last decade, much evidence to ablation prior to PDT are some additional to 40 years. On histology, the lesions appear 4 support the use of photodynamic therapy options for treatment of thicker lesions. as well-circumscribed lobular epithelial (PDT) to treat basal-cell carcinoma has Recurrence rates with ALA-PDT were shown proliferations with peripheral palisading and emerged. Photodynamic therapy involves the to be 5% at a median of 17 months in a study glycogenation. Clinically, patients are also 11 application of a photosensitizing precursor by Soler et al. and 12% at 12 months in a found to have adenoid facies, craniomegaly, 12 that is preferentially absorbed by tumor tissue phase II clinical trial by Wang et al.; however, oral papillomas and keratoses of the dorsal and converted into photoactive porphyrin. more long-term follow-up is needed to prove hands and wrists. Cowden syndrome may A light source is then used to excite the lasting efficacy of ALA-PDT. Overall, ALA- be associated with gastrointestinal polyps, porphyrins, which leads to production of PDT is recommended for the treatment of thyroid carcinoma, and fibroadenoma or free radicals and thus causes targeted cell sBCC, but more research is needed before it adenocarcinoma of the breast.7 damage.4,8 In 2007, Braathen et al. developed can be recommended as a first-line treatment Birt-Hogg-Dubé syndrome (BHDS) is an international consensus on the guidelines for nBCC. characterized by multiple fibrofolliculomas: for use of PDT in nonmelanoma skin cancers. Along with efficacy, cosmetic outcomes and 2 mm to 4 mm whitish, smooth papules They report multiple large phase III studies of patient preference should be factors when (sometimes pedunculated) over the face, topical methyl aminolevulinate photodynamic choosing treatment for BCC. A prospective neck, oral cavity and upper trunk. The lesions therapy (MAL-PDT) on superficial BCC randomized trial of 97 patients with nodular usually appear after age 25. Histologically, (sBCC) and nodular BCC (nBCC) lesions. BCCs showed a five-year local control rate of the tumors are made up of anastomosing In the sBCC studies, three-month complete 96% for those treated with surgical excision, as strands, two to four cells thick, of epithelial resolution rates ranged from 80% (in complex opposed to 76% for those treated with PDT.13 cells radiating from the hair follicle. The cases, recurrent or large lesions, or lesions Mohs surgery has shown the highest efficacy strands are circumscribed by loose mucinous occurring in the “H-zone” of the face) to 97% for facial BCCs, as all margins are examined connective tissue. The genetic defect is of the in primary sBCC. Efficacy was also high in intra-operatively.14 However, surgery is often BHD gene on chromosome 17p11.2. There the nBCC group, with three-month complete impractical in Gorlin patients due to the is generally autosomal-dominant inheritance, response rates of 73% to 94%. Histologically multiplicity of tumors that develop on the face, but the syndrome may be caused by a new controlled studies have confirmed these often starting at a young age. In a randomized mutation. BHDS has been associated with efficacy rates. Four-year follow-up of a phase comparator study, 89% of sBCC patients were renal tumors, spontaneous pneumothorax and III study of MAL-PDT on sBCC shows rated as having ‘‘good’’ or ‘‘excellent’’ cosmetic pulmonary cysts.7 recurrence rates comparable with cryotherapy: outcomes with MAL-PDT as compared to 22% recurrence for MAL-PDT vs. 19% 10 Tuberous sclerosis presents with multiple 50% in the cryotherapy group. In a review recurrence for cryotherapy at 48 months. angiofibromas or “adenoma sebaceum” of current studies, cosmetic outcomes were Lesions 1 cm or less in diameter were shown MCCALL, ROZENBERG 53 quoted as “excellent” or “good” by 82% and radiation therapy and subsequently developed with BCNS were followed for a mean of 95% of patients treated with PDT for nBCC multiple BCCs on the scalp, temple, forehead, eight months after enrollment. The mean lesions, respectively.9 Wang et al. reported neck and back. Topical 20% ALA solution was per-patient rate of new surgically eligible ‘‘excellent’’ or ‘‘good’’ cosmetic outcomes in applied to the affected areas for an incubation basal-cell carcinomas was just two per year 93% of patients with both sBCC and nBCC period of 45-60 minutes and then treated with vismodegib, as opposed to 29 in the treated with ALA-PDT and just 54% of with 10 Joules of blue light. The treating placebo group. The percent change from those treated with cryotherapy.12 In addition, dermatologist and patient’s family estimated baseline of existing clinically significant basal- cosmesis with PDT has been found to be that over 90% of lesions had resolved after six cell carcinomas was -65% in the treatment superior to surgery. Patients also showed a treatments.8 group vs. -11% in the placebo group. Some significant preference for PDT over previous patients had clinical regression of all tumors, In a recent study, PTCH heterozygous therapies when surveyed in multiple phase III and no tumors were shown to progress mice were used as mouse models of Gorlin studies.9 during treatment with vismodegib. Biopsy syndrome. Multiple MAL-PDT sessions were samples from sites of clinically regressed Recently, PDT has been specifically researched shown to prevent the development of BCC in tumors showed no residual BCC 83% of the in the treatment of BCCs in Gorlin syndrome. these mice when exposed to long-term UV time. After one month, patients treated with Loncaster et al. treated a group of 33 patients radiation.16 vismodegib had a 90% reduction in hedgehog with Gorlin syndrome, a total of 138 BCC The selective COX-2 inhibitor celecoxib has target-gene expression in their BCC and a lesions, with PDT. Topical MAL, topical ALA recently shown some efficacy in NBCCS. A diminished rate of tumor-cell proliferation. and systemic photosensitizers were used in double-blind, placebo-controlled, randomized Unfortunately, 54% of patients (14 of 26) different subjects, and all were treated with red phase II study by Tang et al. proved celecoxib receiving vismodegib discontinued treatment light. Local control rates, based on ultrasound to be modestly effective in reducing the BCC due to adverse events such as loss of taste, analysis, were 56.3% and 48.5% at 12 months burden and the rate of BCC formation in muscle cramps, hair loss and weight loss.21 and 24 months, respectively. The average Gorlin patients and mouse models. In mice reduction in lesion thickness was 68% and with the PTCH1 gene mutation, celecoxib was 65% at 12 months and 24 months, respectively. shown to reduce microscopic tumor burden by Discussion Lesion thickness prior to treatment proved to 35%. In Gorlin patients, the NSAID decreased be the most important predictor of treatment The patient described in the above case the development of new BCCs by 50% in outcome. Lesions less than 1 mm thick had meets two of the major criteria for BCNS: patients with milder disease (<15 BCCs). The a 73% 12-month local control rate; lesions multiple BCCs and palmar pits. The findings concordance between the anti-BCC effects between 1 mm and 2 mm thick had a control of epidermoid and ovarian cysts also support of celecoxib in human and mouse models for rate of 40.8%; and those greater than 2 mm the diagnosis. The pervasive family history BCNS supports the hypothesis that the studies had a 59.3% control rate. The higher control of BCC and the history of frontal bossing and on chemoprevention in these mice can predict rate in the >2mm-thick group may be due brain tumor in the brothers lead us to believe the effects of such treatments on humans. to the use of a systemic photosensitizer and there is a family history of BCNS. If her family Although there were no serious adverse events optical-fiber insertion in these lesions. No members were formally diagnosed, she would during this study, the reported cardiac side scarring was noted in any of the subjects, meet three of the major diagnostic criteria. effects should raise caution in its widespread including those treated with optical-fiber The glioblastoma diagnosed in the patient’s use. Topical NSAIDS are a suggested area insertion.4 niece, though not the classically described of study in order to decrease cardiac effects. medulloblastoma, is also thought to be caused Morpheaform BCCs have been shown to have Gilchrist et al. report successful treatment by a dysfunction in the hedgehog signaling of two BCNS patients with ALA-PDT using elevated levels of COX2 and are inherently pathway22 and is thus suggestive of a Gorlin intense blue light. Patient 1 was a 46-year-old more aggressive tumors, so these patients may syndrome diagnosis. Despite technically female who was treated for an estimated 200 be good candidates for celecoxib.17 meeting the BCNS criteria, it seems more BCCs annually in the five years preceding Vismodegib is a novel small-molecule likely that the patient may have MHIBCC. the study. During the first eight months of inhibitor of the transmembrane protein Research shows that over 90% of BCNS treatment with PDT, she developed eight new smoothened (SMO), a key player in the patients develop odontogenic keratocysts of BCCs, six of which resolved with subsequent hedgehog pathway. A phase 1 trial showed the jaw,3 which the patient did not. Also, her PDT treatment and just two going on to need a 58% response rate and a median response facial papules have remained stable for many surgery. Most impressive, over the next six duration of 12.8 months in 33 patients years, and she was only first diagnosed with years the patient only developed one BCC with advanced BCC.18,19 The phase 2 trial a nodular BCC at age 55. This is not out of that required surgery, and the appearance of was performed on 96 patients to further proportion to her age or skin color. her skin was notably improved. The second investigate the efficacy and safety of the drug. patient was a 67-year-old male who had Crawford et al. described a similar case of The majority of patients with both locally undergone approximately 50 BCC surgeries a 67-year-old male with a history of BCC advanced disease and metastatic disease in the three years prior. The resulting first diagnosed at age 50, who was found to showed tumor shrinkage. Additionally, 54% disfigurement had caused him to become have multiple infundibulocystic BCC, two of patients with locally advanced BCC had suicidal. During the 11-month PDT treatment infiltrative BCC on the nose and shallow complete responses with no residual tumor period, he required no surgery, and his mood palmar pits.3 The authors acknowledged cells on histology. Adverse events included greatly improved. He was lost to follow-up that their patient met the criteria for BCNS muscle spasms, alopecia, dysgeusia, weight for a period of 12 months. When he returned syndrome but, due to the indolent course and loss, fatigue, nausea, decreased appetite and he was found to have one BCC on the eyelid lack of other organ involvement, likely had diarrhea. Fatal events were reported in seven which was treated with Mohs surgery and two MHIBCC. The case described by Crawford patients but were thought to be related to pre- additional lesions on the face that responded et al. and the case described here raise the existing risk factors.20 to repeat ALA-PDT.15 question, are these diseases truly separate Tang et al. report success of vismodegib in entities or a continuum of one disease? Schweiger et al. report a case of a 20-year- the treatment and prevention of BCCs in old female with NBCCS. The patient was BCNS, MHIBCC, GBFHS and MHT are BCNS patients. In a randomized, double- all related in that they each represent a previously treated for medulloblastoma with blind, placebo-controlled trial, 41 patients 54 AN INTERESTING CASE OF FAMILIAL FIRM FACIAL PAPULES: BASAL CELL NEVUS SYNDROME OR MULTIPLE HEREDITARY INFUNDIBULO- CYSTIC BASAL CELL CARCINOMA? defect in the sonic hedgehog/patched/ Online Journal October 2011;17(10):23. photodynamic therapy sessions smoothened (SHH/PTCH/SMO) pathway. 6. Wheeler CE Jr, Carroll MA, Groben with topical methylaminolaevulinate As hypothesized by Crawford et al., it seems PA, et al. Autosomal dominantly in PTCH heterozygous mice. Br J logical that milder phenotypes may be due inherited generalized basaloid follicular Dermatol 2006;154:740-2. to less severe gene defects, and vice versa. In hamartoma syndrome: Report of a new 17. Tang JY, Aszterbaum M, Athar M, et al. this model, more deleterious gene defects disease in a North Carolina Family. J Am Basal Cell Carcinoma Chemoprevention like frameshift mutations or deletions would Acad Dermatol 2000,43:189-206. with Nonsteroidal Anti-inflammatory be responsible for severe disease, and a Drugs in Genetically Predisposed truncated protein would cause milder disease.3 7. Vincent A, Farley M, Chan E, James PTCH1+/- Humans and Mice. Cancer Gerstenblith et al. disagree, reporting that WD. Birt-Hogg-Dube syndrome: A Prev Res (Phila). 2010 January; 3(1):25- phenotypic variation does not appear to be review of the literature and the 34. linked to the type of gene mutation present. differential diagnosis of firm facial In fact, 70% of PTCH1 gene mutations in papules. J Am Acad Dermatol 18. Von Hoff DD, LoRusso PM, Rudin CM, Gorlin syndrome have been shown to be mere 2003;49:698-705. et al. Inhibition of the hedgehog pathway 2 protein truncations. This then raises the 8. Schweiger ES, Kwasniak L, Tonkovic- in advanced basal-cell carcinoma. N Engl question, why is there nearly 100% penetrance Capin V. A patient with nevoid basal J Med 2009; 361:1164-72. but with such clinical variability? More cell carcinoma syndrome treated 19. LoRusso PM, Rudin CM, Reddy JC, et research is needed in this area. Overall, we successfully with photodynamic al. Phase I trial of hedgehog pathway believe that these diseases of SHH/PTCH/ therapy: A case report and review of the inhibitor vismodegib (GDC-0449) in SMO dysfunction are a continuum of one literature. Journal of Drugs in patients with refractory, locally advanced disease and that our patient falls on the more Dermatology 2010;9(2):167-8. or metastatic solid tumors. Clin Cancer benign end of the spectrum. 9. Braathen LR, Szeimies RM, Basset- Res 2011; 17:2502-11. New treatment options with better cosmetic Seguin N, et al. Guidelines on the use 20. Sekulic A, Migden MR, Oro AE, et outcome have eliminated a great deal of of photodynamic therapy for al. Efficacy and safety of vismodegib in morbidity associated with these conditions. nonmelanoma skin cancer: An advanced basal-cell carcinoma. N Engl J There is a large body of literature supporting international consensus. J Am Acad Med 2012;366:2171-9. the use of MAL-PDT for BCC in the general Dermatol 2007;56:125-43. population and recently in BCNS patients. 21. Tang JY, Mackay-Wiggan JM, ALA-PDT also seems like a promising 10. Thissen MR, Neumann MH, Schouten Aszterbaum M, et al. Inhibiting the treatment for BCC in BCNS with good LJ. A systematic review of treatment hedgehog pathway in patients with cosmetic outcome, but more long-term modalities for primary basal cell basal-cell nevus syndrome. N Eng J Med efficacy data is needed. There is also some carcinomas. Arc Dermatol 2012;366:2180-8. data to suggest that PDT helps prevent new 1999;135:1177-83. 22. Shahi MH, Lorente A, Castresana JS. BCC lesions in Gorlin syndrome, but more 11. Soler AM, Warloe T, Tausjo J, Berner Hedgehog signalling in evidence is needed. It would also be helpful A. Photodynamic therapy by topical medulloblastoma, glioblastoma to compare the efficacy and cosmetic results aminolevulinic acid, dimethylsulphoxide and neuroblastoma. Oncol Rep. 2008 of PDT vs. topical immunomodulators, as this and curettage in nodular basal cell Mar;19(3):681-8. has not been studied to our knowledge. carcinoma: a one-year follow-up study. Acta Derm Venereol 1999;79:204-6. 12. Wang I, Bendsoe N, Klinteberg CA, References: Enejder AM, et al. Photodynamic 1. Bree AF, Shah MR. Consensus statement therapy vs. cryosurgery of basal cell from the first international colloquium carcinomas: results of a phase III clinical on basal cell nevus syndrome (BCNS). trial. Br J Dermatol 2001;144:832-40. Am J Med Genet Part A 2011;155:2091- 2097. 13. Rhodes LE, de Rie MA, Leifsdottir R, et al. Five-year follow-up of a 2. Girstenblith MR, Goldstein AM, randomized prospective trial of methyl Tucker MA. Chapter Seven - Hereditary aminolevulinate photodynamic therapy Genodermatoses with Cancer vs. surgery for nodular basal Predisposition. Hematol Oncol Clin cell carcinoma. Arch Dermatol North Am. 2010 Oct;24(5):885-906. 2007;143(9):1131e1136. 3. Crawford Capt. KM, Kobayashi Maj. 14. Smeets NW, Krekels GA, Ostertag JU, et T. Nevoid basal cell carcinoma syndrome al. Surgical excision vs. Mohs or multiple hereditary infundibulocystic micrographic surgery for basal cell basal cell carcinoma syndrome? J Am carcinoma of the face: randomised Acad Dermatol 2004; 51:989-95. controlled trial. Lancet 4. Loncaster J, Swindell R, Slevin F, et 2004;364:1766e1772. al. Efficacy of photodynamic therapy 15. Gilchrist BA, Brightman LA, Thiele JJ, as a treatment for Gorlin syndrome- Wasserman DI. Photodynamic Therapy related basal cell carcinomas. Clinical for Patients with Basal Cell Nevus Oncology 2009;21:502-508. Syndrome. Dermatol Surg 2009; 5. Leger M, Quintana A, Tzu J, Yee H, 35:1576-1581. Kamino H, Sanchez M. Nevoid basal cell 16. Caty V, Liu Y, Viau G, Bissonnette R. carcinoma syndrome. Dermatology Multiple large surface MCCALL, ROZENBERG 55 Recurrent HSV-associated erythema multiforme: a case report of atypical morphology and distribution

Tim A. Galperin, D.O.,* John P. Minni, D.O.,** Dwayne D. Montie, D.O.***

* Dermatology Clinical Research Fellow, University of California, San Francisco, San Francisco, CA ** Private Practice Dermatology, Okeechobee, FL *** Private Practice Dermatology, Saint Lucie West, FL

Introduction Erythema multiforme (EM) is characterized by an acute polymorphous eruption of macules, papules, plaques, bullae, and targetoid lesions with an acral distribution pattern and limited mucosal involvement.1,2 It is usually a self-limited skin condition with resolution in three to five weeks,1 but it may recur in some individuals. The most commonly associated etiological factors are infections, such as herpes simplex virus (HSV) and Mycoplasma pneumoniae, and medications, notably barbiturates, penicillins, sulfonamides, thiazide diuretics, and nonsteroidal anti-inflammatories.3,4 Two common types of EM are HSV-associated erythema multiforme (HAEM) and drug-induced erythema multiforme (DIEM). Clinically, HAEM lesions are commonly targetoid, located on the distal acral extremities and progress proximally; they have minimal mucosal involvement and may or may not have prodromal symptoms. DIEM lesions, on the other hand, consist of vesicles, bullae, erythematous plaques, and occasional targetoid lesions most often located centrally on the body, with prominent mucosal involvement and prodromal symptoms.1,3,5 Prodromal symptoms, if present, include a mild pruritis or burning sensation at the site of the eruption. Histologically, HAEM lesions have a predominance of CD4+ T helper 1 (Th1) cells and moderate-to-pronounced dermal edema, whereas DIEM lesions have a predominately CD8+ T cell infiltrate with minimal dermal edema. Immunohistochemistry shows HAEM lesional skin is positive for HSV DNA and INF-γ, while DIEM lesions are negative for HSV deoxyribonucleic acid (DNA) and positive for TNF-α.6 We report a case of recurrent HSV-associated erythema multiforme with an atypical morphology and distribution.

Figures 1a, 1b. Multiple annular papules and plaques on shoulders and left arm. 56 RECURRENT HSV-ASSOCIATED ERYTHEMA MULTIFORME: A CASE REPORT OF ATYPICAL MOPHOLOGY AND DITRIBUTION Case Report A 7-year-old Caucasian male presented to the office with a chief complaint of a rash occurring shortly after sun exposure to the trunk and upper arms. His mother described a several-month history of a pruritic, erythematous rash on the face and trunk occurring several minutes to several hours after sun exposure. On the initial physical exam, the patient had multiple annular plaques on his sun-exposed upper arms and shoulders (Figures 1a, 1b). Biopsy of a representative lesion revealed interface dermatitis with a lymphoid infiltrate along the dermo-epidermal junction and keratinocyte necrosis (Figures 2a, 2b). An Epstein-Barr virus in-situ hybridization test was negative. The initial differential diagnoses for this patient were juvenile spring eruption vs. HAEM vs. DIEM. The initial treatment involved a low-potency topical steroid to the affected area, sunscreen, and photo-protective clothing. Figure 2a. Interface dermatitis with a lymphoid infiltrate along the dermo-epidermal During the follow-up visit, three weeks later, junction, keratinocyte necrosis, and viral cytopathic changes (5x magnification). the mother stated that the steroids were of no benefit. Upon further questioning, the patient’s mother admitted the patient suffers from frequent cold sores. On follow-up exam, the dermatitis had evolved to feature targetoid plaques (Figure 3). An HSV IgG level was ordered to aid in the diagnosis. Further biopsies and HSV-specific tissue studies were not performed. The HSV IgG was positive, which, along with the history of recurrent herpes labialis and an absent history of medication use, led to the diagnosis of HSV- associated erythema multiforme. The patient was started on acyclovir at 20 milligrams per kilogram four times per day and counseled on strict sun avoidance. The rash cleared rapidly after several days of treatment, but upon discontinuation of the acyclovir, the rash returned. At that point, the patient was told to continue low-dose, 400 milligram daily acyclovir therapy, which prevented subsequent episodes.

Discussion Figure 2b. Interface dermatitis with a lymphoid infiltrate along the dermo-epidermal Erythema multiforme typically occurs junction, keratinocyte necrosis, and viral cytopathic changes (10x magnification). in adults between the ages of 20 and 40,5 although all age groups can be affected. agents of EM are infections, notably HSV, causes include malignancy, immunizations, 3,4,8 The Severe Cutaneous Adverse Reactions M. pneumoniae, and fungi. However, sarcoidosis, connective-tissue diseases, and 12 (SCAR) study concluded that EM patients are multiple other infectious agents such as inflammatory bowel disease. In the present 9 10 typically young and more commonly male, hepatitis C, cytomegalovirus, and human case, the clinical history and serology were 11 with males having as much as a 10-fold higher immunodeficiency virus have also been both positive for HSV, helping to confirm rate of recurrence compared with females.7 implicated. The medications most commonly the diagnosis of HSV-associated erythema On the other hand, a retrospective review associated with EM include barbiturates, multiforme. penicillins, sulfonamides, and nonsteroidal conducted by Wetter and Davis looking at 48 Patients with HAEM can have a clinically anti-inflammatories,3,4 although numerous patients with recurrent EM showed a female evident HSV reactivation without an episode 4 other medications have been associated predominance for the disease. of EM, or they can have an episode of EM with the disease as well. Other documented 1,3,4 The most commonly implicated etiological without a clinically evident HSV infection. GALPERIN, MINNI, MONTIE 57 Dermatol Online J. 2003; 9(1). 2. Revuz, J. Erythema Multiforme. In: Lebwohl MG, Heymann WR, Berth- Jones J, Coulson I, eds. Treatment of Skin Disease: Comprehensive Therapeutic Strategies. 3rd ed. Saunders- Elsevier, 2010: 220-223. 3. Lamoreux MR, Sternbach MR, Hsu WT. Erythema Multiforme. Am Fam Physician. 2006; 74(11):1883-1888. 4. Wetter DA, Davis MDP. Recurrent erythema multiforme: Clinical characteristics, etiologic associations, and treatment in a series of 48 patients at Mayo Clinic, 2000 to 2007. J Am Acad Dermatol. 2010;62(1):45-53. 5. Habif TP. Hypersensitivity syndromes and vasculitis. In: Habif TP, ed. Clinical Dermatology: A Color Guide to Diagnosis and Therapy. 4th ed. New York, NY: Mosby, 2004:626–634. 6. Kokuba H, Aurelian L, Burnett J. Herpes simplex virus associated erythema multiforme (HAEM) is mechanistically distinct from drug-induced erythema multiforme: interferon-gamma is expressed in HAEM lesions and tumor necrosis factor-alpha in drug-induced Figure 3. Multiple targetoid plaques. erythema multiforme lesions. J Invest Dermatol. 1999;113:808–815. In our case, there was no direct link between inflammatory cytokine, which initiates an 7. Kelly JP, Auquier A, Rzany B, et al. the herpes labialis outbreaks and the EM inflammatory cascade1 that ultimately results An international collaborative case- episodes. It is possible that this patient had in the prototypical skin manifestations. In control study of severe cutaneous a subclinical HSV reactivation prior to the addition, studies have shown that viral DNA adverse reactions (SCAR). Design and EM eruptions, and since these eruptions can persist for up to one to five months after methods. J Clin Epidem. typically followed sun exposure, it stands to HAEM lesional skin has cleared, raising the 1995;45(9):1099-1108. reason that ultraviolet (UV) radiation may possibility that these patients have an inability 1,21 8. Villiger RM, von Vigier RO, Ramelli have been the trigger for the subclinical HSV to clear the virus efficiently. GP, et al. Precipitants in 42 cases reactivation. Several case reports have shown The treatment of recurrent HAEM of erythema multiforme. Eur J Pediatr. that recurrent HAEM can be precipitated by involves the use of daily acyclovir, which has 1999;158:929–932. 13-15 and studies have shown that sun exposure, been shown to suppress recurring episodes. UV radiation is a causative factor of HSV 9. Dumas V, Thieulent N, Souillet AL, et al. Valacyclovir or famciclovir, with a greater reactivation.16,17 Our patient’s lesions were Recurrent erythema multiforme and oral bioavailability than acyclovir, can be limited to the upper arms and shoulders, chronic hepatitis C: efficacy of interferon used if patients do not respond to acyclovir which is atypical, since classic HAEM lesions 1,14 alpha. Br J Dermatol. 2000;142:1248– therapy. Our patient initially improved 1249. occur on the distal extremities and progress after several days with acyclovir therapy, 3 There are a handful of cases proximally. but upon cessation of the medication and 10. Seishima M, Oyama Z, Yamamura in the literature of patients presenting with re-exposure to sunlight, the eruption returned. M. Erythema multiforme associated photo-distributed lesions in HAEM,17,18 which Consequently, we placed the patient on daily with cytomegalovirus infection seems less likely in our case, as the patient had acyclovir. Some patients unresponsive to in nonimmunosuppressed patients. no evident lesions on his sun-exposed distal suppressive antiretroviral therapy have been Dermatology. 2001;203:299–302. extremities and upper chest. 5 treated with hydroxychloroquine, dapsone, 11. Schechner AJ, Pinson AG. Acute human 22 HAEM is a delayed-type hypersensitivity and even azathioprine, although the evidence immunodeficiency virus infection reaction. The pathogenesis is believed to begin for the use of these agents in HAEM is limited. presenting with erythema multiforme. with a clinical or subclinical reactivation of Am J Emerg Med. 2004;22:330–331. HSV that leads to a transient viremia and 12. Huff JC, Weston WL, Tonnesen MG. the transport of HSV DNA fragments via References Erythema Multiforme: a critical review peripheral blood mononuclear cells to the 1. Aurelian L, Ono F, Burnett J. Herpes of characteristics, diagnostic criteria, and skin surface.1,6,20 This leads to recruitment simplex virus (HSV)-associated causes. J Am Acad Dermatol. of HSV-specific CD4+ helper T cells (T 1) H erythema multiforme (HAEM): a viral 1983;8:763-775. and the TH1 release of interferon-γ, a pro- disease with an autoimmune component.

58 RECURRENT HSV-ASSOCIATED ERYTHEMA MULTIFORME: A CASE REPORT OF ATYPICAL MOPHOLOGY AND DITRIBUTION 13. Weston WL, Morelli JG. Herpes simplex virus-associated erythema multiforme in prepubertal children. Arch Pediatr Extranodal NK/T-cell Lymphoma, Adolesc Med. 1997;151:1014-1016. Nasal Type 14. Osterne RLV, Brito RGM, Pacheco IA, et al. Management of Erythema Jordan Fabrikant, DO,* Donna Tran, DO,** Stanley E. Skopit, DO, MSE, FAOCD*** Multiforme Associated with Recurrent Herpes Infection: A Case Report. J Can *2nd -year Dermatology Resident, Larkin Community Hospital – Nova Southeastern Dent Assoc. 2009;75(8):597-601. University College of Osteopathic Medicine, Department of Dermatology, Miami, FL 15. Perez-Carmona L, Vano-Galvan S, Carrillo-Gijon R, et al. Photosensitive **Intern, Botsford Hospital, Farmington Hills, MI erythema multiforme presenting as juvenile spring eruption. Photodermatol, ***Program Director, NSUCOM/Larkin Community Hospital , Miami, FL Photoimmuno, & Photomed. 2010;26:53- 54. 16. Ichihashi M, Nagai H, Matsunaga Abstract: K. Sunlight is an important causative Extranodal natural killer/T-cell lymphoma, nasal type, is a rare and aggressive form of factor of recurrent herpes simplex. Cutis. non-Hodgkin’s lymphoma (NHL), characterized by natural-killer (NK) cell phenotype, 2004;74(5):14-18. Epstein-Barr virus (EBV) positivity, and vascular damage and destruction. It is uncommon 17. Goade DE, Nofchissey RA, Kusewitt DF, in the United States and more prevalent in Asia and in the native populations of Central et al. Ultraviolet light induces and South America. Clinical presentation is non-diagnostic, and histologic examination reactivation in a murine model of with immunohistochemistry is necessary for diagnosis and staging. We report a case of cutaneous herpes simplex virus-1 extranodal NK/T-cell lymphoma, nasal type, arising on the back of a 66-year-old man. infection. Photochem Photobiol. 2001;74(1):108-114. 18. Wolf P, Soyer HP, Fink-Puches R, et al. Recurrent post-herpetic erythema multiforme mimicking polymorphic light eruption and juvenile spring eruption: report of two cases in young boys. Br J Dermatol. 1994;131:364-367. 19. Fraser-Andrews EA, Morris-Jones R, Novakovic L, Hawk JLM. Erythema multiforme following polymorphic light eruption: a report of two cases. Clin Exp Dermatol 2005;30:232-234. 20. Brice SL, Leahy MA, Ong L, et al. Examination of non-involved skin, previously involved skin and peripheral blood for Herpes Simplex Virus DNA Figure 1. 20 mm x 30 in patients with recurrent herpes mm soft, fixed, and associated erythema multiforme. J Cutan flesh-colored nodule Pathol 1994;21:408-412. on left upper back 21. Aurelian L, Ono F, Sharma BK, et al. CD34+ cells in the peripheral blood Case Report transport Herpes Simplex Virus (HSV) A 66-year-old man with no significant past ), CD8(dim+), CD10(-), CD11b(-), DNA fragments to the skin of patients medical history presented with a nodule on CD16(partial dim+), CD25(-), CD30(-), with erythema multiforme (HAEM). J his left upper back of six weeks duration. CD34(-), CD45(+), CD34RO(dim+), Invest Dermatol. 2005;124:1215-1224. He denied any symptoms other than mild CD52(+), CD56(+), and CD57(-). Also present 22. Schofield JK, Tatnall FM, Leigh IM. pruritus. Physical examination revealed a 20 were 12% small, mature T-lymphocytes, 5.2% Recurrent erythema multiforme: clinical mm x 30 mm soft, fixed, and flesh-colored mature, polytypic B-lymphocytes, and 0.27% features and treatment in a large series of nodule on his left upper back (Figure 1). There plasma cells. In situ hybridization for Epstein- patients. Br J Dermatol 1993;128:542- were no enlarged lymph nodes. Barr virus showed almost 100% positivity 545. of tumor cells. Molecular studies for T-cell A biopsy revealed an atypical lymphoid gene rearrangement showed an atypical TCR- infiltrate. Immunohistochemical stains gamma DNA fragment pattern suspicious for revealed a 19% population of small to clonality. medium-sized cells with the following immunophenotypes: CD1a(-), CD2(+), surface CD3(-), CD4(-), CD5(-), CD7(-

FABRIKANT, TRAN, SKOPIT 59 Figure 2. CD2, CD8, CD4 (left to right). CD2 is diffusely positive, as is CD8. The atypical lymphocytes are negative for CD4; CD4 highlights reactive T-cells.

Figure 3. TIA-1, Granzyme B, and CD56 (left to right) all show positivity. These are the cytotoxic markers.

The findings of the hematoxyline and eosin, Bone marrow involvement is uncommon, of poor outcome include high plasma levels 4 immunohistochemistry, molecular, and flow though it may disseminate rapidly or be of EBV DNA and tumor invasiveness. 3 cytometry confirmed the diagnosis of Epstein- complicated by a hemophagocytic syndrome. Systemic chemotherapy remains the initial Barr virus related NK/T-cell lymphoma, choice of treatment, but the results have been 6 nasal type. He was subsequently referred to Histopathologically, a diffuse infiltrate of disappointing. oncology to further evaluate for systemic polymorphous, atypical lymphocytes is seen in involvement, as well as for appropriate staging the dermis and often the subcutis. Prominent In conclusion, we present a rare case of and treatment. angiocentricity and angiodestruction are extranodal NK/T-cell lymphoma, nasal type, often accompanied by extensive necrosis.1 arising on the back of a 66-year-old man. Discussion The key diagnostic features are the Diagnostic hallmarks include angiocentricity, Extranodal NK/T-cell lymphoma is a rare demonstration of NK- and T-cell markers angiodestruction, immunophenotype variant of non-Hodgkin’s lymphoma. It is most on immunophenotyping, typically CD2, positivity for CD2, CD3ε and CD56, and common in Asia and in the native populations cytoplasmic CD3 epsilon (ε), and the NK-cell evidence of EBV infection. Prognosis is poor of Central and South America, where it marker CD56. In addition, presence of EBV despite chemotherapy as initial treatment of primarily affects men in their fifth decade.1 is demonstrated by in situ hybridization for choice. Our patient was referred to oncology 4 It is rare in the United States and Europe. EBV-encoded small nuclear RNAs (EBERs). to further evaluate presence of systemic The pathogenesis of extranodal NK/T-cell The differential diagnosis of NK/T-cell involvement for subsequent staging and lymphoma, nasal type, is unknown. However, lymphoma, nasal type, includes other NK and therapy. the strong association with EBV infection T-cell malignancies and EBV-associated T-cell suggests a probable pathogenic role for the or NK-cell lymphoproliferative disorders. virus.1 References: Although rare, extranodal NK/T-cell 1. Tababi S, Kharrat S, Sellami M, et al. Extranodal NK/T-cell lymphoma, nasal lymphoma, nasal type, is an aggressive Extranodal NK/T-cell lymphoma, nasal type, is characterized by a high incidence of lymphoma, characterized by rapid progression type: Report of 15 cases. European nasal involvement with symptoms of nasal of disease, relapses, and extremely poor Annals of Otorhinolaryngology, Head obstruction, epistaxis, nonspecific rhinitis prognosis. The most important factor and Neck Diseases. 2012;129(3):141-147. or sinusitis.1 The tumor is locally invasive predicting poor outcome is the presence of 2. Wood PB, Parikh SR, Krause JR. and can infiltrate the surrounding tissues. extracutaneous involvement at presentation. Extranodal NK/T-cell lymphoma, nasal The skin, as in our case, is the second most A retrospective analysis of 53 patients with type. Proceedings (Baylor University common site of involvement and may be a extranodal NK/T-cell lymphoma, nasal Medical Center). 2011;24(3):251-254. primary or secondary manifestation of the type, reported a median survival of 27 3. Gill H, et al. Extranodal Natural-Killer/ disease. Other extranasal involvement includes months in patients presenting with only T-cell Lymphoma, Nasal Type. Advances lungs, testes, gastrointestinal tract, or central skin lesions, compared with four months for in Hematology[Internet]. 2010 nervous system.3 Systemic symptoms such as patients presenting with both cutaneous and [cited 2010 Dec 20]. Pages 1-5. Available 5 fever, malaise, and weight loss may be present. extracutaneous disease. Other predictors from http://www.hindawi.com/journals/

60 EXTRANODAL NK/T-CELL LYMPHOMA, NASAL TYPE ah/2010/627401/. 4. Reyes VE Jr, Al-Saleem T, Robu VG, Smith MR. Extranodal NK/T- An Unexpected Finding of Sinonasal cell lymphoma nasal type: Efficacy of Melanoma in a Patient Believed to Have pegaspargase. Report of two patients from United States and review of Chronic Sinusitis: A Case Report literature. Leuk Res. 2010 Jan;34(1):e50-4. 5. Bekkenk MW, Jansen PM, Meijer CJLM, Liza M. Brown, BS,* Richard M. Rubenstein, MD,** William Smothermon, MD*** Willemze R. CD56+ hematological neoplasms presenting in the skin: a * Medical Student, 4th year, Lake Erie College of Osteopathic Medicine, Bradenton, FL retrospective analysis of 23 new cases ** Co-Director, Wellington Regional Medical Center Dermatology Program, Wellington, and 130 cases from the literature. Ann FL Oncol. 2004;15(7):1097-1108. *** Department of Pathology, Wellington Regional Medical Center, Wellington, FL 6. Cheung MMC, Chan JKC, Lau WH, et al. Primary non-Hodgkin lymphoma of the nose and nasopharynx: clinical Background: features, tumor immnophenotype, and Sinonasal mucosal malignant melanoma is an exceedingly rare entity, representing treatment outcome in 113 patents. J Clin less than 1% of all melanomas.1 Compared to their cutaneous counterparts, mucosal Oncol. 1998;16:70-77. melanomas have a much poorer prognosis. Due to their rare nature and benign symptomology, most mucosal melanomas are not found until metastases have occurred. A case report is presented with this rare finding. Case Report: An 85-year-old Caucasian female presented The patient continued to have epistaxis with chief complaint of “recurrent nose bleeds after treatment and was referred to an ENT for the past year.” The patient described the specialist, where she had CT images taken bleeding as occurring a few times a week, of her frontal and maxillary sinuses. The consisting of bright red blood, and lasting findings were consistent with what was a few minutes per episode. She denied believed to be sinus-wall thickening and hence any other symptoms such as headache, a chronic sinusitis. fever, or upper respiratory symptoms. Her Nine months later, the patient, still with past medical history was significant only epistaxis, and with hopes of treating her for hypertension, hypothyroidism and “chronic sinusitis,” underwent an elective hyperlipidemia. After a physical exam was endoscopic left frontal sinusotomy, left completed, the patient was discharged with ethmoidectomy, left maxillary antrostomy and antibiotics to treat what was believed to be septoplasty. Pathology results confirmed sinus sinusitis.

Figure 1: High-powered (40x magnification). H&E stain of sinus contents showing spindle cells with elongated nuclei and ropes of collagen, arising from abnormal mitoses.

BROWN, RUBERSTEIN, SMOTHERMON 61 chronic sinusitis with mild lymphocytes and plasma cells. The right forehead mass pathological exam showed the very same cellular spindle-cell neoplasm as produced in her sinus cavity (Figures 1 and 2). Due to the new findings of a spindle- cell neoplasm, an all-inclusive immunohistochemistry panel for the work-up of spindle-cell tumors was obtained to rule out entities such as dermatofibrosarcoma, spindle- cell squamous carcinoma, and melanoma. S-100 stain was shown to be 1+ positive in all tumor cells, and the more-specific stain Pan- Melanoma (Melan A, tyrosinase, and S-100) was shown to be 4+ in all tumor cells (Figures 3 and 4). HMB45 stain also proved to be 4+ in all tumor cells. Immunohistochemistry stains confirmed the diagnosis of malignant melanoma in this spindle-cell neoplasm involving the patient’s forehead and subcutaneous tissues and extending into the sinus subepithelial and connective tissues. After the diagnoses of malignant melanoma Figure 2: High-powered (40x magnification). H&E stain of spindle-cell tumor was established, the patient was sent to infiltrating bones of nasal cavity. outpatient oncology and was found via PET to have metastatic lesions to multiple contents containing lymphocytes, plasma cells this time as well as removal of the mass on her lymph nodes in her chest as well as multiple and chronic inflammation, corresponding right forehead. metastatic lesions to her liver. The patient again to a diagnosis of chronic sinusitis. Better sampling technique due to the now denied any personal history of skin cancer The patient returned one month later with a greater involvement of both sinuses and or familial cases of melanoma. The patient new complaint of a small, skin-colored nodule forehead allowed for a different pathology to currently reports being treated with post- on her right forehead, along with continued be shown. Gross description of sinus contents surgical radiation to her sinus cavities. nasal bleeding. The patient underwent a right this time revealed multiple pieces of tan and frontal sinusotomy and was found during the pale, soft hemorrhagic tissue. Gross dissection Discussion time of surgery to have a free passage of fluid of the forehead mass showed a 0.9 cm x 0.6 cm Melanomas are tumors derived from from her previous left sinusotomy that tracked firm, tan piece of tissue. neuroectodermal cells called melanocytes. to her right anterior forehead, producing what Pathological examination of the new sinus These cells are found in skin adnexa, basal seemed to appear as a mucocele. A revision of contents via H&E stain revealed a very cellular layers of skin, and some mucosal membranes the left frontal sinusotomy was performed at spindle-cell neoplasm with an overlying

Figure 3: High-powered (40x magnification). S-100 stain showing Figure 4: High-powered (40x magnification). Pan- Melanoma stain 1+ (1% to 25% of cells) staining brown, confirming a sinonasal showing 4+ (75% to 100% of cells) staining brown, confirming melanoma. sinonasal melanoma.

62 AN UNEXPECTED FINDING OF SINONASAL MELANOMA IN A PATIENT BELIEVED TO HAVE CHRONIC SINUSITIS: A CASE REPORT such as the conjunctiva, nasopharynx, melanomas, which lack the BRAF mutation.12 or liver.19,20 sinonasal or genital mucosa.2 Primary Fluorescence in situ hybridization shows mucosal melanoma of the head and neck is an that a c-KIT protein expression occurred in uncommon neoplasm that represents 0.5% to 96.9% of sinonasal mucosal melanomas, while Conclusion: 2% of all malignant melanomas. Specifically, mutations in NRAS occurred in over 22% Sinonasal melanoma is a severe and 13 sinonasal melanoma accounts for less than 1% of sinonasal mucosal melanomas. These devastating disease. It is a rare entity that may 3 of malignant melanomas. In contrast to its newfound molecular fingerprints could lead present with benign symptoms. Physicians cutaneous counterpart, mucosal melanomas the way to new treatment considerations need to be aware of mucosal melanomas and are not believed to be directly influenced for primary sinonasal mucosal melanomas include the oral mucosa, nasal mucosa, and by sunlight/UV light. This theory draws targeting these specific NRAS and c-KIT conjunctiva when completing their full-body on the lack of sunlight/UV-light exposure mutations. Some experimental studies have skin exams and looking for melanoma. Also, to the affected areas. Although their roles shown marked tumor regression in patients a clinical depiction of chronic sinusitis may remain unclear, irritants and carcinogenic with metastatic mucosal melanoma who were be a more serious entity, such as a potential compounds in the air, such as tobacco smoke treated with single-agent imatinib, due to sinonasal melanoma. The best prognosis and formaldehyde, have been implicated in the the inhibition of c-KIT. Further studies are would result from early detection and early 4 13,14 development of mucosal melanomas. needed to explore this treatment option. excision. Surgery is the mainstay of treatment, At presentation, the most common symptoms Currently, no universally accepted staging with no increase in survival rates with of patients with sinonasal melanoma are system for mucosal melanoma exists. Due to concurrent radiotherapy and chemotherapy. epistaxis and nasal congestion or obstruction. the absence of histologic landmarks analogous Despite current treatment modalities, the Discharge, facial pain, and edema are common to the papillary and reticular dermis, and the prognosis for these patients remains dismal. in more advanced cases.5 These symptoms advanced stages of most cases at presentation, Staying aware of advances in immunotherapy, can easily be mistaken for the presenting signs the prognostic value of various levels of such as the creation of affordable medications of sinusitis. The major presenting signs of invasion established in the Clark classification against the c-KIT and NRAS mutations found chronic sinusitis are nasal obstruction, facial for cutaneous melanoma does not apply to in these tumors, is essential, as they may pain, and nasal discharge.6,7 In sinonasal mucosal melanoma.15 PET scans to evaluate provide hope for mucosal-melanoma patients. melanoma, the maxillary sinuses are most the stage and extent of disease at diagnosis Consent: Informed consent was obtained from commonly involved, with the origin in frontal will best help to assess disease severity. The the patient for publication of this report and or sphenoid sinuses being extremely rare, following is the system that suffices for staging: any accompanying images. which is what makes the case presented here Competing interests: The authors declare that even more interesting. Patients will typically they have no competing interests. present with these symptoms between the Stage I – Localized disease ages of 60 and 80 years, although diagnoses Stage II – Metastases to regional lymphatics Authors’ contributions: LB and WS may occur at any age.8 Due to its rare nature participated in investigation and diagnosis. LB Stage III – Distant metastatic disease and benign symptomology, most mucosal drafted the manuscript, while RR co-authored melanomas are not found until already and reviewed the manuscript. All authors read in advanced stages of development, and Compared to its cutaneous counterparts, and approved the final manuscript. 9 prognosis is generally poor. mucosal melanomas have a much poorer Acknowledgements prognosis. In addition, sinonasal melanomas Compared to other mucosal melanomas, Thank you to Dr. Neil Goldberg for taking the in particular have a dismal prognosis, sinonasal melanoma shows vascular and time to share his insight and views on this case 10 specifically when there is infiltration into the deep-tissue invasion more frequently. and our manuscript. Melanin pigment can be helpful in the skull or facial soft tissue.4,15 Wide excision is diagnosis of mucosal melanoma, but in the primary treatment modality for sinonasal most cases pigment is absent. Pathologically, melanomas.16 A study conducted between References: sinonasal-melanoma malignant cells are either 1963 and 1996 of 58 individuals with sinonasal 1. Kingdom TT, Kaplan MJ. Mucosal epithelioid or spindled, with enlarged nuclei melanoma showed that regardless of treatment melanoma of the nasal cavity and with prominent nucleoli; increased mitotic modality, five-year survival rate remained the paranasal sinuses. Head Neck 1995; activity with atypical mitotic figures are same, less than 30%, with a median survival of 17:184-189. commonly present.11 Immunohistochemical 21 months.17 Although radiotherapy improved stains for S-100 protein, HMB-45, and Pan regions of the melanoma locally, there was 2. Dwivedi R, Dwivedi R, Kazi R, Kumar S, Melanoma stain are helpful for diagnosis and no statistical difference in survival time of Agarwal SP. Mucosal melanoma of nasal are characteristically positive.3 patients being treated with excisional therapy cavity and paranasal sinus. J Can Res alone versus those receiving surgery and Ther 2008; 4:200-2. radiotherapy. The addition of chemotherapy 3. Kardon, D, Lester D, Thompson R. Of note, distinct molecular features have been had no impact on survival, nor did the site Sinonasal Mucosal Malignant found in mucosal melanomas that differentiate of the tumor, the surgical procedure, the Melanoma: Report of an Unusual Case them from their cutaneous counterparts. presence of lymph node metastases or the Mimicking Schwannoma. Ann Diagn For instance, activating mutations of the age of the patient.18 Additional studies have V600E Pathol 2000; 4: 303-307. BRAF oncogene have been found in up to shown that even with adjuvant radiotherapy, 75% of cutaneous melanomas and are absent up to half of patients will show sites of distant 4. Seetharamu N, Ott P, Pavlick A. 12 completely in mucosal melanomas. New and metastases and local recurrence. Nasal sinus Mucosal Melanomas: A Case-Based promising BRAF-inhibiting agents such as melanomas have a 20% chance of metastases Review of the Literature. The Oncologist vemurafenib, designed to combat metastatic to overlying cutaneous tissue, with the most July 2010; 15(7): 772-781. melanoma, will not work for these mucosal likely location of metastases being to the lungs 5. Dauer EH, Lewis JE, Rohlinger AL,

BROWN, RUBERSTEIN, SMOTHERMON 63 Weaver AL, Olsen KD. Sinonasal 17. Lund VJ, Howard DJ, Harding L, Wei melanoma: a clinicopathologic review of WI: Management options and survival in 61 cases. Otolaryngol Head Neck Surg. malignant melanoma of the sinonasal March 2008; 138(3):347-52. mucosa. Laryngoscope. 1999 Feb;109(2 6. Slavin RG, Spector SL, Bernstein IL, et Pt 1):208-11. al. The diagnosis and management 18. Owens JM, Roberts DB, Myers JN. of sinusitis: a practice parameter update. The role of postoperative adjuvant J Allergy Clin Immunol. Dec 2005;116(6 radiation therapy in the treatment of Suppl):S13-47 mucosal melanomas of the head and 7. Benninger, MS, Ferguson BJ, Hadley JA, neck region. Arch Otolaryngol Head et al. Adult chronic rhinosinusitis: Neck Surg. 2003 Aug;129(8):864-8. definitions, diagnosis, epidemiology, 19. O’Regan KN, Ramaiya NH, Jagannathan and pathophysiology. Otolaryngol Head JP, Dipiro P, et al. Patterns of disease Neck Surg. 2003 Sep;129(3 Suppl):S1-32. spread in metastatic mucosal melanoma. 8. Nagashree S, Ott PA, Pavlick AC. J Clin Oncol. 2010;28:15. Mucosal Melanomas: A Case-Based 20. Savoia P, Fava P, Deboli T, Quaglino Review of the Literature P, Bernengo MG. Zosteriform cutaneous Oncologist. 2010 July; 15(7): 772–781. metastases: a literature meta-analysis 9. Manolidis S, Donald PJ. Malignant and a clinical report of three melanoma mucosal melanoma of the head and cases. Dermatol Surg. Sep neck: review of the literature and 2009;35(9):1355-63. report of 14 patients. Cancer. 1997 Oct 15;80(8):1373-86. 10. Prasad ML, Busam KJ, Patel SG, Hoshaw-Woodard S, Shah JP, Huvos AG. Clinicopathologic differences in malignant melanoma arising in oral squamous and sinonasal respiratory mucosa of the upper aerodigestive tract. Arch Pathol Lab Med. 2003 Aug;127(8):997-1002. 11. Manju L. Prasad Update on Pigmented Lesions of the Sinonasal Tract. Head Neck Pathol. 2007 September; 1(1): 50–54. 12. Ascierto PA, et al. The role of BRAF V600 mutation in melanoma. Journal of Translational Medicine 2012, 10:85. 13. Turri-Zanoni M, Medicina D, Lombardi D, et al. Sinonasal mucosal melanoma: Molecular profile and therapeutic implications from a series of 32 cases. Head Neck. July 2012. 14. Satzger I, Schaefer T, Kuettler U, et al. Analysis of c-KIT expression and KIT gene mutation in human mucosal melanomas. British Journal of Cancer 2008; 99:2065–2069. 15. Saida T, Kawachi S, Takata M, et al. Histopathological characteristics of malignant melanoma affecting mucous membranes: a unifying concept of histogenesis. Pathology. Oct 2004;36(5):404-13. 16. Bridger AG, Smee D, Baldwin MA, Kwok B, Bridger GP. Experience with mucosal melanoma of the nose and paranasal sinuses. ANZ J Surg. 2005 Apr;75(4):192-7.

64 AN UNEXPECTED FINDING OF SINONASAL MELANOMA IN A PATIENT BELIEVED TO HAVE CHRONIC SINUSITIS: A CASE REPORT CONTINUING TO SUPPORT YOUR PATIENTS WITH COPAY SAVINGS 100

80 100

100 For mild to moderate rosacea 100 66

The ﬁ rst and only gel approved 75 to treat all 3 symptoms 40

50 19

19 INF LA MMATOR 25 Y PA PULES 7.4 ER S 7.4 10 25 50 75 90 100 YT LE HEM TU 10.2 A US Y P

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AT O 3 M 2.2 M LA in th INF e presen 3.1 ce of papules and pustules 0 40

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0 70 Although some reduction of erythema which was 40 40

present in patients with papules and pustules of 40 70

rosacea occurred in clinical studies, efﬁ cacy for 70 40 treatment of erythema in rosacea in the absence of 40 40

70 70

papules and pustules has not been evaluated. 40 70 70 40

70 40

70 20 3 Symptoms, 1 Medicine 40 40

40 70

for clearer-looking skin 10 40 • 61% of patients achieved treatment success 100 100

1 40 in 12-week clinical studies 40

100 40

40 40 100 40

100 100 30

3% 30 70

70 30

70 INDICATION & USAGE In clinical trials with FINACEA, the most common local adverse events (AE’s) FINACEA® (azelaic acid) Gel, 15% is indicated for topical treatment of (inclusive of mild, moderate and severe categories) were: burning/stinging/ 100 tingling (29%), pruritus (11%), scaling/dry skin/xerosis (8%) and 100 inﬂ ammatory papules and pustules of mild to moderate rosacea. 100 erythema/irritation (4%). Contact dermatitis, edema and acne were 60 Although some reduction of erythema which was present in patients 60 observed at frequencies of 1% or less. 100 with papules and pustules of rosacea occurred in clinical studies, 100 100 efﬁ cacy for treatment of erythema in rosacea in the absence of papules Rarely reported AE’s included: worsening of asthma, vitiligo depigmentation,

30 small depigmented spots, hypertrichosis, reddening (signs of keratosis and pustules has not been evaluated. 30 pilaris) and exacerbation of recurrent herpes labialis. Post-marketing IMPORTANT SAFETY INFORMATION safety information: Skin (facial burning and irritation); Eyes (iridocyclitis on 70

2009 70 accidental exposure with FINACEA to the eyes). To report SUSPECTED FINACEA Gel, 15% is contraindicated in individuals with a history of ADVERSE REACTIONS, contact Bayer HealthCare at 1-866-463-3634

100 hypersensitivity to propylene glycol or any other components of the or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 100 70 30

100 formulation. There have been isolated reports of hypopigmentation after FINACEA is for topical use only. It is not for ophthalmic, oral or intravaginal 60 use of azelaic acid. Since azelaic acid has not been well studied in patients 60

100 use. In case of accidental eye exposure, wash eyes with large amounts

100 with dark complexion, these patients should be monitored for early signs of hypopigmentation. FINACEA and its vehicle caused irritant reactions at the of water and consult a physician if eye irritation persists. Wash hands

30 100 following application of FINACEA. application site in human dermal safety studies. Skin irritation (e.g. pruritus, 30 burning or stinging) may occur during use with FINACEA, usually during See adjacent page for Brief Summary of full Prescribing Information.

70 Model used for illustrative purposes only.

the ﬁ rst few weeks of treatment. If sensitivity or severe irritation develops 70 and/or persists during use with FINACEA, discontinue use and institute Reference: 1. FINACEA [package insert]. Morristown, NJ: Intendis, Inc; 2010. appropriate therapy. ISO 12647-7 Digital Control Strip 100

CL_658024_M04DR_FIN 3_Symptoms_JAOCD.indd 1 1/8/13 1:54 PM Dermal embryofetal developmental toxicology studies have not been performed with azelaic acid, 15%, gel. Oral embryofetal developmental studies were conducted with azelaic acid in rats, rabbits, and cynomolgus monkeys. Azelaic acid was administered during the period of Finacea® organogenesis in all three animal species. Embryotoxicity was observed in rats, rabbits, and monkeys at oral doses of azelaic acid that generated some maternal toxicity. Embryotoxicity (azelaic acid) Gel,15% was observed in rats given 2500 mg/kg/day (162 times the maximum recommended human dose based on body surface area), rabbits given 150 or 500 mg/kg/day (19 or 65 times the maximum recommended human dose based on body surface area) and cynomolgus monkeys For Dermatologic Use Only–Not for Ophthalmic, Oral, or Intravaginal Use given 500 mg/kg/day (65 times the maximum recommended human dose based on body Rx only surface area) azelaic acid. No teratogenic effects were observed in the oral embryofetal BRIEF SUMMARY developmental studies conducted in rats, rabbits and cynomolgus monkeys. CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION An oral peri- and post-natal developmental study was conducted in rats. Azelaic acid was administered from gestational day 15 through day 21 postpartum up to a dose level of 2500 INDICATIONS AND USAGE mg/kg/day. Embryotoxicity was observed in rats at an oral dose that generated some maternal FINACEA Gel, 15%, is indicated for topical treatment of inflammatory papules and pustules toxicity (2500 mg/kg/day; 162 times the maximum recommended human dose based on of mild to moderate rosacea. Although some reduction of erythema which was present in body surface area). In addition, slight disturbances in the post-natal development of fetuses patients with papules and pustules of rosacea occurred in clinical studies, efficacy for treatment was noted in rats at oral doses that generated some maternal toxicity (500 and 2500 of erythema in rosacea in the absence of papules and pustules has not been evaluated. Patients mg/kg/day; 32 and 162 times the maximum recommended human dose based on body should be instructed to avoid spicy foods, thermally hot foods and drinks, alcoholic beverages surface area). No effects on sexual maturation of the fetuses were noted in this study. and to use only very mild soaps or soapless cleansing lotion for facial cleansing. Because animal reproduction studies are not always predictive of human response, this drug CONTRAINDICATIONS should be used only if clearly needed during pregnancy. FINACEA Gel, 15%, is contraindicated in individuals with a history of hypersensitivity to propylene Nursing Mothers: Equilibrium dialysis was used to assess human milk partitioning in vitro. glycol or any other component of the formulation. At an azelaic acid concentration of 25 µg/mL, the milk/plasma distribution coefficient was 0.7 and the milk/buffer distribution was 1.0, indicating that passage of drug into maternal milk WARNINGS may occur. Since less than 4% of a topically applied dose of azelaic acid cream, 20%, is FINACEA Gel, 15%, is for dermatologic use only, and not for ophthalmic, oral or intravaginal use. systemically absorbed, the uptake of azelaic acid into maternal milk is not expected to cause There have been isolated reports of hypopigmentation after use of azelaic acid. Since azelaic a significant change from baseline azelaic acid levels in the milk. However, caution should be acid has not been well studied in patients with dark complexion, these patients should be exercised when FINACEA Gel, 15%, is administered to a nursing mother. monitored for early signs of hypopigmentation. Pediatric Use: Safety and effectiveness of FINACEA Gel, 15%, in pediatric patients have not PRECAUTIONS been established. General: Contact with the eyes should be avoided. If sensitivity or severe irritation develops Geriatric: Clinical studies of FINACEA Gel, 15%, did not include sufficient numbers of subjects with the use of FINACEA Gel, 15%, treatment should be discontinued and appropriate therapy aged 65 and over to determine whether they respond differently from younger subjects. instituted. In a transgenic mouse study, chronic use of FINACEA Gel led to an increased number of ADVERSE REACTIONS animals with papillomas at the treatment site (see PRECAUTIONS: Carcinogenesis, Overall, treatment related adverse events, including burning, stinging/ tingling, dryness/tightness/ Mutagenesis, and Impairment of Fertility). The clinical relevance of the findings in animal scaling, itching, and erythema/irritation/ redness, were 19.4% (24/124) for FINACEA Gel, studies to humans is not clear. 15%, and 7.1% (9/127) for the active comparator gel at 15 weeks. Information for Patients: Patients using FINACEA Gel, 15%, should receive the following In two vehicle controlled, and one active controlled U.S. clinical studies, treatment safety was information and instructions: monitored in 788 patients who used twice daily FINACEA Gel, 15%, for 12 weeks (N=333) or • FINACEA Gel, 15%, is to be used only as directed by the physician. for 15 weeks (N=124), or the gel vehicle (N=331) for 12 weeks. • FINACEA Gel, 15%, is for external use only. It is not to be used orally, intravaginally, or for Table 3. Cutaneous Adverse Events Occurring in ≥1% of Subjects in the Rosacea Trials by the eyes. Treatment Group and Maximum Intensity* • Cleanse affected area(s) with a very mild soap or a soapless cleansing lotion and pat dry FINACEA Gel, 15% Vehicle with a soft towel before applying FINACEA Gel, 15%. Avoid alcoholic cleansers, tinctures N=457 (100%) N=331 (100%) and astringents, abrasives and peeling agents. Mild Moderate Severe Mild Moderate Severe • Avoid contact of FINACEA Gel, 15%, with the mouth, eyes and other mucous membranes. n=99 n=61 n=27 n=46 n=30 n=5 If it does come in contact with the eyes, wash the eyes with large amounts of water and (22%) (13%) (6%) (14%) (9%) (2%) consult a physician if eye irritation persists. Burning/ • The hands should be washed following application of FINACEA Gel, 15%. stinging/ • Cosmetics may be applied after FINACEA Gel, 15%, has dried. tingling 71 (16%) 42 (9%) 17 (4%) 8 (2%) 6 (2%) 2 (1%) • Skin irritation (e.g., pruritus, burning, or stinging) may occur during use of FINACEA Gel, Pruritus 29 (6%) 18 (4%) 5 (1%) 9 (3%) 6 (2%) 0 (0%) 15%, usually during the first few weeks of treatment. If irritation is excessive or persists, use of FINACEA Gel, 15%, should be discontinued, and patients should consult their physician Scaling/dry (See ADVERSE REACTIONS). skin/xerosis 21 (5%) 10 (2%) 5 (1%) 31 (9%) 14 (4%) 1 (<1%) • Avoid any foods and beverages that might provoke erythema, flushing, and blushing (including Erythema/ spicy food, alcoholic beverages, and thermally hot drinks, including hot coffee and tea). irritation 6 (1%) 7 (2%) 2 (<1%) 8 (2%) 4 (1%) 2 (1%) • Patients should report abnormal changes in skin color to their physician. Contact • Avoid the use of occlusive dressings or wrappings. dermatitis 2 (<1%) 3 (1%) 0 (0%) 1 (<1%) 0 (0%) 0 (0%) Drug Interactions: There have been no formal studies of the interaction of FINACEA Gel, 15%, Edema 3 (1%) 2 (<1%) 0 (0%) 3 (1%) 0 (0%) 0 (0%) with other drugs. Acne 3 (1%) 1 (<1%) 0 (0%) 1 (<1%) 0 (0%) 0 (0%) Carcinogenesis, Mutagenesis, Impairment of Fertility: *Subjects may have >1 cutaneous adverse event; thus, the sum of the frequencies of preferred Systemic long-term animal studies have not been performed to evaluate the carcinogenic terms may exceed the number of subjects with at least 1 cutaneous adverse event. potential of azelaic acid. In a 26-week dermal carcinogenicity study using transgenic (Tg.AC) FINACEA Gel, 15%, and its vehicle caused irritant reactions at the application site in human mice, FINACEA Gel, 15%, and the gel vehicle, when applied once or twice daily, did not increase dermal safety studies. FINACEA Gel, 15%, caused significantly more irritation than its vehicle the number of female Tg.AC animals with papillomas at the treatment site. No statistically in a cumulative irritation study. Some improvement in irritation was demonstrated over the significant increase in the number of animals with papillomas at the treatment site was course of the clinical studies, but this improvement might be attributed to subject dropouts. observed in male Tg.AC animals after once daily application. After twice daily application, No phototoxicity or photoallergenicity were reported in human dermal safety studies. FINACEA Gel, 15%, and the gel vehicle induced a statistically significant increase in the number In patients using azelaic acid formulations, the following additional adverse experiences have been of male animals with papillomas at the treatment site when compared to untreated males. reported rarely: worsening of asthma, vitiligo depigmentation, small depigmented spots, hyper- This suggests that the positive effect may be associated with the vehicle application. The trichosis, reddening (signs of keratosis pilaris), and exacerbation of recurrent herpes labialis. clinical relevance of the findings in animals to humans is not clear. Post-marketing safety-Skin: facial burning and irritation; Eyes: iridocyclitis on accidental Azelaic acid was not mutagenic or clastogenic in a battery of in vitro (Ames assay, HGPRT in V79 exposure with FINACEA Gel, 15%, to the eye (see PRECAUTIONS). cells {Chinese hamster lung cells}, and chromosomal aberration assay in human lymphocytes) Distributed under license; U.S. Patent No 6,534,070 and in vivo (dominant lethal assay in mice and mouse micronucleus assay) genotoxicity tests. www.myfinacea.com Oral administration of azelaic acid at dose levels up to 2500 mg/kg/day (162 times the ©2010, Intendis, Inc. All rights reserved, July 2010 maximum recommended human dose based on body surface area) did not affect fertility Manufactured by Intendis Manufacturing S.p.A., Segrate, Milan, Italy or reproductive performance in male or female rats. Distributed by: Pregnancy: Teratogenic Effects: Pregnancy Category B Morristown, NJ 07962 There are no adequate and well-controlled studies of topically administered azelaic acid in Intendis is part of the Bayer Group pregnant women. The experience with FINACEA Gel, 15%, when used by pregnant women is too limited to permit assessment of the safety of its use during pregnancy. 6706803BS 66 From hard-to-reach spots to large body areas... We’ve Got

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Topical Aerosol, USP (0.147mg/g) 1 The Only Triamcinolone in an Aerosol Spray Formulation cools skin; decreases itch Minimal ingredients -- vehicle contains isopropyl palmitate (a moisturizer); low dehydrated alcohol content No touch, precise application at any angle Available in Delivers 0.2% triamcinolone* 63 g and 100 g sizes Relief Never Felt So Good Indication: Kenalog® Spray (triamcinolone acetonide topical aerosol, USP) is indicated for relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses. Important Safety Information: Systemic absorption of topical corticosteroids has produced reversible hypothalamic-pituitary-adrenal (HPA) axis suppression, manifestations of Cushing’s syndrome, hyperglycemia, and glucosuria in some patients. Conditions which augment systemic absorption include the application of the more potent steroids, use over large surface areas, prolonged use, and the addition of occlusive dressings. Children may absorb proportionally larger amounts of topical corticosteroids and thus be more susceptible to systemic toxicity (see PRECAUTIONS, Pediatric Use). You are encouraged to report negative side effects of prescription drugs to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch For topical use only. Please see adjacent page for full prescribing information. For more information, visit www.kenalogspray.com Reference: 1. Data on file. Ranbaxy Laboratories, Inc. Princeton, NJ. * After spraying, the nonvolatile vehicle remaining on the skin contains approximately 0.2% triamcinolone acetonide. Each gram of spray provides 0.147 mg triamcinolone acetonide in a vehicle of isopropyl palmitate, dehydrated alcohol (10.3%), and isobutane propellant. KENALOG® is a licensed trademark of Bristol-Myers Squibb Company. KS 1212 67

Kenalog JOCAD 3-14-13 indd.indd 1 3/14/13 11:41 AM 68

Kenalog JOCAD 3-14-13 indd.indd 2 3/14/13 11:41 AM