Volume 27

JAOCDJournal Of The American Osteopathic College Of Dermatology

pg. 12 An Osteopathic Approach to Raynaud’s Phenomenon

Also in this issue: Tinea Faciei Presenting as a Perioral Cutaneous Pili Migrans Misdiagnosed VapoRub™ for ? last modified on December 19, 2013 2:08 PM

JOURNAL OF THE AMERICAN OSTEOPATHIC COLLEGE OF DERMATOLOGY Page 1 Journal of the American Osteopathic College of Dermatology

2013-2014 AOCD OFFICERS

PRESIDENT Suzanne Sirota-Rozenberg, DO, FAOCD

PRESIDENT-ELECT Rick Lin, DO, FAOCD

FIRST VICE-PRESIDENT Alpesh Desai, DO, FAOCD

SECOND VICE-PRESIDENT Karthik Krishnamurthy, DO, FAOCD

THIRD VICE-PRESIDENT Daniel Ladd, DO, FAOCD

Editor-in-Chief IMMEDIATE PAST-PRESIDENT Karthik Krishnamurthy, DO Bradley Glick, DO, FAOCD SECRETARY-TREASURER Jere J. Mammino, DO, FAOCD

TRUSTEES John P. Minni, DO, FAOCD Bryan Sands, DO, FAOCD Sponsors: Danica Alexander, DO, FAOCD Reagan Anderson, DO, FAOCD Bayer Michael Whitworth, DO, FAOCD AuroraDx  Tracy Favreau, DO, FAOCD  Immediate Past-President Medicis David L. Grice, DO, FAOCD Ranbaxy EEC Representatives James Bernard, DO, FAOCD JAOCD Michael Scott, DO, FAOCD Founding Sponsor Finance Committee Representative Steven K. Grekin, DO, FAOCD

AOBD Representative Stephen Purcell, DO, FAOCD

Executive Director AOCD • 2902 N. Baltimore St. • Kirksville, MO 63501 Marsha A. Wise, BS 800-449-2623 • FAX: 660-627-2623 • www.aocd.org COPYRIGHT AND PERMISSION: Written permission must be obtained from the Journal of the American 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. Copyright © 2003 by the Journal of the American Osteopathic College of Dermatology Print and layout by: S&S Printing and Graphics LLC, 401 N. Marion St., Kirksville, MO 63501 Copy editing by: Julia Layton, Freelance Writing and Editing Page 2 JOURNAL OF THE AMERICAN OSTEOPATHIC COLLEGE OF DERMATOLOGY Journal of the American Osteopathic College of Dermatology

Table of Contents Volume 27 JAOCD Editors...... 4 Letter from the Editor-in-Chief...... 5 Letter from the Executive Director...... 6 Letter from the President...... 7 FEATURE ARTICLE: An Osteopathic Approach to Raynaud’s Phenomenon Riddhi J. Shah, DO, Jenifer R. Lloyd, DO, Michael P. Rowane, DO...... 12

EDITOR’S PICKS: Tinea Faciei Presenting as a : An Elusive Dermatophytosis with Many on the Sarah Ferrer-Bruker, DO, Nicole Swenson, DO, Sean Sukal, MD, PhD...... 15 A Case of Cutaneous Pili Migrans: A Creeping Eruption Mimicking Larva Migrans Sarah Ferrer-Bruker, DO, Nicole Swenson, DO, Sean Sukal, MD, PhD...... 17 Vicks VapoRub® May Have Nailed It as a Safe First-Line Treatment for Uncomplicated Onychomycosis Jonathan S. Crane, DO, FAOCD, Louis I. Padgett, BS, J. Kate Jackson, PA-C...... 19

ORIGINAL ARTICLES AND CASE REPORTS Basal Cell Nevus Syndrome in an African-American Female: A Case Report and Review of the Literature Emily Kate Matthews, DO, Yuri Kim, BS, Robin Shecter, DO...... 22 -like Kaposi’s Sarcoma: An Atypical Histologic Variant Jamie Groh, DO, Michael Wile, MD, Robin Shecter, DO...... 25 Neurofibromatosis in Pregnancy: A Case Report and Discussion Brandon Markus, DO, Bill Lear, MD, Angela Bohlke, MD, MPH...... 27 A Rare Case of Pagetoid Reticulosis Presenting in a Pregnant Patient Jeremy K. Bingham, DO, Kevin Svancara, BS, Vernon T. Mackey, DO, FAOCD, FASMS...... 29 Painful, Erosive and Exudative Plaque on the Scalp of an Elderly Male Cherise Khani, DO, Peter Saitta, DO, FAOCD, Cindy Hoffman, DO, FAOCD, Ronald Brancaccio, MD, FAAD...... 31 A Case of Subcutaneous Fat Necrosis of the Newborn Charlotte Noorollah, DO, Sourab Choudhury, DO, Suzanne Sirota Rozenberg, DO...... 32 Use of Acitretin in a Patient with Epidermolytic Hyperkeratosis: A Case Report and Literature Review Dorene Niv, BS, Heather Kelly, BS, Patrick Keehan, DO, FAOCD...... 34 Case Report: Follicular in an Adolescent Ashvin Garlapati, DO, Mayha Patel, BS, Stanley Skopit, DO, MSE, FAOCD...... 36 Gianotti-Crosti Syndrome: A Case Presentation and Discussion Travis Hamblin, DO, Dustin Portella, BS, Steven Grekin, DO, FAOCD...... 38 Pyoderma Gangrenosum: A Case Report and Proposed Evidence-based Guidelines for Working-up the Condition Steven Brooks, DO, MS, Suzanne Sirota Rozenberg, DO, FAOCD...... 40 A Basal Cell Carcinoma Simulator: Case Report and Review of the Clinical, Dermoscopic and Reflectance Confocal Microscopy Features of Sebaceous Kimberly Hull, DO, Theresa Cao, DO, Angela Combs, DO, Tracy Favreau, DO, Harold Rabinovitz, MD, ...... 42 Hypopigmented Mycosis Fungoides: Case Report and Review Holly Kanavy, DO, Angela Macri, BS, Harleen Sidhu, MD, Craig Austin, MD...... 44 Scalp Psoriasis Treated with Excimer Laser, Clobetasol Propionate Spray, and Calcitriol Ointment: A Case Report Monica Huynh, BA, Ethan Levin, MD, John Koo, MD...... 48 Lamellar : A Case Report and Review Steffany B. Steinmetz, DO, Stanley E. Skopit, DO, MSE, FAOCD...... 50

JOURNAL OF THE AMERICAN OSTEOPATHIC COLLEGE OF DERMATOLOGY Page 3 Editor-In-Chief Founding Editor Assistant Editor Karthik Krishnamurthy, DO Jay Gottleib, DO Julia Layton, BA, MFA Associate Editors

Aaron Bruce, DO Michelle Foley, DO Michael Scott, DO Scott Wickless, DO Bozeman, Montana Ormond Beach, FL Seattle, WA Dallas, Texas

Editorial Board

Sami Abbasi, DO Brad Glick, DO Scott Lim, DO Andrew Racette, DO Brownstown, MI Margate, FL Erie, PA Phoenix, AZ

Brad Abrams, DO Marcus Goodman, DO Chava Lustig, DO Richard Rudnicki, DO Sarasota, FL Roswell, GA Weston, FL Mesquite, TX

Derrick Adams, DO Melinda Greenfield, DO Jere Mammino, DO Amara Sayed, DO Red Bluff, CA Albany. GA Winter Springs, FL San Marcos, TX

Kevin Belasco, DO Denise Guevara, DO Chris Manlio, DO Joseph Brant Schneider, DO Milwaukee, WI Weston, FL Loxahatchee, FL Shawnee Mission, KS

Brett Bender, DO Andrew Hanly, MD John Minni, DO Gregg Severs, DO Farmington Hills, MI Miami, FL Port St. Lucie, FL Scranton, PA

Richard Bernert, MD Joel Harris, DO Tony Nakhla, DO Sean Stephenson, DO Scottsdale, AZ Madison Heights, MI Orange County, CA Troy, MI

Ryan Carlson, DO Heather Higgins, DO Navid Nami, DO Jacqueline Thomas, DO Hilliard, OH Troy, MI Newport Beach, CA Fort Lauderdale, FL

Igor Chaplik, DO David Horowitz, DO Jon Keeling, DO Jim Towry, DO Aventura, FL Torrence, CA Lexington, KY Ocala, FL

Michael P. Conroy, MD Matt Leavitt, DO Dimitria Papadopoulos, DO Columbus, OH Maitland, FL Bellmore, NY

Matthew Elias, DO Mark Lebwohl, MD John Perrotto, DO Lighthouse Point, FL New York, NY West Palm Beach, FL

Merrick Elias, DO Angela Leo, DO Stephen Purcell, DO Delray Beach, FL New York, NY Allentown, PA

Page 4 JAOCD EDITORS Letter from the Editor-in-Chief

Karthik Krishnamurthy, DO, FAOCD Editor-in-Chief

Dear JAOCD readers,

Thank you all for your continued support and great submissions, as well as for your patience as we revamp the format and appearance of the journal. We have had four different styles this year, and we’d love to get your feedback on which is most appealing.

I would also like to take this opportunity to invite my fellow members to the 2014 Dallas meeting, being held February 20-24 at the Ritz Carlton. This is an exciting meeting for many reasons. First, as Program Chair, I have scheduled 26 Category 1-A CME credits! The speaker line-up is refreshing and high-impact, with medical/surgical experts such as Ron Rapini, MD (“Unusual Infections”), David Fivenson, MD (“What’s Under that ?”), Jennifer Cather, MD (“Managing Psoriasis Patients Across the Life Course”), and James Q. Del Rosso, DO (Pharmacologic Q&A).

There will also be an emphasis on less-visible issues we face as physicians -- answers to questions we cannot find in textbooks, journals, or labs. Clifford Lober, MD, JD, will be talking about “Legal Dilemmas in Dermatology,” including real-life cases and scenarios. Kelly Nelson, MD, will shed light on “Issues in Patient Safety.” I have invited the web-blog phenomenon James Dahle, MD, the “White Coat Investor,” to share tips and strategies specifically aimed at physicians and practices in a non-proprietary information session between colleagues. Lloyd Cleaver, DO, will be updating and demystifying OCC requirements. Finally, Faith McNicholas, the manager for Coding & Reimbursement / Governmental Affairs for the AAD, will give us an extended, interactive update on the implementation of ICD-10. She recently gave a similar talk at our Einstein Grand Rounds, and I can attest to her expertise and approachability. Rounding out our meeting, topics in melanoma, Mohs, dermatopathology, and cosmetic dermatology will be covered.

This meeting will be our first to implement the feedback from member surveys, taking into account preferences in content, accessibility, and increased number of offered CME hours. I urge you not to miss out on this unique opportunity to attend such a well-rounded and innovative program line-up.

Happy holidays to all, Karthik Krishnamurthy, DO, FAOCD Editor-in-Chief, Journal of the American Osteopathic College of Dermatology 2nd Vice President, American Osteopathic College of Dermatology Program Chair, 2014 Dallas Meeting

LETTER FROM THE EDITOR-IN-CHIEF Page 5 Letter from the Executive Director

Marsha Wise Executive Director, AOCD

Greetings, everyone! The 2013 Annual Meeting is now behind us, and new officers were elected at our annual business meeting on October 1, 2013. The AOCD has many committees working for the entire AOCD membership. If you would like to be a member of a committee, please contact the AOCD office for more information (www.aocd.org). The AOCD has grown tremendously over the last decade. We had many exciting changes during 2013 with the move to our new, spacious office, and the website update. We encourage everyone to log on to the new site (www.aocd.org) and explore the wealth of information located on it. If you have username or password problems, please let us know. We are happy to assist!

2014 AOCD Dues Renewal It’s time to renew your dues for 2014. Your membership in the AOCD and participation in our CME events are greatly appreciated, and your continued support helps us to achieve the AOCD’s objectives: 1. To maintain the highest possible standards in the practice of dermatology. 2. To stimulate study and to extend knowledge in the field of dermatology. 3. To promote a more general understanding of the nature and of the services rendered by osteopathic dermatologists to the other divisions of medical practice, hospitals, clinics, and the public. 4. To contribute to the best interests of the osteopathic profession by functioning as an affiliated organization of the American Osteopathic Association.

Meetings Update AOCD Midyear 2014 will be held February 20-23, 2014, in Dallas, TX, at the Ritz Carlton. You must contact the Ritz Carlton directly for room reservations (www.ritzcarlton.com/en/Properties/Dallas/Default.htm).

Meeting Evaluations and Surveys AOA requirements for CME continue to evolve. Thank you to everyone for participating in the various surveys throughout the year and for returning meeting evaluations. The results are tabulated and reviewed by the Board of Trustees and the CME committee. Locations for future AOCD Midyear Meetings will be chosen based on survey results. The AOCD Board of Trustees and National Office wish you a happy and healthy holiday season.

Best, Marsha A. Wise

Page 6 LETTER FROM THE EXECUTIVE DIRECTOR Letter from the President

Suzanne Sirota Rozenberg DO, FAOCD President, AOCD

Dear Colleagues,

What an interesting start to my tenure it has been. If you think being President is a quiet job, think again. In the first six weeks, we’ve been addressing the many exciting events and goals on our agenda for the coming year.

First, our JAOCD is on the forefront with its high standards and increasing visibility. Our peer-reviewed journal showcases our residents, members and program directors. No article is unchecked. The design is evolving. Karthik and the rest of the journal team are doing a great job.

Our college is hard at work for you. Marsha Wise, with a click of a button, has all of the answers you need. John Grogan keeps our residents in check, and Shelly Wood is recruiting those sponsors. Our annual convention showcased local and across-the- country talent. As our college grows, our own talent will be even more present. The new CME rules for conferences require 50 percent DO lecturers. I know our future program chairs are already working toward this goal. If anyone is interested in lecturing, touch base with Rick Lin and Dan Ladd. Our Dallas meeting is set to go, and I hope to see you all there. Over 100 members have signed up already. Come get your CME and socialize with your colleagues!

The finance committee has been extremely effective, with Marsha keeping us fiscally responsible. Nice work! Your EEC committee, too, is at it. Basic standards for the residencies are constantly being reviewed and revised. Thank you to the in-training exam committee for all your efforts. We strive to produce the best dermatologists in the country.

So, what’s on the horizon? The AAD ad hoc task force is working to bridge the gap between DO and MD dermatologists. Our goal is to work together, not separately. It is also working to dispel the incorrect perceptions of DOs amongst the MDs. We have a real friend in Dirk Elston. I ask all of you to be our advocates. Educating our colleagues and patients about DO dermatologists is essential. Striving for excellence in practice and residencies should be everyone’s goal.

Please don’t be a stranger to our college. Be on a committee, come to our meetings, advocate for us. You will find it highly rewarding.

Fondly, Suzanne Sirota Rozenberg, DO, FAOCD President, AOCD

LETTER FROM THE PRESIDENT Page 7 etter from the President L

your patients’

problems are

NO-TOUCH RELIEF The Only Mid-Potency Topical Aerosol Spray1

INDICATIONS AND USAGE: Kenalog® Spray (Triamcinolone Acetonide Topical Aerosol, USP) is indicated for relief of the inflammatory and pruritic manifestations of -responsive dermatoses. CONTRAINDICATIONS: Topical are contraindicated in those patients with a history of hypersensitivity to any of the components of the preparations. For external use only. Please see full Prescribing Information on reverse and also at KenalogSpray.com. REFERENCE: 1. Fowler J, Fowler L. Physician and patient assessment of triamcinolone acetonide spray for steroid-responsive dermatoses. J Clin Aesthet Dermatol. 2010;3:27-31.

Kenalog® is a licensed trademark of Bristol-Myers Squibb Company. KNGJI1 09/13

KEN11889-A_StandardSizeA_DR ROB.crw1.indd 1 10/10/13 12:43 PM ® Rx only consulting your physician. KENALOG SPRAY 9. Kenalog Spray is ammable. Avoid heat, ames or smoking when applying Kenalog Spray. Triamcinolone Acetonide Topical Aerosol, Laboratory Tests USP A urinary free cortisol test and ACTH stimulation test may be helpful in evaluating HPA axis (0.147 mg/g) suppression. For dermatologic use only Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been performed to evaluate the carcinogenic potential or the Not for ophthalmic use effect on fertility of topical corticosteroids. DESCRIPTION Studies to determine mutagenicity with prednisolone and hydrocortisone showed negative The topical corticosteroids constitute a class of primarily synthetic used as results. anti-in ammatory and antipruritic agents. The steroids in this class include triamcinolone Pregnancy: Teratogenic Effects acetonide. Triamcinolone acetonide is designated chemically as 9- uoro-11β, 16α, 17, Category C. Corticosteroids are generally teratogenic in laboratory animals when administered 21-tetrahydroxypregna-1, 4-diene-3, 20-dione cyclic 16, 17- acetal with acetone. The structural systemically at relatively low dosage levels. The more potent corticosteroids have been shown to be formula is: teratogenic after dermal application in laboratory animals. There are no adequate and well- controlled studies in pregnant women on teratogenic effects from topically applied corticosteroids. Therefore, topical corticosteroids should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Drugs of this class should not be used extensively on pregnant patients, in large amounts, or for prolonged periods of time. Nursing Mothers It is not known whether topical administration of corticosteroids could result in sufcient systemic absorption to produce detectable quantities in breast milk. Systemically administered corticosteroids are secreted into breast milk in quantities not likely to have a deleterious effect on C24H31FO6, MW 434.50 the infant. Nevertheless, caution should be exercised when topical corticosteroids are administered to a nursing woman. A two-second application, which covers an area approximately the size of the hand, delivers an amount of triamcinolone acetonide not exceeding 0.2 mg. After spraying, the nonvolatile Pediatric Use vehicle remaining on the contains approximately 0.2% triamcinolone acetonide. Each gram of spray provides 0.147 mg triamcinolone acetonide in a vehicle of isopropyl palmitate, Pediatric patients may demonstrate greater susceptibility to topical corticosteroid-induced dehydrated alcohol (10.3%), and isobutane propellant. HPA axis suppression and Cushing’s syndrome than mature patients because of a larger skin surface area to body weight ratio. CLINICAL PHARMACOLOGY Topical corticosteroids share anti-in ammatory, antipruritic and vasoconstrictive actions. HPA axis suppression, Cushing’s syndrome, and intracranial hypertension have been reported The mechanism of anti-in ammatory activity of the topical corticosteroids is unclear. Various in children receiving topical corticosteroids. Manifestations of adrenal suppression in children laboratory methods, including vasoconstrictor assays, are used to compare and predict include linear growth retardation, delayed weight gain, low plasma cortisol levels, and absence of potencies and/or clinical efcacies of the topical corticosteroids. There is some evidence to response to ACTH stimulation. Manifestations of intracranial hypertension include bulging suggest that a recognizable correlation exists between vasoconstrictor potency and therapeutic fontanelles, headaches, and bilateral papilledema. efcacy in man. Administration of topical corticosteroids to children should be limited to the least amount Pharmacokinetics compatible with an effective therapeutic regimen. Chronic corticosteroid therapy may interfere with The extent of percutaneous absorption of topical corticosteroids is determined by many factors the growth and development of children. including the vehicle, the integrity of the epidermal barrier, and the use of occlusive dressings. Topical corticosteroids can be absorbed from normal intact skin. In ammation and/or other ADVERSE REACTIONS disease processes in the skin increase percutaneous absorption. The following local adverse reactions are reported infrequently with topical corticosteroids, but may Once absorbed through the skin, topical corticosteroids are handled through pharmacokinetic occur more frequently with the use of occlusive dressings (reactions are listed in an approximate pathways similar to systemically administered corticosteroids. Corticosteroids are bound to decreasing order of occurrence): burning, itching, irritation, dryness, , , plasma proteins in varying degrees. Corticosteroids are metabolized primarily in the and are acneiform eruptions, hypopigmentation, perioral dermatitis, allergic , maceration then excreted by the kidneys. Some of the topical corticosteroids and their metabolites are also of the skin, secondary infection, skin atrophy, striae, and . excreted into the bile. OVERDOSAGE INDICATIONS AND USAGE Topically applied corticosteroids can be absorbed in sufficient amounts to produce systemic effects Kenalog Spray (Triamcinolone Acetonide Topical Aerosol, USP) is indicated for relief of the (see PRECAUTIONS, General). in ammatory and pruritic manifestations of corticosteroid-responsive dermatoses. DOSAGE AND ADMINISTRATION CONTRAINDICATIONS Directions for use of the spray can are provided on the label. The preparation may be applied to any Topical corticosteroids are contraindicated in those patients with a history of hypersensitivity to area of the body, but when it is sprayed about the face, care should be taken to see that the eyes any of the components of the preparations. are covered, and that inhalation of the spray is avoided. PRECAUTIONS Spray is flammable; avoid heat, flame or smoking when using this product. General Systemic absorption of topical corticosteroids has produced reversible hypothalamic- Three or four applications daily of Kenalog Spray (Triamcinolone Acetonide Topical Aerosol) are pituitary-adrenal (HPA) axis suppression, manifestations of Cushing’s syndrome, hyperglycemia, generally adequate. and glucosuria in some patients. Conditions which augment systemic absorption include the application of the more potent HOW SUPPLIED steroids, use over large surface areas, prolonged use, and the addition of occlusive dressings. Kenalog Spray (Triamcinolone Acetonide Topical Aerosol, USP) Therefore, patients receiving a large dose of any potent topical steroid applied to a large surface area or under an occlusive dressing should be evaluated periodically for evidence of 63 g (NDC 10631-093-62) aerosol can. HPA axis suppression by using the urinary free cortisol and ACTH stimulation tests, and for impairment of thermal homeostasis. If HPA axis suppression or elevation of the body 100 g (NDC 10631-093-07) aerosol can. temperature occurs, an attempt should be made to withdraw the drug, to reduce the frequency of application, substitute a less potent steroid, or use a sequential approach. Storage and Handling Recovery of HPA axis function and thermal homeostasis are generally prompt and complete Store at room temperature; avoid excessive heat. Contents under pressure; do not puncture or upon discontinuation of the drug. Infrequently, of steroid withdrawal may incinerate. Keep out of reach of children. occur, requiring supplemental systemic corticosteroids. Children may absorb proportionally larger amounts of topical corticosteroids and thus be To report SUSPECTED ADVERSE REACTIONS, contact the FDA at 1-800-FDA-1088 or more susceptible to systemic toxicity (see PRECAUTIONS, Pediatric Use). www.fda.gov/medwatch. If irritation develops, topical corticosteroids should be discontinued and appropriate therapy instituted. RANBAXY In the presence of dermatological infections, the use of an appropriate antifungal or Jacksonville, FL 32257 USA antibacterial agent should be instituted. If a favorable response does not occur promptly, the corticosteroid should be discontinued until the infection has been adequately controlled. Information for the Patient Patients using Kenalog Spray should receive the following information and instructions: 1. This medication is to be used as directed by the physician. It is for external use only; avoid Revised August 2011 contact with the eyes and inhalation of the spray. 2. Patients should be advised not to use this medication for any disorder other than for which it was prescribed. 3. The treated skin area should not be bandaged or otherwise covered or wrapped as to be occlusive unless directed by the physician. 4. Patients should report any signs of local adverse reactions. 5. Parents of pediatric patients should be advised not to use tight-tting diapers or plastic pants on a child being treated in the diaper area, as these garments may constitute occlusive dressings. 6. Do not use Kenalog Spray on the underarms or groin areas unless directed by your physician. 7. If no improvement is seen within 2 weeks, contact your physician. 8. Do not use other corticosteroid-containing products while using Kenalog Spray without rst

©Ranbaxy Pharmaceuticals, Inc. Printed in the USA DERM-3567-1212

KEN11889-A_StandardSizeA_DR ROB.crw1.indd 2 10/10/13 12:43 PM Think of me

Specifically Designed with Tolerability in Mind1

• Indicated for the topical treatment of vulgaris in patients 12 years or older. • Suspended crystalline tretinoin in vehicle designed to deliver the active ingredients to the skin.2 • Hydrogel alcohol-free aqueous base.1

Important Safety Information for ZIANA Gel • The most commonly reported adverse events were nasopharyngitis, pharyngolaryngeal pain, dry skin, cough, and sinusitis. • Diarrhea, bloody diarrhea, and colitis (including pseudomembranous colitis) have been reported with the use of topical clindamycin. ZIANA Gel should be discontinued if significant diarrhea occurs. Systemic absorption of clindamycin has been demonstrated following topical use of this product. • If a reaction suggesting sensitivity or chemical irritation occurs, use of the medication should be discontinued. • Avoid exposure to sunlight and sunlamps. Patients with sunburn should not use the product. Use with caution in patients who require considerable sun exposure due to occupation or who are inherently sensitive to the sun. Avoid excessive exposure to the sun, cold, and wind, which can irritate skin. Daily use of sunscreen and protective clothing are recommended. • Keep away from eyes, mouth, angles of nose, and mucous membranes. • This drug is contraindicated in patients with regional enteritis, ulcerative colitis, or history of antibiotic-associated colitis. • Concomitant use of topical medications with a strong drying effect can increase skin irritation. Use with caution. To learn more, contact your Medicis, The Dermatology Company representative.

See reverse side for a Brief Summary of the Full Prescribing Information. 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

JOURNAL OF THE AMERICAN OSTEOPATHIC COLLEGE OF DERMATOLOGY Page 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 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 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 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 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. have been established from these cases, 5 of the reports describe the rare birth defect category, 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. 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, 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 vehicle gel alone: discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the 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 ® 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 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) 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 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) Manufactured for: sinusitis 19 (1) 19 (1) 15 (2) 4 (1) Medicis, the Dermatology company note: Formulations used in all treatment arms were in the Ziana® vehicle gel. scottsdale, aZ 85256 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 , scaling, itching, burning, and stinging: Ziana is a registered trademark of Medicis pharmaceutical corporation. Table 2: ZIAnA® Gel-Treated Patients with local Skin Reactions prescribing information as of october 2008. local Reaction Baseline End of Treatment 300-13B n=1835 n=1614 n (%) n (%) erythema 636 (35) 416 (26) scaling 237 (13) 280 (17) itching 189 (10) 70 (4) Burning 38 (2) 56 (4) 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 in the 12-week studies. eighteen out of 442 subjects (4%) reported gastrointestinal symptoms. An Osteopathic Approach to Raynaud’s Phenomenon

Riddhi J. Shah, DO,* Jenifer R. Lloyd, DO,** Michael P. Rowane, DO***

* Traditional Rotating Intern, University Hospitals Regional Hospitals, Richmond Heights, OH **Director, Residency Program, University Hospitals Regional Hospitals, Department of Dermatology, Case Western Reserve University, Cleveland, OH ***Director of Medical Education, University Hospitals Regional Hospitals, Richmond Heights, OH

Abstract Raynaud’s phenomenon is characterized as episodic, paroxysmal vasospasm and ischemia of the extremities. It is due to an imbalance of vasodilatation and vasoconstriction factors. There are three primary anatomic areas of focus that can be implicated in triggering a Raynaud’s attack: 1) any hyperactivity of the sympathetic involving thoracic segments 2 through 8; 2) increase in muscle tension to the soft tissues of the neck and upper back; 3) narrowing of the thoracic outlet. Due to its unique pathogenesis, Raynaud’s phenomenon can be treated both medically and through osteopathic manipulation. Common medications prescribed include noncardioselective dihydropyridine calcium-channel blockers, nitrates, and . Osteopathic treatment can be used as primary or supplemental treatment. Its aim is to relieve the restriction of involved territories and so decrease the release of catecholamines, which stimulate the constriction of vascular smooth muscle and compromise blood flow distally. Definition, Epidemiology, Pathophysiology Treatment The pathophysiology of Raynaud’s phenomenon There are several treatment options available for Presentation is not clear. It is believed to be due to an primary and secondary Raynaud’s phenomenon. Raynaud’s phenomenon is characterized as imbalance of vasoconstriction and .1 First-line treatment involves lifestyle episodic and paroxysmal vasospasm and ischemia In primary disease, there is excess activation of modifications including avoiding stress, hand and of the extremities, usually involving the fingers and 1 the sympathetic nervous system directly affecting leg warmers, avoiding cold environments or rapid toes, on exposure to cold or a stressful stimulus. the vascular tone in the extremities it supplies. changes in temperature, and smoking cessation if It was first described by Maurice Raynaud in 1,3 2 The usual disturbance involves thoracic vertebral applicable. Patients can perform the swing-arm 1862 as “a local asphyxia of the extremities.” It segments 1 through 3.5 There is also a decrease maneuver, which involves rapidly windmilling the is a triphasic color change of the digits -- from in vasodilators, including calcitonin-gene-related arms around the body with the goal of increasing white (vasoconstriction), to blue (tissue hypoxia), peptide, which is released by nerves. In patients blood flow distally to the fingers.7 to red (reperfusion) -- accompanied by severe 3 with both primary and secondary Raynaud’s pain. Attacks vary in frequency and duration First-line medications are the noncardioselective phenomenon, skin biopsies have revealed among individuals. In those with severe disease, 6 dihydropyridine calcium-channel blockers. 3 diminished release from neurons. ulceration and gangrene of the digits can occur. Nifedipine, a short-acting agent, is most Endogenous levels of nitric oxide, a potent commonly prescribed at 10 mg to 30 mg doses Raynaud’s phenomenon can be further classified vasodilator activated by high levels of cyclic three times daily. These drugs cause relaxation of as primary (idiopathic) or secondary to guanylyl nitro peptide (cGNP), are also the vascular smooth-muscle cells via inhibition underlying disease. Underlying conditions can decreased in primary and secondary disease.1 of the voltage-gated channels.1,3 This in turn include, but are not limited to, systemic sclerosis, Prostaglandins, whose role is to inhibit promotes vasodilatation and increased blood flow mixed connective-tissue disease, and systemic aggregation and increase fibrinolysis, are also to the periphery. These have been aggressively . Raynaud’s phenomenon found to be deficient in patients with Raynaud’s studied and are routinely prescribed by physicians. affects 3% to 5% of the general population, with 1 1 phenomenon. Individuals consuming large However, when prescribing these drugs, patients a higher predominance in women. Some well- quantities of inhibitors on a regular are to be cautioned about side-effects including known triggers include a positive family history, basis may thus be at risk. headache, , and reflex tachycardia.1 estrogen exposure, emotional stress, smoking, and hand-vibration syndrome.4 Two key players that increase vasoconstriction Topical nitrate therapy is also a relatively common and are likely involved in the pathogenesis of agent used in the treatment of Raynaud’s Differentiation between primary and secondary Raynaud’s phenomenon are endothelin-1 and phenomenon.1,3 Sustained release patches of Raynaud’s phenomenon can be difficult. Some angiotensin- II.1 Endothelin-1 is not only glycerol trinitrate were shown in clinical trials key exam findings thought to be related only to involved in vasoconstriction but also in structural to decrease the number (P<0.05) and severity primary disease include the lack of tissue necrosis, vascular changes and remodeling, which can (P<0.05) of attacks in primary and secondary normal fold capillaries, negative antinuclear further contribute to the ischemic process that Raynaud’s phenomenon.9 However, use maybe antibody test, and a normal erythrocyte 7 1 occurs in this disease. Angiotensin II is part of limited due to the high potential for side effects sedimentation rate. Additionally, primary the renin-angiotensin system (RAS) in the kidney. like headache and hypotension, which can be disease usually begins before 30 years of age Circulating levels of angiotensin II are increased disabling to patients. and lacks other signs/symptoms of underlying in primary and secondary disease. Therefore, illness. It is essential to take a thorough history Prostaglandins have a side-effect profile similar to inhibition of angiotensin II, via angiotensin- and physical to help evaluate. Other diagnostic calcium-channel blockers, but their mechanism of converting inhibitors or angiotensin- modalities that can help include infrared action differs. They have the combined ability to receptor blockers, is a potential future treatment thermography, laser Doppler flowmetry, portable inhibit platelet aggregation, increase fibrinolysis, for Raynaud’s phenomenon.8 radiometry, and digital plethysmography, which and simultaneously promote vasodilation. are generally done by a specialist.3 Despite the multitude of beneficial effects, no oral prostaglandin is as effective as intravenous prostaglandins in the treatment of Raynaud’s

Page 12 AN OSTEOPATHIC APPROACH TO RAYNAUD’S PHENOMENON phenomenon, limiting outpatient-management blood supply to the bilateral arms; 3) narrowing and thoracic soft-tissue are two osteopathic potential.1,3 of the thoracic outlet, which can compromise manipulative treatments (OMT) that can help blood flow distally and often disrupt the nerve ease tension on the cervical fascia (Figures 1 Phosphodiesterase type V (PDE-V) inhibitors 5 increase the amount of cyclic guanosine endings as well. and 2). Soft-tissue is a direct technique, which monophosphate (cGMP) available to promote The neck is composed of three cervical fascia: involves lateral and linear stretching and deep vascular smooth-muscle relaxation and blood superficial colli fascia, middle colli fascia, and pressure, with separation of muscle origin and flow.3 Two case series have found that oral deep colli fascia. These fascia envelop important insertion, while monitoring tissue response and sildenafil reduces the frequency and severity of bony and neurovascular structures. The middle motion changes by palpation. These techniques attacks in patients with secondary Raynaud’s colli fascia is continuous with the subclavius provide a gentle but firm stretching of the fascia phenomenon.10,11 muscle, which is situated between the clavicle and as well as the muscles of the neck and upper back first rib, passing upward and laterally to a groove to increase range of motion and improve blood Endothelin-receptor antagonists have been supply to the periphery. shown to decrease the number of digital on the undersurface of the middle third of the ulcerations in patients with secondary Raynaud’s clavicle. Any spasm, adhesion, or fibrosis can lead phenomenon in the Randomized Placebo- to compression of the thoracic inlet, bringing the controlled Investigation of Digital Ulcers in clavicle closer to the first rib and thus causing Scleroderma (RAPIDS-1) trials.12 They function decreased blood flow to the periphery, causing by inhibiting vasoconstriction as well as vascular the ischemic changes that occur with Raynaud’s remodeling and fibrosis. Bosentan was the agent phenomenon. The deep colli fascia consists of used in the RAPID-1 trial. It is a competitive well-defined fibrous sheets. The subclavian artery antagonist of endothelin-receptor subtypes A and brachial nerves run behind the clavicles as and B.1 After four months of treatment with the axillary sheet of the deep colli fascia. Any tension to this fascia will compress this vital bosentan, there was a 48% reduction in digital 5 12 neurovascular supply to the extremity. ulcers compared to placebo. Current use of this Figure 1: Cervical soft-tissue techniques drug is still limited as more insight is sought into The scalene muscles of the neck are crucial this class of drugs. Additionally, there is potential gateways to the blood supply to the upper for increased hepatic transaminases with extremities. The subclavian artery runs between bosentan, which can occur in 10% of patients.1 the anterior and middle scalene on its route to the Alpha-adrenoreceptors play a key role in shoulder, where it will become the axillary artery temperature regulation and sympathetic-nervous and then subsequently the brachial artery with regulation of vascular tone. Prazosin, which further divisions in the arm. Any compression inhibits the alpha-1 postsynaptic receptor, of the anterior and middle scalene can therefore has been used in several trials to see if there is compromise the blood supply to the arm, putting an improvement in patients with secondary patients at further risk of developing a Raynaud’s attack. This is one of the several key areas that Raynaud’s phenomenon. Though found to reduce 5 the severity of Raynaud’s attacks, side effects can lead to thoracic-outlet syndrome. including dizziness, headache, palpitations, Thoracic-outlet syndrome can also occur between Figure 2: Thoracic soft-tissue techniques nausea, and hypotension are common and limit the clavicles and first rib, with an abnormal the use of these agents in patients.1,3 insertion of the pectoralis minor muscle, or due Several other experimental agents have been to the presence of a cervical rib. The Adson’s, Myofascial release is another form of OMT, first used in the treatment of primary and secondary Wright’s, and costoclavicular tests assess the described by the father of osteopathy, Andrew Raynaud’s phenomenon, such as HMG-CoA- blood supply to the radial artery, helping to Taylor Still. This technique can be used to reductase inhibitors, aspirin, serotonin-reuptake further evaluate the presence of thoracic-outlet free the clavicle and open up the thoracic inlet inhibitors, angiotensin-converting enzyme syndrome. Patients with this syndrome are at by engaging the restrictive barrier or through inhibitors, angiotensin-receptor blockers, and increased risk of developing primary Raynaud’s an indirect treatment by engaging the tissues A.1,3 However, more research phenomenon. in the direction of freer motion (Figures 3 needs to be done before any of these agents can Lastly, it is crucial to address the cervical and and 4). Through continual palpatory feedback, be implemented in treatment for this disease. upper thoracic spine in an individual with an inherent release of the involved tissues is Raynaud’s phenomenon. The sympathetic trunk achieved. In respect to the clavicles, they can be emerges from the thoracic spine, and its ganglions gently translated laterally and held until release is Osteopathic Approach felt. These maneuvers eliminate any tension on Primary Raynaud’s phenomenon, unlike are located in front of the heads of the ribs. These the subclavian artery on its path underneath the secondary forms, is mainly a functional disease. ganglions, specifically at the levels of T2 through clavicle. Thus, along with medical management of the T8, supply the upper extremity with sympathetic patient, osteopathic medicine may play an integral fibers. The postganglionic sympathetic fibers, The first rib is another important player in the role in decreasing the severity and number of which join the spinal nerves, are vasoconstrictors cause of Raynaud’s phenomenon. Using the attacks. There are three primary areas of focus of blood vessels in the arm. Therefore, osteopathic direct technique, high-velocity/low-amplitude that can be implicated in triggering an attack: treatment should focus on thoracic segments 2 (HVLA), the malpositioning of the first rib can 1) any hyperactivity of the sympathetic nervous through 8. Additionally, the stellate ganglion, C7, be eliminated, opening up the thoracic inlet and system, which leads to an increased release of has vascular branches extending from it as well as allowing the neurovascular supply to run smoothly catecholamines, stimulating the constriction of the thoracic sympathetic nerves that supply the from the neck down the arms (Figure 5). This is 5 vascular smooth muscle; 2) increase in muscle subclavian arteries. the most aggressive OMT technique, involving tension to the soft tissues of the neck and upper There are several techniques that can address engagement of the restrictive barrier and then back region, which can cause constriction of the these restrictions. First, cervical soft-tissue application of a directional force to correct the

SHAH, LLOYD, ROWANE Page 13 techniques; 3) supine direct myofascial release 10. Lichtenstein JR. Use of sildenafil citrate clavicular spread technique; 4) supine direct in Raynaud’s phenomenon: comment on the and indirect myofascial release of the thoracic article by Thompson et al. Rheum. 2003 inlet technique; 5) sitting high-velocity/low- Jan;48(1):282-3; amplitude treatment of the first rib. In a previous 11. Kumana CR, Cheung GT, Lau CS. Severe study, this protocol demonstrated OMT as a digital ischaemia treated with phosphodiesterase viable therapeutic intervention in affecting the inhibitors. Ann Rheum Dis. 2004 autonomic nervous system.14 The treatment Nov;63(11):1522-4. of the thoracic and the cervicothoracic regions should duplicate this change to sympathetic 12. Korn JH, Mayes M, Matucci Cerinic nervous system activity and benefit patients with M, Rainisio M, Pope J, Hachulla E, Rich E, Figure 3: Direct myofascial release clavicular Raynaud’s phenomenon, but a formal clinical Carpentier P, Molitor J, Seibold JR, Hsu V, spread trial would be necessary to confirm. Guillevin L, Chatterjee S, Peter HH, Coppock J, Herrick A, Merkel PA, Simms R, Denton By combining the medical and osteopathic CP, Furst D, Nguyen N, Gaitonde M, Black C. approach, we can successfully treat our patients Digital ulcers in systemic sclerosis: prevention suffering from Raynaud’s phenomenon. This will by treatment with bosentan, an oral endothelin enable us to address the various structural and receptor antagonist. Arthritis Rheum. 2004 functional changes in the chemical and hormonal Dec;50(12):3985-93. modulators, receptor activation, and muscle and tissue strain and stress that can trigger this 13. Pope J, Fenlon D, Thompson A, Shea potentially devastating disease. B, Furst D, Wells G, Silman A. Prazosin for Raynaud’s phenomenon in progressive systemic sclerosis. Cochrane Database Syst Rev. 2000;(2):CD000956. Figure 4: Direct and indirect myofascial References 14. Henderson AT, Fisher JF, Blair J, Shea C, 1. Baumhäkel M, Böhm M. Recent achievements release of the thoracic inlet Li TS, Bridges KG. Effects of rib raising on the in the management of Raynaud’s Phenomenon. autonomic nervous system: a pilot study using Vasc Health Risk Manag. 2010 Apr 15;6:207-14. dysfunctional rib. Proper positioning is crucial noninvasive biomarkers. J Am Osteopath Assoc. to a therapeutic effect. Similarly, HVLA can 2. Raynaud M. On local asphyxia and symmetrical 2010 Jun;110(6):324-30. be applied to the thoracic region to address the gangrene of the extremities, 1862, and New hyperactivity of the sympathetic nervous system research on the nature and treatment of local contributing to the catecholamine surge and asphyxia of the extremities, 1872. In: London: Correspondence: Jenifer R. Lloyd, DO, Lloyd vasoconstriction of the peripheral digits. There New Sydenham Society, 1988. Barlow T, trans. Dermatology & Laser Center, 8060 Market St., are several other HVLA techniques that can be Youngstown, OH 44512; Phone: (330)758- 3. Goundry B, Bell L, Langtree M, Moorthy used depending on the physician’s comfort level, 9189; Fax: (330)758-4487; [email protected] A. Diagnosis and management of Raynaud’s such as the supine thoracic double arm thrust phenomenon. Br Med J. 2012 Feb 7;344. (“Kirksville Crunch”), knee-in-the back, and epigastric thrust. 4. Fraenkel L. Raynaud’s phenomenon: epidemiology and risk factors. Curr Rheumatol Rep. 2002; 4:123-8. 5. Kalcakosz-Takacs T. Treatment of Primary Raynaud’s Syndrome with Osteopathy. Wiener Schule für Osteopathie. 2007 Mar;01. 6. Bunker CB, Terenghi G, Springall DR, Polak JM, Dowd PM. Deficiency of calcitonin gene- related peptide in Raynaud’s phenomenon. Lancet. 1990;336(8730):1530-1533. 7. Bakst R, Merola JF, Franks AG Jr, Sanchez M. Raynaud’s phenomenon: pathogenesis and management. J Am Acad Dermatol. 2008 Oct;59(4):633-53. 8. Kawaguchi Y, Takagi K, Hara M, Fukasawa C, Figure 5: Sitting high-velocity/low-amplitude Sugiura T, Nishimagi E, Harigai M, Kamatani treatment of first rib N. Angiotensin II in the lesional skin of systemic sclerosis patients contributes to tissue fibrosis via Potentially, a clinical trial involving OMT in angiotensin II type 1 receptors. Arthritis Rheum. patients with Raynaud’s phenomenon could 2004 Jan;50(1):216-26. be done using the five OMT techniques in the 9. Teh LS, Manning J, Moore T, Tully MP, O’Reilly following order to minimize the necessity of D, Jayson MI. Sustained-release transdermal patients’ positional adjustments and increase glyceryl trinitrate patches as a treatment for treatment efficiency: 1) prone thoracic soft- primary and secondary Raynaud’s phenomenon. tissue techniques; 2) supine cervical soft-tissue Br J Rheumatol. 1995 Jul;34(7):636-41. Page 14 AN OSTEOPATHIC APPROACH TO RAYNAUD’S PHENOMENON Tinea Faciei Presenting as a Perioral Dermatitis: An Elusive Dermatophytosis with Many Faces on the Face

Sarah Ferrer-Bruker, DO,* Nicole Swenson, DO,** Sean Sukal, MD, PhD***

*1st-year Dermatology Resident, West Palm Hospital/ Palm Beach Centre for Graduate Medical Education, West Palm Beach, FL **3rd-year Internal Medicine Resident, West Palm Hospital/ Palm Beach Centre for Graduate Medical Education, West Palm Beach, FL *** Director, Sukal Skin Institute, Boca Raton, FL

Abstract Tinea faciei has the most variable clinical presentation of all the dermatophytoses. Treatment is often delayed due to missed diagnosis on initial clinical evaluation. The following case demonstrates an example of tinea faciei’s clinical variability, presenting seemingly as common perioral dermatitis with further workup revealing dermatophytosis. We provide a literature review of tinea faciei’s potential presentations, differential diagnosis, work-up, and treatment.

Introduction (Figure 1). Of note, no scale was present in the oral terbinafine at a dose of 250 mg per day. At Facial dermatophyte infections may present area of the patient’s . her follow-up visit, the patient showed marked in multiple configurations, often deviating clinical improvement, with full resolution of from the typical ringed, erythematous, scaling and symptoms at four weeks (Figure 3). pathognomonic picture. Termed “tinea incognito,” initial misdiagnosis and application of steroids or other anti-inflammatory agents may alter these lesions, potentially further delaying diagnosis. Depending on which site on the face it affects as well as its potential variable morphology, tinea faciei may mimic other erythematous facial such as acne, , perioral dermatitis, lupus erythematosus, seborrheic dermatitis, and Figure 1 contact dermatitis. The following case exemplifies tinea faciei’s clinical variability. It presented as She denied photosensitivity; exposure to Figure 3 common perioral dermatitis, but further workup new products, grooming habits, animals, revealed dermatophytosis, which responded supplements, or travel; and previous use of topical excellently to an oral antifungal agent. corticosteroids besides those recently prescribed She continued this regimen for a total of three to her. There were no other lesions elsewhere. months for treatment of her concomitant Case Presentation An initial diagnosis of perioral dermatitis was onychomycosis of the lower-extremity nails, A 72-year-old woman presented to the clinic with made with consideration for possible rosacea, without recurrence of any perioral lesions. a history of an increasingly painful, erythematous and the patient was instructed to immediately rash of 10 days duration in a perioral distribution. discontinue topical steroids. She was placed Discussion Assuming this was an irritant or allergic on a course of oral doxycycline and topical Tinea faciei accounts for 3% to 4% of all cases dermatitis related to cosmetics, her primary metronidazole gel. A biopsy was taken at this of tinea corporis, with causative agent varying physician prescribed the patient a topical steroid. time for confirmation of the diagnosis. At her according to geography and potential reservoirs.1 She used the steroid from days 2 to 4 after onset, one-week follow-up appointment, her perioral The dermatophytes Trichophyton tonsurans, with further worsening of symptoms. Her rash and discomfort persisted. Biopsy results Trichophyton rubrum, and Microsporum medical history was significant for hypertension, showed hyperkeratosis with parakeratotic scale, canis are the most common causative species, hypercholesterolemia, depression, and bilateral and PAS stain demonstrated many fungal hyphal particularly in the United States.2-5 One knee replacements. From a dermatologic elements consistent with dermatophyte infection characteristic of a dermatophyte is an acquired standpoint, she had a history of a facial basal-cell (Figure 2). ability to metabolize and subsist upon keratin, carcinoma treated with Moh’s , hyaluronic- a protein resistant to most other organisms, acid filler injections many years prior, and about allowing the fungi to invade where keratin is the 15 years of toenail onychomycosis. She had no major structural protein.6 recent changes in medications and had been on Classified as a dermatophyte infection involving the same antidepressant, antihypertensive, and non-bearded areas of the face, tinea faciei affects lipid-lowering agent for years. females more frequently than males, likely On exam, the patient was anxious and distressed, because dermatophyte infections on the bearded complaining of severe burning. Groups of areas of males are often diagnosed as tinea many single and confluent pink papules on a barbae.1 It may present in both children and mildly swollen, erythematous base were noted adults, and is more prevalent in those who are in surrounding her mouth with extension to her Figure 2 regular contact with animals (both domestic and chin, sparing the vermillion border of the upper livestock), have histories of recent travel, and live in tropical, humid climates.5 Doxycycline and topical metronidazole were discontinued, and the patient was started on Unfortunately for patients, it has been reported FERRER-BRUKER, SWENSON, SUKAL Page 15 that in 70 percent of cases of tinea faciei, other reaction in the area of application.17 daily for two weeks, can be used for superficial dermatoses are considered first, and many lesions Acute zinc deficiency from malnutrition can tinea infections. Liver function testing should be persist for more than six months -- and even up done at baseline and during sustained treatment, 2,7,8 also present as dermatitis, notably in a perioral 18 to 2 years -- before a correct diagnosis is made. distribution. Zinc deficiency may also as in the 12-week course of terbinafine for Tinea faciei is thought to have the most variable involve other areas of the body in a periorificial onychomycosis. Other systemic therapies include presentation of the dermatophytoses, likely due distribution, in contrast to tinea faciei, which is pulse dosing of fluconazole 150 mg weekly for to the complex structure of the face and a large confined to the face. two to four weeks or griseofulvin 500 mg daily range of depth and extent of invasion manifesting for two to four weeks.24 In our case, the patient as many different lesions. A typical presentation Commonly seen in highly sebaceous areas of showed marked clinical improvement after a may consist of single or multiple erythematous the face and body, seborrheic dermatitis can four-week course of terbinafine. Also, avoidance patches with an annular configuration and an involve the nasolabial fold and glabella. The of direct contact with infected animals or other active scaly border; however, this may be modified typical presentation is erythematous patches with persons should be recommended.3 19 with lesions that may or not be raised and may yellow-white scale and crust. When confined or may not consist of papules, vesicles, or crusts. to the face and flared, this may present with a clinical picture similar to tinea faciei. Conclusion There may be itching, burning, or no symptoms Tinea faciei, although relatively simple to treat, at all. If the lesions surround a particular facial Sarcoidosis is also a great masquerader and may at times be an elusive diagnosis. Patients structure, such as the oral cavity, as with our can be included in the differential for papular frequently suffer weeks to months after initial patient, certain differential diagnoses must be lesions on the face that appear erythematous-to- presentation to a physician’s office before the considered. violaceous. diagnosis is made.1 With its broad spectrum of presenting morphology, it may clinically mimic Differential Diagnosis Diagnosis and Treatment other causes of erythematous facial eruptions. Acne vulgaris can sometimes present similarly to Laboratory testing to confirm the presence Particularly in patients who do not respond to an inflamed tinea faciei, with lesions consisting of a dermatophyte infection include KOH therapy, a dermatophyte infection of the face is of pustules, papules, nodules, or comedones. preparation, fungal culture, tissue biopsy and an important diagnosis to consider. Treatment with topical agents may cause PCR.3,21 The clinically representative area should irritation and erythema, further confounding the be sampled, usually from an active area with scale. 9 References similar clinical appearance. Potassium hydroxide (KOH) solution in 10 1. Lin RL, Szepietowski JC, Schwartz RA. Tinea Tinea faciei presenting as rosacea has been percent to 15 percent is applied to the specimen, faciei: an often deceptive facial eruption. Int J described in the literature, as well.11 Usually and numerous hyphae with septa are present in a Dermatol. 2004;43:437–40. positive sample. Fungal culture is obtained with affecting the central face, rosacea is characterized 2. Alteras I, Sandbank M, David M, et al. 15-year by persistent erythema, papules, pustules and a swab and grown on Sabouraud’s dextrose agar 3 survey of tinea faciei in the adult. Dermatologica. telangiectasias. Other features of rosacea include or dermatophyte test medium. However, growth 1988;177:65–69. ocular involvement, flushing, and discomfort at in culture medium may occur in as few as 20% 10 3. Drake LA, Dinehart SM, Farmer ER, et the site of involvement. of specimens, due to low dermatophyte count or previous antifungal treatment.22 Polymerase chain al. Guidelines of care for superficial mycotic Another differential diagnosis is perioral reaction (PCR) is not yet widely available, but infections of the skin: tinea corporis, tinea cruris, dermatitis, a papulopustular of the new assays are in development for identification tinea faciei, tinea manuum, and tinea pedis. J Am skin surrounding the mouth, usually sparing the of dermatophytes.21 Special stains, either PAS or Acad Dermatol. 1996;34:282–286. vermillion border. Chronicity is common. It is GMS, are needed because dermatophytes are not 4. Kemna ME, Elewski BE. A US epidemiologic mostly seen in decades three to five in women; visualized well with H&E. The histopathologic survey of superficial fungal disease. J Am Acad however, the incidence is increasing in men due features are variable, ranging from hyperkeratosis Dermatol. 1996;35:539-542. 12,13 Skin lesions to changes in grooming habits. with patchy parakeratosis to marked spongiosis occur as grouped follicular erythematous papules, 5. Szepietowski J, Schwartz RA. Tinea faciei. 2001 and perivascular lymphocytic infiltrate. Fungal and vesicles with possible confluence. Burning [Amended 2012 Jan 25; cited 2013 Feb] In: James 5 elements must be present on biopsy to confirm may accompany lesions, but rarely itching. Use 23 WD, Elston D, eds. Emedicine Dermatology the diagnosis. of topical corticosteroids may cause perioral [Internet]. St. Petersburg: eMedicine Corp, 2001. dermatitis, either as a direct effect from prolonged Tinea faciei is generally curable, with treatment Available from: http://www.emedicine.com/ use or in a rebound effect.14 options including topical and systemic antifungal derm/topic740.htm. agents, in addition to avoidance of risk factors. There have been case reports of lesions of 6. Crissey JT, Lang H, Parish LC. Manual Topicals such as clotrimazole, ketoconazole, tinea faciei mimicking cutaneous lupus of Medical Mycology. Blackwell Science, and miconazole applied daily or twice daily erythematosus.16 Since lesions of cutaneous Cambridge 1995. p.36. for approximately three to four weeks, and an lupus are largely photodistributed, facial lesions additional one week after resolution of lesions, 7. Jorquera E, Moreno JC, Camacho F. Tinea when annular, erythematous, and scaly, with faciei: epidemiology. Ann Dermatol Venereol. may be used in most cases of superficial tinea or without scarring, deserve its diagnosis as a 11 1992;119:101– 4. faciei. Topical terbinafine may be effective as 15 consideration. well, possibly with a shorter treatment time. 8. Romano C, Ghilardi A, Massai L. Eighty- The two main groups of contact dermatitis, Recurrent and persistent infections may be four consecutive cases of tinea faciei in Siena, allergic and irritant, have similar clinical facial associated with combination antifungal and a retrospective study (1989–2003). Mycoses. inflammatory presentations. Over time, an corticosteroid topical preparations, which 2005;48:343–6. allergic contact dermatitis may develop to are widely used by non-dermatologists. In 9. Strauss JS. Guidelines of care for acne vulgaris cosmetics or other skin care products via a cases of inflammatory, persistent, or extensive management. J Am Acad Dermatol. delayed-hypersensitivity reaction. Usually, patient dermatophyte infection, a systemic agent such as history is telling, as are the distribution of lesions, oral fluconazole, griseofulvin or terbinafine may 2007 Apr 1;56(4):651-63. as irritants will usually cause an eczematous be used. Systemic terbinafine, dosed at 250 mg 10. Wilkin J, Dahl M, Detmar M, Drake L,

Page 16 TINEA FACIEI PRESENTING AS A PERIORAL DERMATITIS: AN ELUSIVE DERMATOPHYTOSIS WITH MANY FACES ON THE FACE Feinstein A, Odom R, Powell F. Standard classification of rosacea: Report of the National Rosacea Society Expert Committee on the A Case of Cutaneous Pili Migrans: Classification and Staging of Rosacea. J Am Acad Dermatol. 2002 Apr;46(4):584-7. A Creeping Eruption Mimicking Larva Migrans

11. Dekio S, Imaoka C, Jidoi J. Corticosteroid- Laurie Lenz, DO,* Andleeb Usmani, DO,** Robin Shecter, DO*** modified tinea faciei simulating rosacea. J Dermatol. Oct 1987;14(5):509-11. *3nd-year Dermatology Resident, Palm Beach Centre for Graduate Medical Education, West Palm Beach, FL **Attending Dermatologist, Palm Beach Centre for Graduate Medical Education, West Palm Beach, FL 12. Wilkinson DS, Kirton V, Wilkinson JD. ***Program Director, Dermatology Residency, Palm Beach Centre for Graduate Medical Education, West Palm Beach, FL Perioral dermatitis: a 12 year review. Br J Dermatol. 1979;101:245–57. Abstract 13. Lipozencic J, Ljubojevic S. Perioral dermatitis. Cutaneous pili migrans is cutaneous condition caused by an embedded hair shaft producing a migratory, Clin Dermatol. 2011 Mar-Apr;29(2):157-61. creeping eruption that may closely mimic cutaneous larva migrans. We present a case of a 3-year-old female 14. Chen AY, Zirwas MJ. Steroid-induced with pili migrans of the left foot that likely resulted from penetration of a foreign hair shaft from the family rosacealike dermatitis: case report and review of bathroom floor where her father frequently cut his hair. Migration of the hair due to walking and muscular contraction caused a presentation that was easily mistaken for the parasitic creeping eruption of cutaneous the literature. Cutis. 2009 Apr; 83(4):198-204. larva migrans. 15. Walling HW, Sontheimer RD. Cutaneous lupus erythematosus: issues in diagnosis and Introduction treatment. Am J Clin Dermatol. 2009;10(6):365. Creeping eruption is a clinical symptom describing a linear or serpiginous, erythematous, 16. Meymandi, S, Wiseman MC, Crawford cutaneous track that is mobile.1 It is most often S. Tinea faciei mimicking cutaneous lupus associated with cutaneous larva migrans, a larval erythematosus: a histopathologic case report. J parasitic infection, but may also be caused by an Am Acad Dermatol. 2003 Feb;(48): S7-8. embedded hair shaft in the condition cutaneous 17. Nosbaum A, Vocanson M, Rozieres A, pili migrans. We present a case of pili migrans in Hennino A, Nicolas JF. Allergic and irritant a child initially mistaken for larva migrans. contact dermatitis. Eur J Dermatol. 2009 Jul- Aug;19(4):325-32. Case Report A 3-year-old Hispanic female from southern 18. Bae YS, Hill ND, Bibi Y, Dreiher J, Cohen Florida presented with a seven-day history of a AD. Innovative uses for zinc in dermatology. painful, migratory black mark to the left sole of the Dermatol Clin. 2010 Jul;28(3):587-97. foot that began one day after playing barefoot in 19. Naldi L, Rebora A. Clinical practice. a sandy public park near her home. The patient’s Seborrheic dermatitis. N Engl J Med. 2009 Jan pediatrician diagnosed her with cutaneous larva 22;360(4):387-96. migrans and prescribed topical thiabendazole ointment to be applied three times a day. The 20. Reddy R, Vitiello M, Kerdel F. Cutaneous patient’s mother reported no improvement in pain Figure 2 sarcoid mimicking tinea imbricata. Int J since starting the treatment. The patient walked Dermatol. 2011 Sep;50(9):1132-4. with a limp at times and other times refused to put 21. Verrier J, Krähenbühl L, Bontems O, Fratti pressure on the foot at all. The mother had marked M, Salamin K, Monod M. Dermatophyte the leading and lagging edges of the line with a pen identification in skin and hair samples using and noted that the line migrated up to 1 cm a day a simple and reliable nested polymerase and had moved from a semicircular configuration chain reaction assay. Br J Dermatol. 2013 on the lateral side of the foot to a curvilinear Feb;168(2):295-301. configuration now on the sole of the foot. Physical examination with dermoscopy (10x 22. Drakensjo IT, Chryssanthou E. Epidemiology magnification) revealed a superficial, 7mm, fine, of dermatophyte infections dark, curvilinear mark to the left sole of the foot in Stockholm, Sweden: a retrospective study from with very mild surrounding erythema (Figure 1). 2005 to 2009. Med Mycol. 2011; 49:484–8. Figure 3 23. Guarner J, Brandt ME. Histopathologic diagnosis of fungal infections in the 21st century. easily extracted using a forceps (Figures 2 and 3). Clin Microbiol Rev. 2011 Apr 24;2:247-80. Pathologic examination of the hair was consistent with a normal human hair shaft. A diagnosis of 24. Lesher JL Jr. Oral therapy of common cutaneous pili migrans was made. On follow- superficial fungal infections of the skin. J Am up, the patient’s mother reported immediate and Acad Dermatol. 1999;40:S31–4. complete relief of symptoms following extraction of the hair and no difficulty with . Correspondence: Sarah Ferrer-Bruker, DO, On further questioning, the patient’s mother revealed that her husband regularly cut his West Palm Hospital, 2201 45th St, West Palm Figure 1 Beach, FL 33407; [email protected] own hair in their bathroom, where the patient frequently walked barefoot. A small incision was made to the leading edge of the mark using a #11 scalpel, and dark brown hair was

LENZ, USMANI, SHECTER Page 17 Discussion References Cutaneous pili migrans is a condition in which a 1. Caumes E. It’s time to distinguish the sign hair shaft migrates below the surface of the skin “creeping eruption” from the syndrome “cutaneous and can closely mimic the creeping eruption of larva migrans.” Dermatol. 2006;213:179-181. cutaneous larva migrans. Pili migrans presents 2. Kim JY, Silverman RA. Migrating hair: A case as a painful, linear, migratory eruption with confused with cutaneous larva migrans. Pediatr a hair shaft often visible at the advancing Dermatol. 2010;27:628-630. edge.2 Similarly, cutaneous larva migrans is a creeping eruption; however, it is caused by 3. Yaffee HS. Imbedded hair resembling larva the penetration of the skin by the larva of migrans. Arch Dermatol. 1957;76:254. non-human-specific nematodes and is usually 4. Luo DQ, Liu JH, Huang YB, et al. Cutaneous contracted in sandy areas of the Caribbean, pili migrans: a case report and review of the the central and southeastern United States, literature. Int J Dermatol. 2009;48:947-950. Africa, southeast Asia and South America. In 5. Franbourg A, Hallegot P, Baltenneck F, et contrast to pili migrans, the migratory tracks al. Current research on ethnic hair. J Am Acad of larva migrans are usually serpiginous and Dermatol. 2003;48:S115-S119. intensely pruritic, and the organism cannot be visualized.1 6. Sakai R, Higashi K, Ohta M, et al. Creeping hair: an isolated hair burrowing in the uppermost Pili migrans was first described byYaffee in dermis resembling larva migrans. Dermatol. 1957 in a report of a 19-year-old female with 2006;213:242-244. a two-week history of migratory hair shaft in the skin of the ankle.3 It has since been reported in more than 21 cases in the literature Correspondence: Laurie M. Lenz, DO, West as reviewed by Kim and Silverman and by Luo Palm Hospital, 2201 45th St, West Palm et al., and it may occur as result of either an Beach, FL 33407; Phone: 909.717.9247; Fax: ingrown hair or penetration of a foreign hair.2,4 561.881.4365; [email protected] Kim and Silverman note that the majority of cases have been reported in Japan (14 out of 21) and hypothesize that this may be due to the large cross-sectional diameter and high tensile strength of Asian hair.2,5 Locations involved included the ankle, sole, toe, breast, cheek, and neck.2,4 Luo et al. note in their review that pili migrans of the abdomen, cheek or neck is more commonly due to ingrown hair but may also occur as a result of penetration of foreign hair.4 In sites where there is no hair growth, such as the sole, it is likely that the source of the hair is exogenous. The proposed mechanism of migration is body motion and muscular contraction while walking. We reported on a 3-year-old Hispanic female with pili migrans mistakenly diagnosed as cutaneous larva migrans. It has been noted that this is a common misdiagnosis at first examination in patients with pili migrans.6 In our case, both history (exposure to sandy environment in the southeastern U.S.) and physical symptoms (subsequent development of a migratory eruption on the sole of the foot) lead to this initial misdiagnosis. However, complaint of pain, lack of pruritus, and physical examination showing a visible hair shaft at the leading edge of the migratory eruption can be valuable clues to the diagnosis of cutaneous pili migrans. In this case, exposure of the wet, pliable skin of a child’s sole to cut hair shafts on the bathroom floor may have been the etiology of the eruption.

Page 18 A CASE OF CUTANEOUS PILI MIGRANS: A CREEPING ERUPTION MIMICKING LARVA MIGRANS Vicks VapoRub® May Have Nailed It as a Safe First-Line Treatment for Uncomplicated Onychomycosis

Jonathan S. Crane, DO, FAOCD,* Louis I. Padgett, BS,** J. Kate Jackson, PA-C***

*Dermatologist, Atlantic Dermatology Associates, PA, Wilmington, NC; Department of Dermatology, Campbell University, Buies Creek, NC **Medical Student, 4th year, University of Pikeville - Kentucky College of Osteopathic Medicine, Pikeville, KY ***Dermatology Physician Assistant, Atlantic Dermatology Associates, PA, Wilmington, NC

Abstract Many dermatologists have been recommending Vicks VapoRub® (Proctor & Gamble Co., Cincinnati, OH) for the treatment of onychomycosis. Because of this, we set upon a literature quest to see if there is logic in this recommendation. We have concluded that there is logic in this recommendation.

Objective onychomycosis have their limitations. Topical and it has shown to be an effective fungicide by To determine if Vicks VapoRub® topical cream agents have generally been shown to be minimally itself. Testing its effectiveness for onychomycosis is a safe and effective alternative to oral systemic effective, while oral agents are associated with is still in its infancy, but positive results have therapy in the treatment of onychomycosis. higher effective cure rates but are associated been shown in patient studies. The anti-fungal with treatment failure, recurrence and toxic side mechanism of works by altering hyphal effects.4 Vicks VapoRub® topical cream has been morphology, causing hyphal aggregates. This Background thrown into the mix of treatments although its reduces the overall diameter of the hyphae, which It is estimated that the human body harbors mechanism of action and point of usage remain in turn causes lysis of the hyphal membranes. more than 10 microorganisms that colonize the 14 largely unexplored. In the past few years, more Thymol has also proven to be lipophilic, which . The mixture of organisms found and more patients have reported using the folk allows access to the cell membrane. This ability at any particular site is termed “indigenous remedy of VapoRub® as a treatment and cure for alters cell permeability and causes the loss of microbiota,” or normal flora, and typically does toenail fungus. The remedy has been used for macromolecules through the fungal membrane, not harm healthy individuals. Non-indigenous many generations but has only recently become resulting in fungal cell death.6,7 flora simultaneously coexists in a constant battle physician recommended. Although no formal to colonize the skin but is usually eliminated by methods of documentation and testing were the skin’s defense system. Trichophyton rubrum performed, we began recommending its use over Results from Trials (T. rubrum) is a species of fungus that has adapted Trial 1: The studies evaluating mentholated the past couple of years and have seen some positive creams as a treatment for onychomycosis are certain mechanisms that allow it to survive results in our practice. We have recommended on the human surface, including the ability to small, but have demonstrated positive results and application of VapoRub® to the affected and suggest the need for larger trials to better compare suppress the human immune response to the adjacent areas twice daily. Its consistency of invading fungus, as well as the ability to breach VapoRub® with more established regimens for application is very important in order to saturate onychomycosis. A 2010 trial was performed by the anatomic barrier, thus causing long-term the nail bed with the active ingredients. The cream chronic infection. T. rubrum invades damaged U.S. Air Force 375th Medical Group Family contains many ingredients, but four in particular, Medicine Program with 18 patients who and even healthy tissue and begins to proliferate thymol, , , and oil of Eucalyptus in the stratum corneum layer of the skin, where it applied VapoRub® once daily to the nail bed. citriodora, have been independently studied and Of the 18, 83% showed positive improvement is better protected against the body’s suppressor shown to play a part in eliminating or controlling 1 at the end of a 48-week study, 27.8% resulted T-cells. The fungal pathogen has become so dermatophytes responsible for onychomycosis.5 specialized that among a recent retrospective in complete mycological cure rates, 55.6% had study examining 4,046 patients, T. rubrum partial clearance, and 16.7% showed no change. accounted for 87% of subungual Onychomycosis, Properties of VapoRub® The group was then given a 5-point Likert scale followed by Trichophyton mentagrophytes and Its active ingredients usually don’t ring a bell satisfaction questionnaire and reported a strong Candida albicans (yeast).15 when it comes to an effective mechanism satisfaction rating average of 9 out of 10, or “very of action against onychomycosis, but one of satisfied.” The study showed the best results for Onychomycosis has shown a rapidly growing them, thymol, may contain a large part of the individuals who cultured Candida parapsilosis and prevalence in the United States. It now accounts fungicidal component used to cure and control T. mentagrophytes, with 100% cure rate in these for an average of 8% of physician visits, ranging onychomycosis. Thymol has been studied as individuals. Those with T. rubrum and other 4% to 18% depending on age and population an active component against T. rubrum, as have dermatophytes had partial cure rates, suggesting studied. Those with weakened immunity or camphor, menthol, and . Minimum VapoRub® may be more effective when used with poor circulation are at the highest risk for inhibitory concentration (MIC) values were synergistically for these pathogens.3 the infection, and males older than 60 years old studied, and it was evident that these compounds Trial 2: Researchers from the Dept. of and 70 years old have the higher prevalence were effective inhibitors of the pathogens 2 Horticulture and the Dept. of Food Safety and of 20% and 30%, respectively. The organism 5 Thymol has responsible for onychomycosis. Toxicology studied the antifungal effects of causes a thickened and discolored nail that is been used as far back as the ancient Egyptians the ingredients in VapoRub® against fungal susceptible to brittle breakage, and over time, its for its preservative properties, and by the ancient pathogens responsible for onychomycosis. The spread to local nails often occurs. Patients with Greeks and Romans for its aromatic flavors. study reported a clinical observation that 32 out the condition may not suffer from physical pain, Native Americans extracted oils from the thyme of 85 (38%) patients showed clinical clearance but often experience significant psychosocial plant (T. vulgaris) and packed the oil around flesh 1,3 in patients who applied VapoRub® once daily problems that can alter self-image. wounds for its antiseptic properties. Its synergistic for five to 16 months; 21 (25%) had no record effects as a bactericidal and fungicidal agent are of change but also no record of compliance; 19 now proving more diverse than were originally Introduction (22%) had only one follow-up visit documented; known. It proves well against strains of bacteria, Commonly used medications used to treat 9 (11%) of the patients reported not following

CRANE, PADGETT, JACKSON Page 19 through with the treatment; and 4 (5%) never 8 9-13 Medication Effectiveness Major Adverse Effects had a follow-up visit. Factoring out patients who had only one or no return visits and those Terbinafine •76 ±3% >10% who were poorly compliant with the treatment, (18 studies, CNS: headache (13%) we narrowed the applicable patients down to 53. 933 patients) 1-10% The efficacy of the treatment then became much stronger, showing a 60.37% effective cure rate.5 CNS: fever (7% granules) For a medication used sparingly with once-a-day Dermatologic: rash (6%), pruritus (3%) external application and negligible side effects, the Gastrointestinal: diarrhea (6%), dyspepsia (3%), taste disturbance results are impressive. (3%), abdominal pain (2%), nausea (granules 2%), toothache (granules 1%) VapoRub® has not been definitively proven to be more effective than oral antifungal medications, Hepatic: liver enzyme abnormalities (3%) which include terbinafine, itraconazole, Respiratory: nasopharyngitis (granules 10%), cough (granules griseofulvin, and fluconazole. The University 6%), pharyngeal pain (granules 2%), rhinorrhea (granules 2%) of Toronto’s Medical Dermatology Division Miscellaneous: influenza (granules 2%) compiled the treatment results of these four <1% systemic medications in a cumulative meta- analysis of 36 trials from 1966-2002.8 The chart Too numerous to list; see citation 9. below reflects the mycological cure rates in Itraconazole •Pulse: >10% controlled randomized trials as compiled by the (pulse and 63 ±7% Gastrointestinal: nausea (3-11%), diarrhea (3-11%) study, as well as documented adverse effects for continuous each medication. therapy) (6 studies, 318 1-10% patients) Cardiovascular: (4%), HTN (3%), chest pain (3%)

CNS: headache (4-10%), fever (2-7%), dizziness (2-4%), anxiety •Continuous: (3%), depression (2-3%), pain (2-3%), malaise (1-3%), abnormal 59 ±5% dreams (2%) (7 studies, Dermatologic: rash (3-9%), pruritus (≤5%) 1,134 Endocrine/Metabolic: hypertriglyceridemia (≤3%), hypokalemia patients) (2%) Hepatic: LFTs abnormal (≤4%) Neuromuscular & skeletal: bursitis (3%), myalgia (≤3%), tremor (2%), weakness (≤2%) Renal: cystitis (3%), UTI (3%) Respiratory: rhinitis (5-9%), URI (8%), sinusitis (2-7%), cough (4%), dyspnea (2%), pharyngitis (≤2%), pneumonia (2%), increased sputum (2%) Miscellaneous: increased diaphoresis (3%), herpes zoster (2%) <2% Too numerous to list; see citation 10. Griseofulvin 60 ±6 percent CNS: dizziness, fatigue, headache, insomnia, mental confusion (3 studies, 167 Dermatologic: angioneurotic edema, -like patients) drug reaction, photosensitivity, rash, urticaria Gastrointestinal: diarrhea, epigastric distress, GI bleeding, nausea, vomiting Genitourinary: menstrual irregularities Hematologic: granulocytopenia, leucopenia Hepatic: hepatotoxicity Neuromuscular & skeletal: Renal: nephrosis, proteinuria Miscellaneous: drug-induced lupus-like syndrome, oral thrush Fluconazole 48 ±5 percent Cardiovascular: angioedema (3 studies, 131 CNS: headache (2-13%), dizziness (1%) patients) Dermatologic: rash (2%) Gastrointestinal: nausea (2-7%), abdominal pain (2-6%), vomiting (2-5%), diarrhea (2-3%), dysgeusia (1%), dyspepsia (1%) Hepatic: alkaline phosphatase increase, elevated ALT/AST, hepatic failure, hepatitis, jaundice Miscellaneous: anaphylactic reactions VapoRub® 27.8% dermal irritation (1 study, 18 allergic reaction patients)

Page 20 VICKS VAPORUB® MAY HAVE NAILED IT AS A SAFE FIRST-LINE TREATMENT FOR UNCOMPLICATED ONYCHOMYCOSIS The outcome of this study demonstrates that References 13. Proctor and Gamble Material Safety Data more traditional systemic oral antifungals show 1. Roujeau JC, Sigurgeirsson B, Korting HC, Kerl Sheet. Vicks VapoRub Ointment; Cough consistently effective results, but with significant H, Paul C. Chronic dermatomycoses Suppressant, Topical Analgesic [Internet]. broad-spectrum adverse reaction profiles.8 Proctor and Gamble; 2011 Jul 28 [Cited 2012 Additionally, oral antifungal medications may of the foot as risk factors for acute bacterial Oct 7] Available from: http://ehsrms.uaa.alaska. require baseline and continued lab monitoring cellulitis of the leg: a case-control study. edu/CMS/Laboratory/MSDS/MSDS%20 for hepatotoxicity.4 Frequent medical follow- Dermatology. 2004 Aug 5;209(4):301-7. by%20vendor/Proctor%20Gamble/Vicks%20 up visits, lab monitoring and medication costs 2. Gupta AK, Jain HC, Lynde CW, Macdonald Vapo%20Rub%20Ointment.pdf can be expensive for patients. By comparison, P, Cooper EA, Summerbell RC. Prevalence VapoRub® has documented adverse effects and epidemiology of onychomycosis in patients 14. Zaias N, Glick B, Rebell G. Diagnosing and of dermal irritation and/or allergic contact visiting physicians’ offices: a multicenter Canadian treating onychomycosis. J Fam Pract. 1996 May; dermatitis, and the expected one-year costs of the survey of 15,000 patients. J Am Acad Dermatol. 42: 513–18. 3 treatment are low, averaging $30. 2000 Aug;43(2 Pt 1):244-8. 15. Romano C, Gianni C, Difonzo EM. 3. Derby R, Rohal P, Jackson C, Beutler A, Olsen Retrospective study of onychomycosis in Italy: Uncomplicated vs. C. Novel treatment of onychomycosis 1985-2000. Institute of Dermatological Sciences, University of Siena, Italy. 2005 Jan;48(1):42-4. Complicated Onychomycosis using over-the-counter mentholated ointment: a The question arises as to when it may be appropriate clinical case series. J Am Board Fam Med. 2011 to treat onychomycosis with statistically proven Jan;24(1):69-74. Correspondence: Jonathan S. Crane, DO, 1099 methods of oral treatment versus with mentholated 4. Goldstein AO, Goldstein BG. Onychomycosis Medical Center Dr., Wilmington, NC 28401; topical ointment. It is important to establish when [Internet]. UpToDate. [updated 2012 May 15; (P) 910-251-9944; (F) 910-343-6006; Email: the complications of onychomycosis outweigh the cited 2012 Oct 1] Available from: http://www. [email protected] risks of the medication side effects of the traditional uptodate.com/contents/onychomycosis oral treatments. Patients who may develop serious complications due to onychomycosis are 5. Ramsewak RS, Nair MG, Stommel M, considered to have a complicated form of the Selanders L. In vitro antagonistic activity of infection. These types of patients are typically monoterpenes and their mixtures against ‘toe immunocompromised with diseases such as nail fungus’ pathogens. Phytother Res. 2003 or COPD and/or have cardiovascular Oct;17(4):376 diseases such as chronic heart failure, peripheral vascular disease and chronic venous insufficiency. 6. Numpaque MA, Oviedo LA, Gil JH, Garcia Onychomycosis has proven to be a significant CM, Durango DL. Thymol and carvacrol: risk factor for acute bacterial cellulitis in patients biotransformation and antifungal activity against who suffer these common diseases, and patients the plant pathogenic fungi with these conditions should be considered as Colletotrichum acutatum and Botryodiplodia higher priority for the use of proven oral systemic theobromae. Trop. Plant Pathol. 2011 Jan;36:3– 1 treatments. 13. 7. Segvic KM, Kosalec I, Mastelic J, Pieckova Conclusion E, Pepeljnak S. Antifungal activity of thyme T. rubrum and other common fungal pathogens (Thymus vulgaris L.) and thymol have become so effective at skin invasion that they against moulds from damp dwellings. Lett. Appl. have overcome both innate and cell-mediated Microbiol. 2007 Jan;44:36-42. immunity to permanently colonize the human tissue in a significant portion of the population. 8. Gupta AK, Ryder JE, Johnson AM. Cumulative Traditional oral treatment regimens for the past meta-analysis of systemic antifungal agents for several decades have been costly and have on the treatment of onychomycosis. Br J Dermatol. rare occasions had harmful effects on patients. 2004;150(3):537. A limited yet potentially promising evaluation 9. Terbinafine (systemic): Drug information of small trials using VapoRub® as a treatment [Internet]. Waltham, MA: UpToDate. [Cited reveals very positive results. While not definitive, 2012 Oct 5] Available from: http://uptodate. the clinical observations and studies mentioned com/contents/terbinafine-systemic-drug- above pull together a growing body of evidence information. that suggests VapoRub® may be a notably effective treatment. Treatment with this over- 10. Itraconazole: Drug information [Internet]. the-counter medicated cream is cost-effective, Waltham, MA: UpToDate. [Cited 2012 Oct 5] devoid of major clinical side effects and does not Available from: http://uptodate.com/contents/ require lab monitoring. More rigorous clinical itraconazole-drug-information. trials with more participants should be conducted 11. Griseofulvin: Drug information [Internet]. to determine more precisely the substance’s Waltham, MA: UpToDate. [Cited 2012 Oct 5] efficacy against onychomycosis. In our practice, Available from: http://uptodate.com/contents/ we have recommended application to affected griseofulvin-drug-information. nail(s) twice daily to reduce opportunity for medication resistance and increase concentration, 12. Fluconazole: Drug information [Internet]. with a total therapy time of at least 12 months.14 Waltham, MA: UpToDate. [Cited 2012 Oct 5] Our evaluation supports Vicks VapoRub® as a Available from: http://uptodate.com/contents/ logical choice for a first-line treatment against fluconzole-systemic-drug-information. uncomplicated onychomycosis.6,7

CRANE, PADGETT, JACKSON Page 21 Basal Cell Nevus Syndrome in an African-American Female: A Case Report and Review of the Literature

Emily Kate Matthews, DO,* Yuri Kim, BS,** Robin Shecter, DO***

*Second-year Dermatology Fellow, Palm Beach Centre for Graduate Medical Education, West Palm Beach, Florida **Fourth-year Medical Student, Nova Southeastern University College of Osteopathic Medicine, Fort Lauderdale, Florida ***Program Director, Palm Beach Centre for Graduate Medical Education, West Palm Beach, Florida

Abstract Basal cell nevus syndrome (BCNS) is an autosomal-dominant, multisystem disorder caused by a germline-inactivating mutation in the PATCHED gene. The three most characteristic manifestations of this syndrome include multiple basal cell carcinomas manifesting at a young age, palmoplantar pits, and odontogenic keratocysts. We present a case of a 30-year-old African American female who presented to the clinic with the chief complaint of a non-healing, growing axillary . The pathogenesis, clinical manifestations, diagnostic evaluation, and treatments of BCNS are discussed.

8 Case Report Discussion various structures within the developing embryo. A 30-year-old African American female Basal cell nevus syndrome, also known as Experimental models with abnormalities of the presented to the outpatient dermatology clinic Gorlin-Goltz syndrome and nevoid basal cell hedgehog signaling pathway were shown to with a chief complaint of a left axillary lesion carcinoma syndrome, was first reported in 1894, exhibit significant developmental anomalies in 9 that had been growing in size over the past but the clinical manifestations were more clearly mice and flies. PTCH1 regulates and represses several months. Dermoscopic evaluation of defined in 1960 by Gorlin and Goltz.1 It is a a transmembrane protein, smoothened (SMO), the lesion demonstrated a pearly papule with rare, autosomal-dominant, multisystem disorder which limits the effect of the SHH signaling. irregular, pigmented globules and superficial caused by mutations in the human PATCHED When HH binds to its receptor, PTCH1, the telangiectasias, clinically consistent with a gene that affects the skin with multiple basal cell repression of SMO is removed, causing signals to pigmented BCC. A full skin exam was then carcinomas (BCCs) in childhood or adolescence be transduced via the Gli1 and Gli2 performed due to the atypical axillary location of and continues throughout life.2 Up to 50% of factors to the nucleus. In basal cell nevus syndrome, the lesion. Bilateral palmoplantar pits (Figure 1), BCNS cases represent new mutations without a the PTCH1 mutation simulates hedgehog frontal bossing, hypertelorism, and marked pectus significant family history.2 Patients may present binding and results in constitutive overexpression deformity were noted. with multiple developmental anomalies such as of transcription factors Gli1 and/or Gli2, which frontal bossing and skeletal anomalies at birth, has been implicated in the development of BCC Figure 1 10 and jaw along with palmoplantar pits in and other tumors. An activating mutation in childhood. BCNS affects approximately 1:60,000 SMO also results in constitutive signaling and people, males and females equally, with a high has been identified in approximately 10% of basal 8 degree of penetrance but variable expressivity.3 cell carcinomas. Similar to the retinoblastoma Age at first diagnosis of BCNS ranges from 3 to gene, two somatic “hits” in the same cell appear to 53 years, with an average age of 20 to 21.4 Race be required for sporadic cases, while one somatic also plays an important role in the expression of “hit” plus the inheritance of one defective allele 11 cutaneous BCCs in patients with BCNS. This underlies familial cases of BCNS. syndrome can affect all races but occurs mostly Patients with BCNS may present with multiple in Caucasians, with a low frequency in Asian and abnormalities, none of which are exclusive to black populations. Of all BCNS case reports, this syndrome. The three most characteristic 5 only 5% involve black patients. Furthermore, abnormalities include BCCs, pits of the palms dark-skinned individuals as well as Asians have and soles, and cysts of the jaw (odontogenic a lower frequency of expressing BCCs with keratocysts).9 The distinguishing trait of BCNS Gorlin syndrome. About 40% of black persons compared to sporadic cases of BCC is the with BCNS have BCCs (and fewer than 15% appearance of BCCs in large numbers starting have more than two BCCs), whereas 80% of at an early age. Histologically, BCNS cannot be Caucasians with BCNS have BCCs.4,6 differentiated from sporadic cases of BCC. In The cause of BCNS is a germline inactivating BCNS, BCCs may resemble angiomas, skin tags, 2 Upon further questioning, the patient revealed she mutation in the PTCH1 (PATCHED1) gene on or melanocytic nevi. The BCCs that occur in had previously been diagnosed with several facial chromosome 9q22.3-q31, the human homolog children are often small, banal-appearing, smooth, 8 BCCs that were surgically removed in her early of the Drosophila patched gene.7 PTCH1 is dome-shaped papules that are acrochordon-like. twenties. She also disclosed a history of “multiple a tumor suppressor gene that functions as a Nodular BCCs occur primarily on the face, cysts” that she had to have surgically removed receptor for the hedgehog (HH) protein. This while superficial BCCs are usually found on the 2 when she was 15 years of age. Gorlin syndrome HH protein along with the PTCH receptor torso. They can appear on any part of the body was diagnosed; she is currently awaiting an MRI are components of the sonic hedgehog (SHH) but are more frequently found on sun-exposed of the brain for chronic headaches. signaling pathway, which is significant for areas, with the first tumor occurring at a mean 7 controlling cell fate, patterning, and growth in age of 23 years. The second most common Page 22 BASAL CELL NEVUS SYNDROME IN AN AFRICAN-AMERICAN FEMALE: A CASE REPORT AND REVIEW OF THE LITERATURE finding, palmoplantar pits, present as depressed Table 1 - Diagnostic Criteria for Basal Cell Nevus Syndrome2 lesions in the stratum corneum, usually 1-3-mm The diagnosis of BCNS requires two major or one major and two minor criteria. in size, sharply marginated, and erythematous, Major Criteria Minor Criteria and they rarely develop into BCCs (Figure More than two BCCs, or one BCC before the Macrocephaly (determined after adjustment for 1).8,12 Up to 87% of patients with BCNS have age of 20 years height) 13 pits. Odontogenic keratocysts are often the Odontogenic keratocysts of the jaw (proven by Congenital malformations: cleft lip or ; first abnormality detected and can cause pain, histology) frontal bossing; “coarse face”; moderate or swelling, drainage, and an increase in molar and severe hypertelorism premolar areas in the maxilla. Three or more palmar or plantar pits Other skeletal abnormalities: Sprengel deformity (unilateral elevation of smaller- sized Other key features of BCNS include anomalies scapula); marked pectus deformity; marked of multiple organ systems. Abnormalities in the syndactyly of the digits musculoskeletal system include macrocephaly, Bilamellar calcification of the falx cerebri Radiologic abnormalities: bridging of the frontal bossing, bifid ribs, vertebral fusion, and sella turcica; vertebral anomalies such as kyphoscoliosis. Patients may manifest with hemivertebrae and fusion or elongation of the vertebral bodies; modeling defects of the hands a larger body size than that of other family and feet; flame-shaped lucencies of the hands members or present with long limbs due to tissue or feet overgrowth, a feature of the SHH signaling Bifid, fused or markedly splayed ribs Bilateral ovarian fibroma pathway activation. CNS manifestations may First-degree relative with NBCC syndrome Medulloblastoma include ectopic calcification with lamellar From: Bolognia JL, Jorizzo JL, Schaffer JV. Dermatology. rd3 ed. 2012. Elsevier Saunders. 2012: 813, 1151, 1776-1777, calcification of falx cerebri, agenesis of the Table 108.5. corpus callosum, medulloblastomas at an early age, meningiomas, and even mental retardation. The lifespan of a patient with BCNS is normal for the patients with metastatic disease and 9.7 Genitourinary features include ovarian fibromas if the BCCs are treated early and if no other months for the locally advanced lesions.17 The and fibrosarcomas. Patients also may present with malignancies develop. It is imperative that patients response rate was 30% in patients with metastatic hypertelorism, congenital blindness, cataracts, are closely monitored with frequent cutaneous basal cell carcinoma and 43% in patients with colobomas, and strabismus.8 Multiple skin tags in examinations, along with biopsies of suspicious locally advanced BCC.17 Also, from the locally a child can be a clue to diagnosing BCNS, and lesions, throughout their lives. Therapy is directed advanced subset of patients, 54% of patients a biopsy should be performed. It is important at the individual lesions as they arise, and the showed no residual BCC on subsequent biopsy to note that variation in severity of BCCs can best treatment modality depends on clinical of the site targeted.17 Vismodegib appears to be be attributed to environmental factors such as presentation, cell type, tumor size, and location.7 a very good option for patients with basal cell exposure to UV light and ionizing radiation. Treatment options include surgical excision, nevus syndrome in whom multiple for Differential diagnoses include Bazex–Dupré– electrodesiccation and curettage (ED&C), hundreds of tumors would result in disfiguring Christol syndrome, Rombo syndrome, cryotherapy, topical 5-fluorouracil, or imiquimod. . In another study, it was found that inhibiting melanocytic nevi, and xeroderma pigmentosa.8 Oral can be given to suppress new the hedgehog pathway with vismodegib in Initial evaluation for diagnosing BCNS includes BCCs. Minimization of discomfort and scarring patients with basal cell nevus syndrome decreased evaluating for a family history of BCNS and is of major concern since the key is to convince the incidence of new BCCs that were eligible for 9 15 whether the patient is taller or heavier than his/ the patient to accept frequent treatments. surgical excision compared to placebo. Some her relatives.9 Yearly panoramic radiographs Patients should be counseled about daily use of patients even had complete clinical regression of the jaw are recommended, with complete broad spectrum sunblock and avoidance of sun of all BCCs as well as disappearance of palmar 15 removal of identified odontogenic keratocysts exposure, radiotherapy, and non-essential X-rays. and plantar pits. However, it appears that as they can be extremely aggressive and lead Genetic counseling may be appropriate, as half of new BCCs do in fact develop after stopping the 15 to resorption of the jawbones or pathological the children of affected individuals are expected medication, but at a much slower rate. The 9 fractures.2 Radiological evaluation should be to develop BCNS. existing BCCs (present at the time of initiation of performed to check for calcification of the falx Vismodegib, an inhibitor of the hedgehog vismodegib) also returned to their pre-treatment 15 cerebri and abnormalities of the ribs, vertebrae, signaling pathway responsible for BCCs, is a size upon discontinuation of the medication. Side effects caused 54% of patients to prematurely and phalanges. Other workup modalities include recently FDA-approved oral medication for stop the medication and included muscle spasms, MRI of the brain, echocardiogram for cardiac the treatment of locally advanced or metastatic alopecia, dysgeusia, and weight loss.15,17 Thus, fibromas, and transvaginal/transabdominalBCCs. In an original article regarding the 2 long-term treatment of patients with basal cell ultrasound for pelvic masses. An MRI of the safety and efficacy of vismodegib, eligibility for nevus syndrome with vismodegib does not seem entire neurological axis may be warranted due to treatment required one of three main subsets feasible owing to the large drop-out rate caused the wide range of skeletal anomalies present in of patients: 1) those with multiple recurrences by side effects. BCNS. of BCCs that were previously excised; 2) those Diagnostic guidelines have been proposed by deemed inoperable by MOHS or plastic surgeons In conclusion, basal cell nevus syndrome is a fairly Kimonis and colleagues.2,4 The presence of due to large size of the tumor or metastatic status; common genodermatosis, but only rarely occurs two major, or one major and two minor criteria 3) those in which surgery was expected to result in African Americans. This case illustrates the 17 supports the diagnosis of BCNS (see Table 1). in significant morbidity and deformity. Patients importance of evaluating patients thoroughly were given vismodegib 150mg PO once daily who present with “unusual” locations of basal cell for a median treatment duration of 10.0 months . Vismodegib may play an important role

MATTHEWS, KIM, SHECTER Page 23 in decreasing the tumor burden and shrinking the National Institute. 2011 April 5 [Cited size of the tumors, but a high rate of side effects 2012 June 8]; Available from: http://www.cancer. will likely prevent its long-term use in patients gov/ncicancerbulletin/040511/page5 with lifelong basal cell nevus syndrome. 15. Tang JY, Mackay-Wiggan JM, Aszterbaum M, et al. Inhibiting the Hedgehog Pathway in References Patients with the Basal-Cell Nevus Syndrome. N 1. Gorlin RJ, Goltz RW. Multiple nevoid basal- Engl J Med. 2012;366:2180-2188. cell epithelioma, jaw cysts and bifid rib. A syndrome. N Engl J Med. 1960;262:908-912. 16. Skvara H, Kalthoff F, Meingassner JG, et al. Topical treatment of Basal cell carcinomas 2. Bolognia JL, Jorizzo JL, Schaffer JV. in nevoid Basal cell carcinoma syndrome with Dermatology. 3rd ed. Philadelphia: Elsevier a smoothened inhibitor. J Invest Dermatol. Saunders; c2012. p. 813, 1151, 1776-1777, Table 2011;131:1735. 108.5. 17. Sekulic A, Migden M, et al. Efficacy and 3. Anderson DE, Taylor WB, Falls HF, Davidson Safety of Vismodegib in Advanced Basal Cell RT. The nevoid basal cell carcinoma syndrome. Carcinoma. New Engl J Med. 2012;366:2171- Am J Hum Genet. 1967;19:12. 2179. 4. Kimonis VE, Goldstein AM, Pastakia B, et al. Clinical manifestations in 105 persons with nevoid basal cell carcinoma syndrome. Am J Med Correspondence: Emily Kate Matthews, DO, Genet. 1997;69:299. Palm Beach Centre for Graduate Medical Education, 2201 45th St., West Palm Beach, FL, 5. Goldstein AM, Pastakia B, DiGiovanna 33407; [email protected] JJ, et al. Clinical findings in two African- American families with the nevoid basal cell carcinoma syndrome (NBCC). Am J Med Genet. 1994;50:272. 6. Muzio LL. Nevoid basal cell carcinoma syndrome (Gorlin syndrome). Orphanet J Rare Dis. 2008;3:32. 7. Habif TP. Clinical Dermatology: A Color Guide to Diagnosis and Therapy. 5th ed. Philadelphia: Mosby Elsevier; c2010. p. 808-811. 8. Spitz JL. Genodermatoses: A Clinical Guide to Genetic Skin Disorders. 2nd ed. Philadelphia: Lippincott Williams & Wilkins; c2005. p. 170- 173. 9. Freedberg IM, Eisen AZ, Wolff K, et al. Fitzpatrick’s Dermatology in General Medicine. 6th ed. New York: McGraw-Hill; c2003. p. 755- 760. 10. Eichberger T, Regl G, Ikram MS, et al. FOXE1, a new transcriptional target of GLI2 is expressed in human epidermis and basal cell carcinoma. J Invest Dermatol. 2004;122:1180. 11. Levanat S, Gorlin RJ, Fallet S, et al. A two- hit model for developmental defects in Gorlin syndrome. Nat Genet. 1996;12:85. 12. Wolff K, Johnson RA. Fitzpatrick’s Color Atlas and Synopsis of Clinical Dermatology. 6th ed. New York: McGraw-Hill; c2009. p. 294-295. 13. James WD, Berger TG, Elston DM. Andrews’ Diseases of the Skin Clinical Dermatology. 5th ed. Philadelphia: Elsevier; c2006. p. 650-652. 14. Winstead ER. For People with Rare Syndrome, Drug brings Relief and Hope.

Page 24 BASAL CELL NEVUS SYNDROME IN AN AFRICAN-AMERICAN FEMALE: A CASE REPORT AND REVIEW OF THE LITERATURE Pyogenic Granuloma-like Kaposi’s Sarcoma: An Atypical Histologic Variant

Jamie Groh, DO,* Michael Wile, MD,** Robin Shecter, DO***

*Dermatology Fellow, PGY-IV, West Palm Hospital/PBCGME, West Palm Beach, FL **Dermatopathologist, Dermpath Diagnostics, Pompano Beach, FL ***Dermatology Residency Program Director, West Palm Hospital/PBCGME, West Palm Beach, FL

Abstract Kaposi sarcoma (KS) is vascular associated with human herpesvirus-8 (HHV-8). The histologic appearance of KS is broad and varies with the stage of the disease. Pyogenic granuloma-like Kaposi sarcoma (PG-like KS) is a rare clinicopathologic variant of Kaposi sarcoma (KS) and can be challenging to diagnose due to clinical and histologic overlap between PG-like KS and pyogenic granuloma (PG). The only definitive distinguishing feature is the presence or absence HHV-8 latent nuclear antigen-1 (LNA-1) staining, which is a specific marker for KS. We report a case of PG-like KS in an elderly man. Introduction KS is a vascular neoplasm associated with HHV-8. HHV-8 has been detected in other conditions, such as multi-centric Castleman’s disease and primary effusion lymphoma, but has not been found to be associated with other vascular tumors.1 PG-like KS is a rare clinical and histologic variant of KS that has been infrequently reported in medical literature.2,3 We report a case of PG-like KS on the foot of an elderly man with negative HIV status.

Case Report A 91-year-old black male presented to an outpatient clinic with a several-month history of a mildly tender polypoid mass on the left lateral heel. He denied any memorable trauma to the Figure A. Clinical picture of exophytic, area. Except for occasional bleeding, the lesion ulcerated nodule, left heel. was otherwise asymptomatic. Medical history was unremarkable. The patient had never received positive for human herpesvirus-8 (Figure E). any blood transfusions or had any memorable After the diagnosis of PG-like KS, the patient recent history of sick contacts, viral syndromes, or was screened for immunodeficiency states travel outside of the U.S. There was no significant including human immunodeficiency and family history for malignancy or blood dyscrasias. hepatitis; both were negative. The patient was The patient denied smoking, drinking, and any offered conservative treatment with monitoring, history of drug abuse. as there was only one lesion. The patient opted for surgical excision of the lesion as it was tender and Physical exam revealed a 3 cm x 2 cm, non- Figures C (top) and D. Higher-power views bleeding. At his six-month follow-up, there was tender, exophytic, friable nodule on the left lateral of lesion shows a spindle-cell proliferation no evidence of reoccurrence. heel (Figure A). The provisional diagnosis was with irregular vascular spaces and hemorrhage, pyogenic granuloma versus traumatized poroma which is more concerning for Kaposi sarcoma. versus angiosarcoma versus melanoma, given the clinical presentation. A 4 mm punch biopsy was performed and placed in 10% formalin for hematoxylin and eosin (H&E) staining. Histologic exam at low power showed a well- circumscribed, exophytic proliferation of well- formed capillaries arranged in lobules and contained within an epidermal collarette consistent with a pyogenic granuloma (Figure B). At higher power, a dermal spindle-cell proliferation with irregular vascular spaces and hemorrhage, more Figure BWell-circumscribed, exophytic lesion consistent with Kaposi sarcoma, was noted with proliferation of well-formed capillaries in (Figure C and D). Based on these architectural lobules and contained in an epidermal collarette Figure E. Positive HHV-8 LNA-1 stain of features, immunohistochemical stain with HHV- resembling a pyogenic granuloma. 8 LNA-1 was performed, which was strongly lesion.

GROH, WILE, SHECTER Page 25 tightly arranged than in the plaque stage, that LNA-1 in a broad spectrum of vascular tumors Discussion replace the completely.2,11 Histologically, and found expression to be limited to KS.1,7-10 KS is a low-grade spindle-cell vascular neoplasm the differential diagnosis for the typical LNA-1 is a gene product made by the DNA caused by human herpesvirus-8, which is presentation of KS varies depending on stage of transmitted by saliva and blood and has been virus when the virus is in its latent form in the lesion, but includes inflammatory dermatosis, the spindle cells of the KS lesions.1,7-10 All contracted from organ transplantation as well. bacillary angiomatosis, angiodermatitis, pseudo- The cutaneous presentation of KS can vary of the human herpesvirus family have Kaposi’s, pyogenic granuloma, bullous KS, and an active and latent period, and HHV-8 is greatly from pink patches to dark-violet plaques, 2,11 arteriovenous malformation. While KS can no exception. In fact, most cells of KS lesions nodules or polyps, depending on clinical variant clinically mimic PG, the distinction can usually contain HHV-8 in its latent state. During the or stage. There are four principal clinical settings be made easily histologically. However, the recent latent period, the HHV-8 gene product LNA-1 in which KS presents: finding of the PG-like KS variant makes the contributes to the oncogenic potential of HHV- 11 Classic KS is an indolent variant typically histologic distinction unreliable. 8 by down-regulating the retinoblastoma protein presenting with lesions on the lower extremities In recent decades, numerous histologic variants transcriptional regulatory pathway and allowing of older males of Jewish or Mediterranean of KS have been described outside of this typical HHV-8 to elude the immune system during 1,3 decent. Early lesions may regress while others continuum. At this time, the clinical significance its latent phase. However, HHV-8 does not evolve, which leads to simultaneous presence of of these variants remains largely unknown. As cause KS unless there is already a defect in the 3 different-staged lesions. suggested by Grayson et al., the wide variety of host’s cellular immunity. Once the virus evades Endemic (African) KS can be classified into histologic presentations of KS can be divided into the immune system, HHV-8 contributes to the four subgroups, including indolent nodular, four large groups: uncontrolled cellular proliferation by stimulating pro-inflammatory interlukin-6, which up- more aggressive florid, infiltrative, and Usual KS lesions. These are the typical histologic regulates vascular endothelial and lymphadenopathic types. The lymphadenopathic lesions associated with disease progression (patch, lymphatic vessel endothelial receptor. HHV-8 type of endemic KS predominately affects plaque and nodular stage).2 3 also prevents of cells by viral interferon children and is fatal. 1,3 Variants reported in the older literature. This and inhibiting tumor suppressor genes. AIDS-related (epidemic) KS affects HIV includes anaplastic and telangiectatic KS, as Therefore, HHV-8 LNA-1 stain is the only stain patients with a CD4+ count <500 cells per cubic well as several lymphedematous KS variants that can definitively distinguish PG from PG- millimeter. The presentation is extremely variable, including lymphedematous, lymphangioma-like, like KS. but it is typically a more aggressive type with 2 lymphangiectatic, and bullous. Treatment goals of KS, regardless of histologic lesions involving skin and viscera.3 Contemporary variants. These are the lesions or clinical presentation, are centered around Immunosuppression-associated KS occurs that have most recently been described in the symptom control, cosmetic improvement, and in patient receiving T-cell inhibitors such literature, including hyperkeratotic, keloidal, prevention of progression, organ compromise as cyclosporine after organ transplant. The and psychological stress. At this time, there is no micronodular, pyogenic granuloma-like, 3-11 presentation is very similar to classic KS and ecchymotic, and intravascular KS.2 Most of cure for KS. One option for localized KS is may resolve if immunosuppressant therapy is these lesions are atypical presentations of one the surgical excision. Typically, this is used to address stopped. However, with prolonged high-dose cosmetically disturbing KS lesions, alleviate “usual KS lesions.” 3 immunosuppressant use, this variant may become discomfort, or control local tumor growth. more aggressive, causing death if there is internal Variants related to therapy. This includes KS that Other local therapies used include external involvement.3 flares as a result of immunotherapy used to treat beam radiation, laser therapy, cryotherapy, either KS or the underlying immunodeficiency, photodynamic therapy, topical alitretinoin The histopathology of KS is essentially identical 2 making the patient susceptible to KS. gel, and intralesional vinblastine. Systemic in all four of the different clinical KS types. Three In this discussion, we will focus on PG-like KS, chemotherapy typically includes anthracyclines main pathological stages have been described in 3,11 and taxanes. Systemic therapy is indicated if the progression of the lesions of KS from patch to which falls into the contemporary variant. PG there is widespread skin involvement, extensive plaque and eventually to nodular.3 The early patch- like KS occurs when a very superficially located oral KS, marked symptomatic edema, rapidly stage KS is characterized by ectatic vessels lined nodular lesion of KS protrudes from the skin, 2 progressive disease, symptomatic visceral KS, by thin endothelial cells dissecting the dermis. eliciting the formation of a collarette. These lesions typically become traumatized due to and KS flare. HHV-8 is susceptible to antiviral Normal adnexal structures and preexisting blood medications such as ganciclovir, but only in vessels often protrude into newly formed blood their superficial location in the skin, ulcerate, and become inflamed, and they present clinically the active phase. Most cells in KS contain vessels, which is referred to as the promontory HHV-8 in its latent phase.3,11 The only clinical sign.11 This sign is not pathognomonic for KS and histologically identical to PG. Histologically, cellularity, lobulation, extravasation of red blood variants that are treated differently are AIDS- as it has also been described in other vascular related and immunosuppression-associated KS, cells, infiltration of and ulceration lesions, including benign vascular tumors and which are treated with reconstitution of the 2,11 are consistent features in both. Endothelial angiosarcoma. The early histologic changes immune system. In AIDS-related KS, optimal differentiation markers such as CD31, CD34, of plaque stage may be inconspicuous and easily control of HIV infection, using antiretroviral 11 and factor VIII-related antigen are used for missed on biopsy. Plaque-stage KS lesions therapy, is a key component in the treatment. identifying tumors of vascular origin, but do not are characterized by a proliferation of spindle 1 In immunosuppression-associated KS, distinguish one vascular tumor from another. cells and vessels. It extends through most of the changing the immunosuppression medication 2,11 Usually, immunohistochemical analysis with dermis and tends to displace collagen. The or decreasing the dose has been associated with antibodies to smooth-muscle cells and factor VIII spindle cells form cleft-like spaces filled with improvement of lesions. The use of sirolimus 2,11 only seen in PG pericytes and mature endothelial red blood cells. The overall picture is that of in place of cyclosporine for post-transplant cells can distinguish between PG and typical KS. a hemorrhagic spindle-cell proliferation in the immunosuppression has been shown to decrease However, in PG-like KS, these stains may also be dermis. In the tumor or nodular stage of KS, there vascular endothelial growth factor as well as positive and are no help in differentiating. Several is a well-defined nodule in the dermis composed interleukins 6 and 10, which are key factors in of vascular spaces and spindle cells, typically more studies have examined the expression of HHV-8 the pathogenesis of KS.3,11

Page 26 PYOGENIC GRANULOMA-LIKE KAPOSI’S SARCOMA: AN ATYPICAL HISTOLOGIC VARIANT In conclusion, KS has been shown to have numerous clinical and histologic variants, including PG-like KS. It is important for KS Neurofibromatosis in Pregnancy: to be in all clinicians’ differential diagnoses of vascular tumors as it can masquerade as several A Case Report and Discussion types of benign-appearing lesions. If a variant of Brandon Markus, DO,* Bill Lear, MD,** Angela Bohlke, MD, MPH*** KS is suspected, utilization of HHV-8 LNA-1 is the only stain that will definitively differentiate * Dermatology Resident, 1st year, Silver Falls Dermatology-Dermatology Residency Program, Salem, OR lesions of KS from other vascular tumors. **Surgical Director, Silver Falls Dermatology, Salem, OR ***Dermatopathologist, Silver Falls Dermatology, Salem, OR References 1. Urquhart J, Uzieblo A, Kohler S. Detection Abstract: of HHV-8 in pyogenic granuloma-like Kaposi Neurofibromatosis type I has an incidence of approximately 1 in 3,000 persons, with half of the cases inherited sarcoma. Am J Dermatopathol [serial online]. and the remainder by new mutations. Neurofibromatosis in pregnancy is underreported, with only a limited August 2006;28(4):317-321. number of studies to date. We report a case of a 32-year-old female in her third pregnancy who met the criteria 2. Grayson W, Pantanowitz L. Histological but was previously undiagnosed with NF1, indicating new-onset neurofibromas during pregnancy. We also variants of cutaneous Kaposi sarcoma. Diagn review the current understanding of cutaneous changes associated with neurofibromatosis and pregnancy. Pathol. 2008;3:31. She had nine café-au-lait macules which were 3. Bolognia J, Jorizzo J, Schaffer J, eds. Case Report A 32-year-old G3P2 female, six months >1.5 cm (Figure 2). There was also freckling Dermatology. 3rd Ed. Amsterdam, Netherlands: of the axilla bilaterally, also known as “Crowe’s Elsevier; 2012:1932-1935. pregnant, presented to the clinic. She had noticed new-onset, painful nodules that first sign” (Figure 1). The patient stated the café-au- 4. Scott P, Motaparthi K, Krishnan B, Hsu S. appeared on the trunk and then the extremities, lait macules and freckling of the axilla had been Pyogenic granuloma-like Kaposi sarcoma: a increasing in both size and color over the past present for as long as she could remember, but diagnostic pitfall. Dermatol Online J. 2012 Mar five months. On examination, she had multiple the painful nodules were all new. The patient had 15;18(3):4. fleshy, hyperpigmented nodules, several of which never been diagnosed with neurofibromatosis. 5. Ryan P, Aarons S, Fitzgibbon J, et al. Human demonstrated the classic “button hole sign.” They Two nodules were biopsied, and on herpesvirus 8 (HHV-8) detected in two patients were present on the back, chest and abdomen, with demonstrated a non-encapsulated intradermal with Kaposi’s sarcoma-like pyogenic granuloma. J a few nodules on the upper and lower extremities. nodule of mildly cellular spindle cells. The spindle Clin Pathol. 2002 Aug;55(8):619-622. cells had indistinct cytoplasm and spindled nuclei 6. Wyatt M, Finlayson C, Moore-Gillon V. with tapering ends that mixed with fine, wavy Kaposi’s sarcoma masquerading as pyogenic collagen matrix consistent with neurofibromas. granuloma of the nasal mucosa. J Laryngol Otol. March 1998;112(3):280-282. 7. Chuck W, Wong KO, Wong CS, et al. Immunostaining for human herpesvirus-8 latent nuclear antigen-1 helps distinguish Kaposi sarcoma from its mimickers. Am J Clin Pathol. 2004; 121: 335-342 8. Patel RM, Goldblum JR, Hsi ED. Immunohistochemical detection of human herpes virus-8 latent nuclear antigen-1 useful in the diagnosis of Kaposi sarcoma. Mod Pathol. Figure 1 2004;17:456-460. Figure 3 9. Schwartz EJ, Dorfman RF, Kohler S. Human herpesvirus-8 latent nuclear antigen-1 expression in endemic Kaposi sarcoma: an immunohistochemical study of 16 cases. Am J Surg Pathol. 2003;27:1546-1550. 10. Dupin N, Fischer C, Kellam P, et al. Distribution of human herpesvirus-8 latently infected cells in Kaposi’s sarcoma, multi- centric Castleman’s disease, and primary effusion lymphoma. Proc Natl Acad Sci USA. 1999;96:4546-4551. 11. Elder D, Elenitas R, Johnson B, Murphy G, Xu X, eds. Histopathology of the skin. 10th ed. Figure 4 Philadelphia, Pennsylvania: Lippincott Williams and Wilkins; 2009:1029-1035 Figure 2 The patient was referred to ophthalmology, Figure 1: Freckling in the axilla (“Crowe’s sign”). and no Lisch nodules or optic gliomas were Correspondence: Jamie Groh, DO, West Palm Figure 2: Multiple pedunculated, flesh-colored found. She reported no physical findings of Hospital/PBCGME, 2201 45th St, West Palm papulonodules along with several café au lait neurofibromatosis in her two children. Other Beach, FL 33407; [email protected] macules. than the development of neurofibromas, she

MARKUS, LEAR, BOHLKE Page 27 had not had any complications with her current References pregnancy. Genetic counseling was offered, 1. Colman SD, Williams CA, Wallace MR. which the patient declined. Benign neurofibromas in type 1 neurofibromatosis (NF1) show somatic deletions of the NF1 gene. Discussion Nat Genet. 1995;11:90-92. Neurofibromatosis type I is inherited in an 2. De Schepper S, Maertens O, Callens T, et al. autosomal-dominant fashion, although new Somatic mutation analysis in NF1 café au lait mutations account for approximately 50 percent spots reveals two NF1 hits in the melanocytes. J of new cases. NF1 plays a role as a tumor Invest Dermatol. 2008;128:1050-1053. suppressor gene, and most NF1 mutations result in reduced intracellular levels of neurofibromin, 3. Gutmann DH, Aylsworth A, Carey JC, et al. which is found in a variety of cell types including The diagnostic evaluation and multidisciplinary neurons, oligodendrocytes and nonmyelinating management of neurofibromatosis 1 and Schwann cells. As observed in other autosomal- neurofibromatosis 2. J Am Med Assoc. dominant genodermatoses, a somatic mutation 1997;278:51. inactivating the remaining allele of the gene can 4. Neurofibromatosis. Conference statement. be found within skin lesions of NF1. Biallelic National Institutes of Health Consensus NF1 inactivation has been identified in Schwann Development Conference. Arch Neurol. 1988; cells from neurofibromas as well as in melanocytes 45:575. from café-au-lait macules in patients with NF1.1,2 This appears to be sufficient to cause most of the 5. Ansari AH, Nagamani M. Pregnancy and clinical manifestations of the disease. neurofibromatosis (von Recklinghausen’s Disease). Obstet Gynecol. 1976;47:9s-25s. As established at the National Institutes of Health Consensus Development Conference 6. Dugoff L, Sujansky E. Neurofibromatosis Type in 1987, two or more of the following are 1 and Pregnancy. Am J Med Genet. 1996;66:7- required for diagnosis of NF1: six or more café- 10. au-lait macules larger than 5 mm in greatest 7. Geller M, Mezitis S, Nunes F. Progesterone diameter in prepubertal individuals and over 15 and Estrogen Receptors in Neurofibromas of mm in postpubertal individuals; two or more Patients with NF1. Clin Med Pathol. 2008;1:93- neurofibromas of any type or one plexiform 97. neurofibroma; freckling in the axillary or inguinal regions; optic glioma; two or more iris Lisch nodules; a distinctive osseous lesion such as sphenoid dysplasia or thinning of long- Correspondence: Brandon Markus, DO, Silver cortex with or without pseudoarthrosis; and a Falls Dermatology, 1430 Commercial St. SE, first-degree relative with NF-1 by the above Salem, OR 97302; [email protected] criteria.3,4 There are a limited number of studies on pregnancy and neurofibromatosis to date. In 1976, Ansara and Nagamani demonstrated growth of neurofibromas with regression in size after pregnancy.5 Another study (n=105) reported new-onset neurofibromas in 60% of their pregnant patients; four patients received their diagnosis for the first time during the study.6 Exploring a hormonal link, Geller et al. demonstrated progesterone-receptor positivity via routine immunohistochemistry in 19 out of 25 neurofibromas collected from both men and women, with no statistically significant difference in expression between sexes.7

Conclusion Although neurofibromas have been reported to occur and increase in size during pregnancy, our case is unique in that our patient did not develop neurofibromas until her third pregnancy. She elected to have several painful neurofibromas removed and is being closely monitored, with no complications in her pregnancy so far.

Page 28 NEUROFIBROMATOSIS IN PREGNANCY: A CASE REPORT AND DISCUSSION A Rare Case of Pagetoid Reticulosis Presenting in a Pregnant Patient

Jeremy K. Bingham, DO,* Kevin Svancara, BS,** Vernon T. Mackey, DO, FAOCD, FASMS***

*3rd-year Resident, Midwestern University/Arizona College of Osteopathic Medicine, Glendale, AZ **4th-year Medical Student, Midwestern University/Arizona College of Osteopathic Medicine, Glendale, AZ ***Program Director, Dermatology Residency, Midwestern University/Arizona College of Osteopathic Medicine, Glendale, AZ

Abstract Pagetoid reticulosis (PG) is a rare form of cutaneous T-cell lymphoma classified into two variants known as Ketron-Goodman (KG) disease and Woringer-Kolopp (WK). We present a rare case of PG in a 20-year-old pregnant patient, with an uncommon immunophenotype of CD4+/CD8+. To our knowledge this is the first reported case of PG involving a pregnant patient. The disease commonly presents as erythematous, scaly plaques, and the two variants are histologically identical.1 Although no standard treatment exists, the disease is typically treated aggressively with chemotherapy, light therapy, radiotherapy, and more commonly a combination of treatments. Our patient presented with a unique challenge in that immediate treatment was desired, but options were extremely limited due to the patient’s pregnancy. Treatment was begun with light therapy using UVB, resulting in improvement of many lesions; however, the patient did develop new lesions. Introduction Case Report finding in the specimen was the presence of Cutaneous T-cell lymphoma has an incidence of In July 2012, a G2P1, 20-year-old female striking epidermotropism of atypical lymphocytes 6.4 persons per million, with pagetoid reticulosis who was 19 weeks pregnant presented with a with abundant, pale-to-clear cytoplasm (Figure constituting less than 1% of all cutaneous one-year history of at least 18 pruritic, raised, 3). They were present predominantly along lymphomas.2,3 It is hypothesized that cutaneous hypopigmented lesions. On physical exam, the lower half of the epidermis and along T-cell lymphomas are malignancies derived lesions were found on the dorsal aspect of both the dermoepidermal junction in a pagetoid from a single clone of T-cells. This produces a hands, bilateral legs, and the left foot (Figures 1 distribution. unique clone of malignant cells developed by and 2). The lesions were primarily localized to the each patient.4 Initially, Langerhans’ cells present distal extremities. The patient denied any history antigens to CD4+ T cells found in peripheral of dermatological diseases, and her personal lymph nodes. The CD4+ T cells are then history was unremarkable for any previous converted to cutaneous T-cell lymphoma cells medical problems. that acquire specific antigens on their cell surfaces. The antigens act as skin-selective receptors. The T cells are then able to adhere to dermal blood vessels and therefore infiltrate the epidermis.5-7 This process describes epidermotropism and Figure 3 is very characteristic of early stage CTCL and variations of CTCL, such as pagetoid reticulosis. Pagetoid reticulosis was first named for its similarity The pattern was also seen in small aggregates to the intraepidermal adenocarcinomatous cells within the epidermis. The dermis contained a found in Paget’s disease of the nipple.8,9 The mild perivascular infiltrate, and atypia of the disease has currently been classified into two dermal component was minimal. A PAS stain was variants: The benign localized variant commonly performed with the appropriate reactive controls. found on the extremities is known as Woringer- Immunoperoxidase stains were also performed Kolopp (WK) and presents with hyperkeratotic Figure 1 with appropriate reactive controls in order to inflammatory plaques; the disseminated type is further characterize the lymphoid infiltrate. The known as Ketron-Goodman (KG) and carries lymphocytes comprised nearly entirely CD3- with it an unfavorable prognosis.1 While the two positive T-cells with rare scattered CD20-positive have no significant differences in morphology or B-cells within the dermis. The intraepidermal histology, they vary significantly in their clinical lymphocytes comprised predominantly CD8- course as the disseminated Ketron-Goodman positive cells with only scattered CD4-positive type can run an aggressive and fatal course.7,8 cells in a ratio of approximately 5:1. There was mild, patchy reduction in immunoreactivity for The clinical differential diagnosis of Woringer- CD5 and a striking loss of immunoreactivity Kolopp is broad due to the nonspecific for CD7 within the intraepidermal component. morphology of a solitary, indolent plaque. Occasionally, intraepidermal lymphocytes were With Ketron-Goodman, there are multiple positive for CD30 cells. The sample was also sent plaques, with a differential diagnosis that for T-cell receptor (TCR) gene rearrangement, includes fungal infections (blastomycosis and which was positive. chromomycosis), porokeratosis of Mibelli, Figure 2 atrophic dermatofibroma, psoriasis, nummular The clinical presentation of multiple plaques on dermatitis, and mycosis fungoides. With distal extremities and histological examination resolving hypopigmented macules, the differential with immunohistochemistry led to the diagnosis diagnosis includes post-inflammatory and post- A skin biopsy from a lesion on the left foot of pagetoid reticulosis. Our patient’s presentation traumatic hypopigmentation and dermatophyte showed hyperkeratosis and mild epidermal of more than 18 plaques on bilateral legs, hands infection. hyperplasia. Variable attenuation of the granular and left foot caused it to be difficult to classify cell layer was also seen. The primary pathologic as either KG or WK. Previous cases have been

BINGHAM, SVANCARA, MACKEY Page 29 described in the literature of WK presenting with of different heterogeneous phenotypes including extremities. In our case, further follow-up will multiple plaques on distal extremities.11 KG is most commonly CD4-/CD8+, CD4+/CD8-, or be conducted after the pregnancy is complete and 8 known for its disseminated plaques and can be CD4-/CD8-. Immunophenotypic evidence has may include more aggressive treatments, such as found on proximal extremities or the trunk. It been studied in great detail to try and understand chemotherapy with other combined treatment is difficult to classify as the classification is one the origin of KG and classify the disease; however, modalities. made clinically. Having presented with multiple while common immunophenotypic trends have plaques on all four extremities, with extension been found as stated above, some researchers report that the differences exceed the similarities References up the legs, the decision was made to treat the 4 1. Mielke V, Wolf HH, et al. Localized and in more than 50% of the reported cases. This was lesions. Due to the patient’s current pregnancy, Disseminated Pagetoid Reticulosis. Arch the case with our patient, who did not present the patient was limited to treatments that Dermatol. 1989;125:402-406. with one of the typical immunophenotypes but could be administered immediately. She was was found to have CD3+, CD8+/CD4+ in a 2. Berti E, Tomasini D, et al. Primary cutaneous recommended that she undergo light therapy ratio of 5:1. Nakada described a patient with a CD8-positive epidermotropic cytotoxic T cell with UVB and began treatment. similar immunophenotype who was treated with lymphomas. A distinct clinicopathological entity The patient presented to our office with a chlorambucil for one month followed by PUVA with an aggressive clinical behavior. Am J Pathol. referral from her OBGYN. With the exception for eight weeks. He reported disappearance of 1999 Aug;155(2):483-92. 12 of her unremarkable prenatal labs, she did the lesion but recurrence after four years. No 3. Criscione VD, Weinstock MA. Incidence of not have any prior workup. At the initial visit standard treatment currently exists for KG, and cutaneous T-cell Lymphoma in the United States. to our office, a biopsy was completed. When many different treatment options have been Arch Dermatol. 2007;143 (7):854-9. tried in the past. Treatments have included the clinicopathologic diagnosis of pagetoid 4. Zengin AY, Topkan E, et al. Woringer-Kolopp UVB, PUVA, steroids, chlorambucil, topical reticulosis was made, we referred the patient to disease coexpressing CD4 and CD8 treated N2 mustard, chemotherapy agents and, most oncology. CBC, CMP, and LDH were normal, with radiation therapy: a case report. Tumori. commonly, combined modality therapy, all 4,12 2008;94:754-757. and monoclonal gammopathy was negative. reported to have widely variable efficacy. Our No imaging has been completed. Oncology patient presented with a significant challenge 5. Habif TP. Clinical Dermatology: A Color Guide th recommended continuing UVB therapy, but any due to the rarity of her disease and her coexisting to Diagnosis and Therapy. 4 ed. Philadelphia: additional treatments, including topical nitrogen pregnancy. Phototherapy with UVB was selected Mosby; 2004. mustard, are on hold at the present time. Her due to its ability to resolve lesions temporarily 6. Dusan S, Bogdanovic Z, et al. Pagetoid case remains ongoing. and its safety for use in pregnant patients. UVB reticulosis of Woringer-Kolopp. Dermatol Online can be an effective treatment of immediate J. 2008;14(1):18. [Accessed January 23, 2013]. Discussion lesions in KG by altering the environment of Available from: http://escholarship.org/uc/ the surface of the skin, creating an inhospitable item/9zd4c6s0 Pagetoid reticulosis is a rare form of disseminated 5 T-cell lymphoma with striking epidermotropism.8 environment for the cancer cells. However, long-term remission is uncommon.12 Regardless 7. Carlesimo M, Tammaro A, et al. A Case of KG typically presents as multiple, diffuse, Ketron-Goodman Disease. Case Rep Dermatol. of treatment choice, long-term follow-up is hyperkeratotic plaques; however, the diagnosis 2009 Dec;1(1):39-43. is one made by pathology. Biopsy will show necessary due to common recurrences, which intraepidermal, highly activated, proliferating T have been reported anywhere from several weeks 8. Shiozawa E, Shiokawa A, Shibata M, et al. 12 Autopsy case of CD4–/CD8 cutaneous T-cell cells with variable loss of pan-T-cell antigens, to 10 years after the disappearance of lesions. lymphoma presenting disseminated pagetoid contrasting with non-activated dermal reactive Our patient had variable success with UVB 2 reticulosis with aggressive granulomatous invasion T cells. The atypical lymphocytes are typically treatment, with multiple lesions that faded while to the and pancreas. Pathol Int. 2005;55:32– surrounded by clear halos in the epidermis, new lesions appeared. However, due to the third 39. creating the typical pagetoid appearance. trimester of the patient’s pregnancy, the patient was noncompliant with a consistent treatment 9. Steffen C. Ketron-Goodman Disease, Woringer- Some argue today that KG should no longer regimen and frequently missed scheduled Kolopp Disease, and Pagetoid Reticulosis. Am J be classified under pagetoid reticulosis due to treatments. Dermatopathol. 2005 Feb;27(1):68-85. its difference in clinical behavior and clinical similarity to mycosis fungoides (MF).1,2 In summary, the case presented here is interesting 10. Pagnanelli G, Bianchi L, et al. Disseminated However, KG has been the topic of much in that to our knowledge, this is the first known Pagetoid Reticulosis Presenting as Cytotoxic debate concerning its association with MF and case of pagetoid reticulosis in a pregnant patient. CD4/CD8 Double Negative Cutaneous T-cell whether it is a variant of the latter based on The case also presented a rare immunophenotype Lymphoma. Acta Derm Vereol. 2002;82(4):314- their clinical and histopathologic similarities.10 of CD4+/CD8+. The diagnosis of pagetoid 316. reticulosis is often delayed for several years because Haghighi et al. demonstrated a few significant 11. Haghighi B, Smoller BR, LeBoit PE. Woringer-Kolopp disease is an uncommon differences between the two. First, KG typically Pagetoid reticulosis (Woringer-Kolopp only has tumor cells found in the epidermis, condition that is rarely suspected. This rare disease): an immunophenotypic, molecular, while MF presents with tumor cells found in condition typically presents as a solitary plaque and clinicopathologic study. Mod Pathol. 2000 both the dermis and epidermis. Another key located on the extremities, with an indolent May;13(5):502-510. difference is found in the composition of the clinical course in the case of Woringer-Kolopp disease or, in Ketron-Goodman patients, a more 12. Nakada T, Hirohiko S, et al. Disseminated dermal infiltrate. KG typically consists of reactive pagetoid reticulosis (Ketron-Goodman disease): lymphocytes and histiocytes, while eosinophils generalized presentation with diffuse cutaneous involvement and a more aggressive clinical Six-year follow up J Am Acad Dermatol. 2002 are not typically present; mycosis fungoides 13 Aug;47(2):183-186.13. contains a polymorphous infiltrate consisting of course. The fact that our patient presented while reactive lymphocytes, histiocytes, plasma cells pregnant served as a distractor and had no bearing 13. Matsuzaki Y, Kimura K, Nakano H, and eosinophils. A third difference can be found on diagnosis once a biopsy was completed. It did, Hanada K, Sawamura D. Localized pagetoid in the T-cell subtype of KG, which includes a however, limit our treatment options. Pagetoid reticulosis (Woringer-Kolopp disease) in early heterogeneous immunophenotype of multiple reticulosis is a diagnosis that will rarely be at the childhood. J Am Acad Dermatol. 2009;61:120– possibilities, most commonly including CD4+ top of a clinician’s differential diagnosis. This 123. [PubMed] T-helper cells, CD8+ T-cytotoxic/suppressor case study hopes to raise awareness regarding cells or CD4/CD8 double-negative cells; MF the disease. Given the impact disseminated characteristically has an immunophenotype of pagetoid reticulosis may pose to the long-term Correspondence: Jeremy Kempton Bingham, only CD4+ cells.11 health of a patient, it should be at least considered Advanced Desert Dermatology, 9179 W. when dealing with solitary or disseminated Thunderbird Rd b105, Peoria, AZ 85381; As stated, KG has been characterized as a number hyperkeratotic plaques on the trunk and proximal [email protected]

Page 30 A RARE CASE OF PAGETOID RETICULOSIS PRESENTING IN A PREGNANT PATIENT Painful, Erosive and Exudative Plaque on the Scalp of an Elderly Male

Cherise Khani, DO,* Peter Saitta, DO, FAOCD,** Cindy Hoffman, DO, FAOCD,*** Ronald Brancaccio, MD, FAAD****

*Department of Dermatology, St. Barnabas Hospital, Bronx, NY **Academic Professor of Dermatology, Department of Dermatology, St. Barnabas Hospital, Bronx, NY ***Program Director, Department of Dermatology, St. Barnabas Hospital, Bronx, NY ****Clinical Professor of Dermatology, Ronald O. Perelman Department of Dermatology, New York University, New York, NY

Abstract Erosive pustular dermatosis of the scalp (EPDS) is a rare disorder affecting the scalp of elderly individuals, distinguished by persistent sterile pustules, crusted erosions, and subsequent scarring alopecia. We present a case of an 83-year-old Caucasian male with EPDS, discuss the clinical and histopathologic findings characterizing the disease, and review therapeutic options. Case Report parapsilosis. Viral cultures were negative for HSV and yeast may occur, as in our patient, but is An 83-year-old Caucasian male presented and VZV. not suspected to contribute to pathogenesis. Staphylococcus aureus and Candida albicans are to our clinic complaining of a bleeding, non- The patient was treated initially with appropriate amongst the most commonly isolated agents; healing, painful lesion on his left frontal scalp. antibiotics without any clinical improvement. Staphylococcus epidermidis, Pseudomonas aeruginosa, He reported that the lesion occurred one year Treatment with silver-nitrate destruction and Proteus mirabilis, coliforms, diphtheroids, previously, after a sunburn to the area, but would intralesional steroids was also unsuccessful. The Candida parapsilosis and Aspergillus ochraceus have only temporarily heal, and that it demonstrated patient received the most benefit from the use been described as well.1 associated . His past medical history of topical dapsone 5% gel, used twice daily, with was significant for type II diabetes, treated with near complete resolution (Figure 2). The lack of Mastroianni et al. hypothesize that physical metformin. The patient did not report any prior any primary infectious presence, the absence of damage to the scalp skin could induce production personal history of skin cancer, nor was there any a tumor, the non-specific histological finding, of autoantibodies against epidermal and dermal significant family history of skin cancer. A review and the clinical presentation all pointed toward a structures, leading to a secondary inflammatory of systems was negative for preceding illness, diagnosis of EPDS. response. Our patient did report sunburn prior to recent weight loss, or constitutional symptoms. the development of the lesion. Trauma previously Physical examination revealed an elevated, 6.0 cm reported in association with EPDS includes x 4.0 cm, moist, erythematous, amoeboid plaque scalp surgery such as craniotomies, skin grafting, with pinpoint erosions and the appearance of synthetic hair fiber implantation, cryotherapy, 5% fluorouracil cream, photodynamic therapy and granulation tissue on the left frontal scalp (Figure 3-6 1). A neoplasm was initially suspected, and a accidental injury. In addition, long-standing 3-mm punch biopsy of the scalp was obtained, as damage by ultraviolet radiation may contribute to well as bacterial, viral, and fungal cultures. the development of EPDS. The differential diagnosis is extensive and includes basal cell, Merkel cell or squamous cell Figure 2 carcinoma, cutaneous metastatic disease, bacterial folliculitis, tinea, herpes infections, discoid lupus erythematosus, bullous disease and temporal Discussion 3 Erosive pustular dermatosis of the scalp (EPDS) arteritis. For these reasons, all patients with was first described by Rye et al. in 1979. suspected EPDS should have bacterial, fungal, Clinically, EPDS has a slow and progressive and viral cultures, as well as biopsies. course, beginning as localized pustules that later Histopathologic findings are non-specific and evolve into eroded areas covered by superficial differ according to the site of biopsy.1 Biopsies Figure 1 crusts. Pustules are painful, and can begin as can show parakeratosis, hyperkeratosis, and discrete lesions, but after months to years enlarge epidermal atrophy or erosion. Occasionally, into confluent plaques with erosions and scarring. subcorneal pustules are seen in the epidermis.6 Microscopic Findings and With the exception of inflammatory markers Inflammatory infiltrates with lymphocytes Clinical Course such as erythrocyte sedimentation rate, C-reactive and plasma cells can be found in the dermis, Three biopsies were performed over a 15-month protein and hypergamaglobulinemia, laboratory particularly surrounding hair follicles and period. Histopathologic analyses of two tests are typically normal. Associations with sebaceous glands. Foreign-body giant cells and specimens revealed pale edematous stroma with , Hashimoto’s thyroiditis, fibrosis can be found near remnants of destroyed increased numbers of capillaries and a mixed autoimmune hepatitis and Takayasu’s arteritis pilosebaceous units.3,6 However, none of the inflammatory cell infiltrate consistent with have all been described in patients with EPDS, aforementioned changes are diagnostic. granulation tissue. A third biopsy was consistent but no direct relationship has been proven as the Patients are often recalcitrant to treatment. Both with a . Bacterial and fungal cultures on 1 majority of patients lack autoimmune disease. topical and oral antibiotics have little efficacy. several different examinations showed growth EPDS is a diagnosis of exclusion, and therefore Other treatment options with variable results of Staphylococcus aureus, Serratia marcescens, all infectious and neoplastic processes must be include steroids (topical, oral and intralesional), Achromobacter xylosoxidans and Candida 5 ruled out. Secondary colonization with bacteria photodynamic therapy, and calcipotriol cream.

NOOROLLAH, CHOUDHURY, SIROTA ROZENBERG Page 31 Zinc sulfate has been shown to provide some improvement secondary to its anti-inflammatory effects.3 Vano-Galvan et al. demonstrated A Case of Subcutaneous Fat Necrosis successful treatment with topical tacrolimus, showing no relapse after three months.4 Oral of the Newborn alters follicular keratinization and suppresses activity, and anecdotal Charlotte Noorollah, DO,* Sourab Choudhury, DO,** Suzanne Sirota Rozenberg, DO*** case reports have shown these anti-inflammatory * Dermatology Resident, 3rd year, St. John’s Episcopal Hospital, Far Rockaway, NY; Episcopal Healthcare System effects on the pilosebaceous unit to yield – South Shore, Far Rockaway, NY improvement of EPDS.1 Recently, improvement ** Pediatric Dermatologist, Brooklyn Dermatology, Brooklyn, NY of EPDS with topical dapsone 5% gel twice daily *** Program Director, Dermatology Residency, St. John’s Episcopal Hospital, Far Rockaway, NY; Episcopal has been described. Dapsone is a sulfone with both Healthcare System – South Shore, Far Rockaway, NY anti-inflammatory and anti-neutrophilic effects. Broussard et al. reported four patients treated with Abstract topical dapsone who showed improvement via Subcutaneous fat necrosis of the newborn (ScFN) is an uncommon, usually self-limited disease affecting full- reduced plaque and erosion size within two weeks term newborns in the first few weeks of life. It can often follow perinatal complications such as hypothermia, meconium aspiration, forceps delivery, or maternal complications such as high blood pressure or gestational to two months of initiating treatment, as well as diabetes. It is often characterized by sharply demarcated, firm plaques typically affecting the upper back and complete resolution of crusting and inflammation sparing the anterior trunk. Prognosis is often excellent, with hypercalcemia as a rare association. Infants within one to four months. No side effects of should be followed for several months with serial calcium-level evaluation. treatment were reported, and all patients revealed 5 stable posttreatment hemoglobin levels. In Case Report is quite rare, and no racial or sexual predilection addition, there has been no reported evidence of A 25-day old female born full-term via normal exists. hemolytic anemia among patients with glucose- spontaneous vaginal delivery presented to the The etiology and pathogenesis remains largely 6-phosphate dehydrogenase deficiency while pediatric dermatology office with a three-week 5 unknown; however, it is believed that a systemic using topical dapsone. history of “hardening” of her skin. The mother and/or a local hypoxia-hypoperfusion episode Finally, routine surveillance of patients with reported that the child was hospitalized in the during the peri-natal period, leading to certain EPDS is required, as recurrences are common, neonatal intensive care unit following delivery cold- or stressed-induced injury to fetal fat, for five days secondary to “fluid in her lungs” results in the development of solidification and the development of 1,2 3,7 from presumed meconium aspiration. While in and/or necrosis. Fetal fat has a high ratio in scars of EPDS has been reported. the hospital, she was found to be hypocalcemic, of saturated (stearic and palmitic acids) to which subsequently resolved, and her pulmonary unsaturated fatty acids. These fetal saturated fatty References function also improved. She was discharged home 1. Mastroianni A, Cota C, Ardigo M, Minutilli E, acids have a higher melting point, and states of after hospital day five and was being breast-fed. hypothermia can result in crystallization of the Berardesca E. Erosive pustular dermatosis of the Her family history was non-contributory. fat, leading to necrosis, injury to adipocytes, scalp: a case report and review of the literature. 1,3 and granulomatous inflammation. The Dermatology. 2005;211:273-276. On physical examination, the infant appeared alert and comfortable. She had non-tender, macrophages in the area of infiltration lead to 2. Pye RJ, Peachey RDG, Burton JL. Erosive pink-to-erythematous, indurated plaques on the increased 1,25-dihydroxyvitamin D3, which pustular dermatosis of the scalp. Br J Dermatol. upper back and shoulders, sparing the anterior leads to increased non-renal intestinal absorption 1979;100:559-566. trunk (Figures 1a,b). The remainder of her skin of calcium and ultimately gives rise to subsequent complications of hypercalcemia.4 3. Van Exel CE, English JC. Erosive pustular examination was within normal limits. Based dermatosis of the scalp and nonscalp. J Am Acad on her history and presentation, a diagnosis of Factors thought to induce such stress to fetal subcutaneous fat necrosis of the newborn was Dermatol. 2007;57(2):S11-14. adipocytes include perinatal complications such made. as asphyxia, hypothermia, meconium aspiration, 4. Vano-Galvan S, Martorell-Calatayud A, Pedro J. Erosive pustular dermatosis of the scalp. J Pak Med Assoc. 2012;62(5);501-502 5. Broussard KC, Berger TG, Rosenblum M, Murase JE. Erosive pustular dermatosis of the scalp: A review with a focus on dapsone therapy. J Am Acad Dermatol. 2012;66(4):680-686. 6. Allevato M, Clerc C, del Sel JM, Donatti L, Cabrera H, Juarez M. Erosive pustular dermatosis of the scalp. Int J Dermatol. 2009;48:1213-1216. 7. Liborija LM, Barisic F, Bulat V, Buljan M, Figure 1a Figure 1b Situm M, Bradie L, Mihic J. Differential diagnosis of the scalp hair folliculitis. Acta Clin Croat. Figures 1a and 1b. Pink-to-erythematous, indurated plaques on the upper back and shoulders, sparing the anterior trunk. 2011;50:395-402.

Discussion newborn failure to thrive, forceps use, and Correspondence: Cherise Khani, St. Barnabas Subcutaneous fat necrosis of the newborn (ScFN) smoking; however, this association remains Hospital, 4451 3rd Ave, Bronx, NY, 10457; is an uncommon, self-limited panniculitis that unclear.1,2 Hogeling et al. reported three neonates [email protected]. appears in full-term or post-term neonates with hypoxic ischemic encephalopathy who 1,2 often in the first two to three weeks of life. were treated with therapeutic hypothermia and The frequency of this disorder is unknown as it developed extensive ScFN as a result.1 Page 32 A CASE OF SUBCUTANEOUS FAT NECROSIS OF THE NEWBORN ScFN is characterized by firm, sharply demarcated Conclusion nodules and plaques that appear on the upper Subcutaneous fat necrosis of the newborn is trunk, arms and buttocks, often in a symmetrical 1,3,5 usually self-limited, benign panniculitic process, distribution. Lesions may appear up to 1 4 with most cases resolving spontaneously. several weeks after delivery. Often, these begin Although rare, hypercalcemia and other metabolic as edematous plaques that progress to become abnormalities can occur, warranting monitoring firm and indurated. Lesions can later become in the months following disease onset and even fluctuant and drain necrotic fat as they resolve. after resolution of lesions. Although the diagnosis can be made clinically, definitive diagnosis is made histologically. References Histologic examination often reveals necrosis of 1. Bolognia J, Jorizzo JL, Rapini RP (eds). fat lobules with crystallization of fat, radial crystals Dermatology. º2nd ed. Vol. 2. St. Louis: Mosby/ in lipocytes and granulomatous inflammation Elsevier; 2008. (Figure 2).1 2. Zhou W, Wiesenthal A. A Firm Plaque on the Figure 2a Back of a Newborn. Dermatol Online J. 2010 Feb 15;16(2):11. 3. Pride H, James W. Subcutaneous Fat Necrosis of the Newborn. eMedicine. 2012 Jan 19. Available from: http://emedicine.medscape.com/ article/1081910-overview 4. Akin M, Akin L, Sarici D. Follow-Up During Early Infancy of Newborns Diagnosed with Subcutaneous Fat Necrosis. J Clin Res Pediatr Endocrinol. 2011;3(4):216-18. 5. Paller A, Mancini AJ, Hurwitz S. Hurwitz Figure 2. Needle-shaped clefts within fat Clinical Pediatric Dermatology: A Textbook of cells, with foamy histiocytes; granulomatous Skin Disorders of Childhood and Adolescence. infiltrate of histiocytes and lymphocytes. Philadelphia: Elsevier Saunders. 2006. 6. Hogeling M, Meddles K, Berk DR, Bruckner Hypercalcemia is the most common and most AL, Shimotake TK, Cohen RS, Frieden IJ. serious complication that has been associated Extensive Subcutaneous Fat Necrosis of with ScFN. This may develop in the fourth to the Newborn Associated with Therapeutic sixth weeks of life and even up to six months after Hypothermia. Pediatr Dermatol. 2012 Jan- the onset of skin lesions.2,4 Morbidity associated Feb;29(1):59-63. with hypercalcemia includes anorexia, irritability, 7. Dirk M, Ferringer T. Dermatopathology. hypotonia, seizures, renal failure and cardiac Edinburgh: Saunders/Elsevier. 2009. arrhythmias. Hypocalcaemia has been described in one case report, similar to our patient’s, 8. Pielop JA. Skin Nodules in Newborns and although it is rare. Other complications of Infants. UpToDate. 2013. Available at: http:// ScFN can include thrombocytopenia. Although www.uptodate.com/contents/skin-nodules-in- the mechanism is unclear, it is believed to be newborns-and-infants. due to local sequestration of in the 9. Mitra S, Dove J, Kumar Somisetty SK. 1 subcutaneous tissue. The thrombocytopenia Subcutaneous Fat Necrosis in Newborn—an can last up to several weeks and usually resolves Unusual Case and Review of Literature. Eur J 2 spontaneously. Pediatr. 2011;170(9):1107-110. The differential diagnosis of ScFN includes sclerema neonatorum (SN), characterized by a diffuse, wax-like hardening of the subcutaneous Correspondence: Charlotte Noorolah, DO, St. tissue. SN generally affects premature, debilitated John’s Episcopal Hospital, 327 Beach 19th St., infants, usually during the first week of life, and Far Rockaway, NY 11691; [email protected] portends a poor prognosis.1 ScFN resolves spontaneously, and treatment is mainly supportive. Treatments for severe hypercalcemia include fluid loading followed by loop diuretics such as furosemide, corticosteroids, and to reduce of calcium.3,8 Infants should be fed a low-calcium, low-vitamin D diet. Although plaques usually resolve without sequelae, some areas may develop deposits of calcium and drain spontaneously, which may heal with scarring. Most plaques, however, undergo resolution within several weeks to months.5 Serial monitoring of calcium levels is advised, as hypercalcemia can be delayed.1,5

NOOROLLAH, CHOUDHURY, SIROTA ROZENBERG Page 33 Use of Acitretin in a Patient with Epidermolytic Hyperkeratosis: A Case Report and Literature Review

Dorene Niv, BS,* Heather Kelly, BS,* Patrick Keehan, DO, FAOCD**

*Medical Student, 3rd year, University of North Texas Health Science Center, Fort Worth, TX ** Board-certified Dermatologist, Premier Dermatology, Fort Worth, TX

Abstract Table 1. Characteristics of EHK subtypes4 Epidermolytic hyperkeratosis (EHK) is a rare, inherited skin disorder that presents in childhood Trait NPS types (without severe PS types (with severe palmoplantar with blistering and erythema, eventually progressing palmoplantar hyperkeratosis) hyperkeratosis) to hyperkeratosis with scaling. The cause is attributed NPS-1 NPS-2 NPS-3 PS-1 PS-2 PS-3 to an autosomal-dominant mutation in the genes Palmoplantar Absent Absent Absent Present Present Present encoding keratins that affect the integrity of intermediate filaments in suprabasal keratinocytes. hyperkeratosis To date, six phenotypes and one recessive form of the Palmoplantar Normal Normal Hyperlinear, Smooth Smooth Cerebriform disorder have been reported. The standard treatment surface minimal scale involves systemic retinoids.10 We report the case of a Digital Absent Absent Absent Absent Present Absent 14-year-old Hispanic male with lifelong multiple contractures linear hyperkeratotic lesions with no history of childhood blisters. At the time of presentation, the Scale Hystrix Brown Fine, white Mild White scale to Tan patient had previously been diagnosed in Mexico peel with epidermodysplasia verruciformis (EV), an Distribution Generalized Generalized Generalized Localized Generalized Generalized autosomal-recessive condition spread by the human 11 Erythroderma Absent Absent Present Absent Present Absent virus. EV presents with flat, -like lesions and hypo- and hyperpigmented macular Blistering Present Present Present Localized Present Neonatal lesions. The patient was prescribed topical steroids Other features Relative Relative Scalp severely Flexures Hyperkeratosis Mild facial and reported no improvement in his condition. He facial sparing of involved involved, not in linear erythema therefore sought additional care, and we initiated sparing face and truncal pattern treatment with acitretin. scalp sparing Introduction with epidermal nevi syndrome (ichthyosis hystrix). palmoplantar involvement. At this time, a Discovered in 1970 by Albert Bernard This condition is comprised by hamartomatous diagnosis of epidermolytic hyperkeratosis was Ackerman, EHK was originally considered a lesions that originate from embryonic skin and suspected. are thought to signify a genetic mosaicism of minor pathologic reaction pattern in skin due 6,7 to its appearance coinciding with multiple skin keratin. There are several histological subtypes 1 of epidermal nevi, with 16% demonstrating conditions. With time, EHK was found to 8 present independently as widespread blistering epidermolytic hyperkeratosis. Like EHK, cases at or soon after birth with eventual ichthyotic of the epidermolytic hyperkeratosis subtype of 2 epidermal nevi have been reported to be caused erythroderma that persisted into adulthood. 6 This genodermatosis displays an autosomal- by keratin 1 mutations and keratin 10 mutations. dominant inheritance pattern, with mutations of It has been reported that patients who suffer from keratins K1 and K10, specifically found in their this type of epidermal nevi may have offspring helix boundary motifs.3 with generalized EHK, including blistering during infancy and childhood.7,9 Clinical EHK is subdivided into six phenotypes based on the presence or absence of involvement of the palms and soles (Table 1).4 Individuals Case Report who display severe sole and palm hyperkeratosis A 14-year-old Hispanic adolescent presented Figure 1 are known to harbor a KRT1 mutation, with chronic skin lesions. He complained of while those with KRT10 mutations lack sole dry, cracking, thick, raised skin lesions. The and palm hyperkeratosis.2 Individuals with patient was accompanied by family members KRT10 mutations have been found to display who stated the lesions have been present since he a predominant truncal involvement of the was 3 months old and have occurred in a stable, disorder.2 EHK may also occur without a family persistent pattern. The family denied any history history. Classified as mosaic clinical EHK, this of childhood blisters. He was biopsied in Mexico presentation is a sporadic condition with similar and was diagnosed with epidermodysplasia histopathologic findings to EHK.5 However, verruciformis. He was given topical steroid patients are found to present clinically with creams that resulted in no improvement in his widespread epidermal nevi due to a postzygotic lesions. Physical exam revealed hyperkeratotic, mutation involving the germ line.5 hyperpigmented and hypopigmented, whorled plaques on his back, chest, neck, and extremities Figure 2 Similar clinical presentation occurs in patients (Fig. 1-2). There were no blisters, odor or

Page 34 USE OF ACITRETIN IN A PATIENT WITH EPIDERMOLYTIC HYPERKERATOSIS: A CASE REPORT AND LITERATURE REVIEW.. A biopsy was performed, which revealed Discussion References orthokeratosis with hypergranulosis and Treatment of both ichthyosis hystrix and EHK 1. Meibodi N, Nahidi Y, Javidi Z. Epidermolytic epidermolytic changes within the epidermis includes topical and oral retinoids, with topical hyperkeratosis in inflammatory linear consistent with EHK (Fig. 3-4). therapies reported as less effective and more likely verrucous epidermal nevus. Indian J Dermatol. to cause local irritation.10 Retinoids inhibit cell 2011;56(3):309-312. growth by their effect on transcription factors in 2. Haruna K, Suga Y, Mizuno Y, et al. R156C skin cell lines, and induce cell apoptosis. Their mutation of keratin 10 causes mild form of success in hyperkeratosis-related conditions epidermolytic hyperkeratosis. Jpn Dermatol may be due to their effect on keratins, with an Assoc. 2007;34:545-548. upregulation of K4, K6, K13, and K19 and a down-regulation of K2e, K1 and K10.7 3. Terheyden P, Grimberg G, Hausser I, et al. Recessive epidermolytic hyperkeratosis caused Acitretin is a treatment option for both EHK and by a previously unreported termination codon ichthyosis hystrix. Studies have shown substantial mutation in the keratin 10 gene. J Invest improvement in keratinization disorders treated Dermatol. 2009;129:2721-2723. Figure 3 with acitretin, with one study reporting 23 of 28 cases cured in patients receiving an average dose of 4. DiGiovanna JJ, Bale SJ. Clinical heterogeneity 0.86mg/kg/day over two months to 36 months.10 in epidermolytic hyperkeratosis. Arch Dermatol. The most frequent side effects discussed included 1994;130:1026-1035. (46.3%) and skin fragility (35.7%), with 5. Ross R, DiGiovanna J, Capaldi L, Argenyi no effect on growth or bone. However, in a Z, Fleckman P, Robinson-Bostom L. study involving patients aged 45, 60, and 69 who Histopathologic characterization of epidermolytic received 0.5-0.75mg/kg/day for 14, 22, and 28 hyperkeratosis: A systemic review of histology years, respectively, clinical condition improved but from the national registry for ichthyosis and reports of spinal hyperostosis occurred. Further related skin disorders. J Am Acad of Dermatol. review of literature reveals fewer significant 2008;59(1):86-90. systemic events when shorter periods of acitretin are prescribed, even at higher dosages.10 6. Tsubota A, Akiyama M, Sakai K, et al. Keratin Figure 4 1 gene mutation detected in epidermal nevus with Variability in response to treatment has epidermolytic hyperkeratosis. J Invest Dermatol. been reported. In a study comparing patients with 2007;127:1371-1374. At follow-up, the family again denied a history of K1 and K10 mutations, good responders included 7. Paller A, Syder A, Chan Y, et al. Genetic and blistering in the neonatal period and also denied patients with K10 mutations who experienced an 7 clinical mosaicism in a type of epidermal nevus. any family history of skin disorders. Genetic upregulation of K4 when treated with retinoids. Patients with K1 mutations exhibited a lower N Engl J Med. 1994;331(21):1408-1415. testing was recommended, but the patient and 7 his family declined. He was prescribed acitretin, tolerability to retinoid treatment. A down- 8. Submoke S, Piamphongsant T. Clinico- and side effects were discussed. At follow-up regulation of K2e was discovered in these patients histopathological study of epidermal naevi. four weeks after treatment was initiated, the following treatment, and this may serve as one Australas J Dermatol. 1983;24:130-136. mechanism of variability in clinical improvement. hyperkeratosis was markedly improved with a 9. Reddy B, Thadeus J, Krishan S, Kumar A, mild side effect of dry (Fig. 5-6). This patient discussed herein presented a Jaishanker T, Gard B. Generalized epidermolytic diagnostic challenge. He was initially diagnosed hyperkeratosis in a child born to a parent with with epidermodysplasia verruciformis in Mexico, systematized epidermolytic linear epidermal but this diagnosis was questioned based on clinical nevus. Int J Dermatol. 1997;36:198-199. exam findings. Two additional biopsies were 10. Nassif P, Nakandakari S, Fogagnolo L, Contin performed, and a diagnosis of EHK was made L, Alves C. Epidermolytic hyperkeratosis: A based on the histological findings. This diagnosis, follow-up of 23 years of use of systemic retinoids. however, was also in question due to the patient’s Braz Ann Dermatol. 2011;86:72-75. negative history of skin blistering and negative family history of the disease, but incomplete 11. Rogers HD, Macgregor JL, Nord KM, Tyring penetrance and variable expressivity of EHK S, Rady P, Engler DE, Grossman ME. Acquired were considered as possibilities. However, taking epidermodysplasia verruciformis. J Am Acad Figure 5 into account the full clinical history in addition Dermatol. 2009;60(2):315-20. to histological evidence, ichthyosis hystrix is currently believed to be the most likely diagnosis.

Conclusion Correspondence: Dorene Niv, MSIII, University It is imperative to consider all clinical and of North Texas Health Science Center - histological information when making a diagnosis Texas College of Osteopathic Medicine, 855 in order to properly treat and counsel patients. Montgomery St., Fort Worth, TX 76107; Ichthyosis hystrix can have a similar clinical [email protected] appearance to EHK, and approximately 16% of cases have the histologic subtype of epidermolytic hyperkeratosis. The patient was started on acitretin and showed improvement of his lesions Figure 6 after one month of treatment with minimal side effects. Although he declined genetic testing at this time, it was still encouraged due to the possibility of full-blown EHK in his offspring.

NIV, KELLY, KEEHAN Page 35 Case Report: Follicular Mucinosis in an Adolescent

Ashvin Garlapati, DO,* Mayha Patel, BS,** Stanley Skopit, DO, MSE, FAOCD***

*Dermatology Resident, 1st year, Larkin Community Hospital/NSU-COM, South Miami, Florida **Medical Student, 4th year, Western University of Health Sciences, Pomona, California ***Program Director, Dermatology Residency Program - LCH/NSU-COM, South Miami, Florida

Abstract Follicular mucinosis, also known as , is a rare disorder characterized by follicular papules and indurated plaques that affects both adolescents and adults. In adolescents, it is usually confined to the head and neck region and runs a benign course that resolves within months to years. In adults presenting with a widespread distribution of lesions, it runs a more malignant course and is usually associated with lymphoma, specifically with mycosis fungoides (MF). We report the case of a 9-year-old male with a past medical history of acute myelogenous leukemia (AML) presenting with grouped follicular papules within hypopigmented patches of alopecia diffusely on his body. The clinical presentation, histology and treatment will be discussed in this case report.

Introduction On physical examination, the lesions presented as Clobetasol ointment was initially tried over Follicular mucinosis (FM) is a rare, chronic grouped follicular papules within hypopigmented a four-week period with no improvement. cutaneous disease of the outer root sheath of the patches of alopecia scattered diffusely all over his More lesions began to appear during that time. hair follicle and sebaceous gland. The dermatologic body but predominantly located on the bilateral Narrowband UVB is currently being used with eruptions present with follicular papules with or upper extremities. No palpable lymph nodes were significant improvement, and the patient’s without indurated plaques. The accumulation of appreciated. The patient denied pruritus, pain, or treatment is ongoing at the time of this paper’s mucinous material in the damaged hair follicles any other symptoms associated with the lesions. publication. and sebaceous glands causes an inflammatory A deep shave biopsy was performed, and condition and subsequent degeneration. The face, histopathology revealed mucin deposits within Discussion neck, and scalp are the most commonly affected the hair follicles, confirming the diagnosis of Follicular mucinosis is a rare, chronic, 1 areas, although lesions may appear anywhere. follicular mucinosis (Figures 3 and 4). T-Cell histopathologic cutaneous disease presenting with We present the case of 9-year-old male with a receptor rearrangement studies were negative. mucin deposits and edema in the outer root sheath history of acute myelogenous leukemia (AML) of hair follicles and sebaceous glands. Clinically, it who was diagnosed with biopsy-proven follicular presents with shiny papules or sharply demarcated, mucinosis that was treated with clobetasol and infiltrated, erythematous scaling plaques on the narrowband ultraviolet B light (UVB) therapy. head and neck, the most frequent sites, as well as the trunk and extremities. The accumulation Case Report of mucinous material in the outer root sheath A 9-year-old male presented with a two-month of the hair follicle and sebaceous glands causes history of “white spots” spreading diffusely over damage and creates an inflammatory condition his body (Figures 1 and 2). The patient’s mother that eventually breaks down the follicle and reported that a few spots grew on his arm over gland. When follicular mucinosis occurs in hair- a period of weeks, and others began to crop up bearing areas of the body, it is named alopecia thereafter. The patient’s medical past included a mucinosa. Alopecia mucinosa was first reported two-year history of AML, which was in complete by Pinkus in 1957.1 That same year, -Falco remission four months prior to onset of the noted a relationship between alopecia mucinosa “white spots.” and mycosis fungoides and decided to categorize Figure 3 alopecia mucinosis into two types: a primary type with no relation to lymphoma, and a secondary type associated with lymphoma.2 Ten years later, in 1969, Emmerson and Coskey re-categorized the disease into three distinct entities.3 The first type has an acute presentation and is called benign primary follicular mucinosis (PFM). PFM is an idiopathic, benign condition Figure 1 presenting as pink papules or plaques confined to the head and neck region with periadnexal polyclonal infiltrates of lymphocytes. PFM affects children and young adults and tends to spontaneously regress in a few months to a year.3,4 The second type, known as cutaneous lymphoma-associated follicular mucinosis, is characterized by cutaneous manifestations of lymphoma such as mycosis fungoides and Figure 2 Figure 4 Sézary syndrome. This type is more widespread and chronic, affecting adults over 40 years of

Page 36 CASE REPORT: FOLLICULAR MUCINOSIS IN AN ADOLESCENT age with no signs of systemic disease.3,5 The distribution of the disease. Lesions confined to 12. Parker SR, Murad E. Follicular mucinosis: third type is associated with a more generalized the head and neck region are generally thought to Clinical, histologic, and molecular remission distribution of larger plaques, more elderly run a benign course, and lesions with a widespread with minocycline. J Am Acad Dermatol. 2010; patients, and an underlying systemic, malignant distribution are associated with a higher rate of 62(1):139-41. lymphoproliferative disorder.3 The most common malignancy. malignant associations are leukemias such as Our patient did have diffuse involvement; Correspondence: Ashvin Garlapati, Larkin Hodgkin’s disease, renal carcinoma, cutaneous however, the initial biopsy did not reveal 6 Community Hospital/NSU-COM, 7031 B-cell lymphoma, and lymphosarcoma. CTCL. The patient is doing well and seeing SW 62nd Ave., South Miami, FL 33143; improvement with narrowband UVB. Per the The etiology of follicular mucinosis is unknown; [email protected] however, cell-mediated immunity is believed to current recommendations, follow-up biopsies play a role in the pathogenesis. The majority of the will be performed in order to monitor for any lymphocytes in follicular mucinosis are T-helper malignant transformation. cells (CD4).7 It has been suggested that released from the T-lymphocytes stimulate the 8 References follicular keratinocytes to secrete mucin. Clonal 1. Pinkus H. Alopecia mucinosa; inflammatory T-cell receptor (TCR) gene rearrangement plaques with alopecia characterized by root-sheath is present in some cases of primary follicular mucinosis. Arch Dermatol. 1957;76(4):419-26. mucinosis.4 2. Alikhan A, Griffin J, Nguyen N, Davis D, Clonal TCR gene rearrangement in FM was Gibson L. Pediatric Follicular Mucinosis: found to be associated with CTCL in some Presentation, Histopathology, Molecular studies; however, other studies have debunked this Genetics, Treatment, and Outcomes over an 11- theory, and as of now TCR gene rearrangement Year Period at the Mayo Clinic. Pediatr Dermatol. studies are equivocal as a diagnostic tool. It has 2013;30(2):192-8. been shown that lesions confined to the head and neck region usually run a more benign 3. Bella-Navarro R, Martí-Fajardo N, Martín- course, while diffuse lesions are associated with a Hernández JM, Jordá-Cuevas E. Follicular higher predilection for malignancy. Alikhan et al. Mucinosis in Childhood: A Case Report and reported a retrospective study of 33 patients with Review of the Literature. Actas Dermosifiliogr. FM, where lesions confined to the head and neck 2012;103(4):335-6. had no incidence of CTCL. However, patients 4. Alonso de Celada RM, Feito Rodriguez M, with diffuse lesions had an increased association Noguera Morel L, Beato Merino MJ, De Lucas 2 with CTCL. Laguna R. Treatment of Primary Follicular On histology, mucin within the follicular Mucinosis with Imiquimod 5% Cream. Pediatr epithelium, acanthosis, mild follicular spongiosis, Dermatol. 2012 Sep 25. doi: 10.1111/j.1525- CD4 predominant lymphocytic inflammation, 1470.2012.01852.x. [Epub ahead of print] and CD2, CD3 and CD5 (+) perifollicular 5. Weir G, E, Fraga G, Aires D. Familial T-cell infiltrate with partial loss of CD7 are seen. follicular mucinosis: A case letter. J Am Acad Follicular mucin can be confirmed by positive Dermatol. 2012;67(6):291-2. colloidal iron staining.9 6. Cheng S, Leach I.H, Perkins W. A novel case of follicular mucinosis after autologous stem- Treatment cell transplantation for multiple myeloma. Clin There is no standard effective treatment for Dermatol. 2011;36(6):635-7. primary FM, and a wide variety of therapies have been described, such as topical and oral antibiotics, 7. Lancer HA, Bronstein BR, Nakagawa H, topical retinoids, isotretinoin, steroids (topical, Bhan AK, Mihm MC Jr. Follicular mucinosis: intralesional, oral), dapsone, methotrexate, a detailed morphologic and immunopathologic immunosuppressive drugs, nitrogen mustard, study. J Am Acad Dermatol. 1984;10(5):760–8. ultraviolet A light (UVA) therapy, and psoralen 8. Sumner WT, Grichnik JM, Shea CR, Moore with UVA (PUVA) treatment. The treatment of JO, Miller WS, Burton CS. Follicular mucinosis as secondary follicular mucinosis is aimed at curing a presenting sign of acute myeloblastic leukemia. the underlying malignancy.10 Case reports have J Am Acad Dermatol. 1998;38(5):803-5. shown the success of photodynamic therapy 9. Camp B, Horwitz S, Pulitzer MP. Adult T-cell (PDT), imiquimod, and minocycline.4,11,12 leukemia/lymphoma with follicular mucinosis: an unusual histopathological finding and a Conclusion commentary. J Cutan Pathol. 2012;39(9): 861–5. Follicular mucinosis in a younger population 10. Rupnik H, Podrumac B, Zgavec B, Lunder usually follows a benign and non-progressive T. Follicular mucinosis in a teenage girl. Acta course, while in an older population, it is usually Dermatoven. 2005;14(3):111-4. associated with cutaneous T-cell lymphoma. However, in cases of benign FM, long-term 11. Fernández-Guarino M, Castaño A.H, Carrillo follow-up with repeated biopsies is still R, Jaén P. Primary follicular mucinosis: excellent recommended, and a minimum period of five response to treatment with photodynamic therapy. years has been suggested.10 In addition, molecular J Eur Acad Dermatol Venereol. 2008;22(3):363– genetics studies are recommended in every 404. suspected patient.2 It is also important to note the GARLAPATI, PATEL, SKOPIT Page 37 Gianotti-Crosti Syndrome: A Case Presentation and Discussion

Travis Hamblin, DO,* Dustin Portella, BS,** Steven Grekin, DO, FAOCD***

*Dermatology Resident, 1st year, Oakwood Southshore Medical Center / MSUCOM, Trenton, MI **Medical Student, 4th year, Des Moines University College of Osteopathic Medicine, Des Moines, IA ***Program Director, Oakwood Southshore Medical Center / MSUCOM, Trenton, MI

Abstract Gianotti-Crosti syndrome, a disease occurring mainly in children, presents with an abrupt onset of symmetrically distributed papules or plaques localized to the extremities, face, and buttocks. It is thought to be a self-limited disease with an infectious etiology, often preceded by an upper respiratory infection. We present a case of an 11-year-old boy with an acute eruption of edematous monomorphic papules followed by complete resolution within six weeks, illustrating the classic presentation of this disease entity. Case Presentation An 11-year-old male presented to our office with an abrupt onset of “bumps” on his bilateral extremities. He reported that one week prior, he’d developed a single lesion on his right knee, followed the next day with numerous similar lesions on his bilateral extremities. They continued to increase in number. He denied pruritus or pain and reported they were completely asymptomatic. His mother stated that one week prior to the onset of the lesions he had complained of a sore throat and had developed a fever but required no medication as it quickly resolved on its own. They denied similar lesions in other family members. The patient was current on all vaccinations including hepatitis B, and was taking no medications. Physical examination revealed a well-nourished patient with multiple skin-colored to pink, edematous papules symmetrically distributed on the patient’s elbows, knees and ankles with sparing of the face and trunk. Lymphadenopathy was noted in the patient’s axillae.

The diagnosis of Gianotti-Crosti was discussed are spared, but the presence of a few truncal with the patient and his mother. Due to the lesions does not exclude diagnosis.2 Although benign nature of the disease and the patient’s commonly asymptomatic, some patients may asymptomatic presentation, an observation-only report pruritus or low-grade fever or present with approach was decided upon, as most lesions axillary or inguinal lymphadenopathy. When generally resolve in three to four weeks. The associated with HBV infection, patients may also patient was seen back in the clinic six weeks later demonstrate hepatomegaly. with full resolution of the lesions noted. The mechanism whereby the GCS eruption develops is not completely understood. Patients Discussion may report a preceding upper respiratory infection Gianotti-Crosti syndrome is an eruption with mild constitutional symptoms. There are primarily seen in children between the ages of six multiple case reports describing an association months and 14 years, with a mean age of 2 years, with a host of different viruses, vaccinations, and 1 although it has been seen in adults. The typical bacteria (Table 1). presentation is an abrupt eruption of flesh- colored or pink-red monomorphic papules or papulovesicles that are symmetrically distributed on the extensor surface of the extremities, face, and buttocks. The trunk and mucus membranes

Page 38 GIANOTTI-CROSTI SYNDROME: A CASE PRESENTATION AND DISCUSSION Table 1. Viruses, Vaccinations, and Bacteria Reported to be Associated with Gianotti-Crosti p. 1353-4. 9-16 Syndrome 8. Zawar V, Chuh A. Efficacy of ribavirin in a Viruses Vaccinations Bacteria case of long lasting and disabling Gianotti- Crosti syndrome. J Dermatol Case Rep. 2008 Hepatitis A Hepatitis A Bartonella henselae Dec;2(4):63-6. Hepatitis B Hepatitis B Mycoplasma pneumonia Epstein-Barr virus Influenza B-hemolytic streptococci 9. Sagi EF, Linder N, Shouval D. Papular Oral polio Borrelia burgdorferi acrodermatitis of childhood associated with Coxsackievirus -- hepatitis A virus infection. Pediatr Dermatol. 1985 Nov;3(1):31-3. HIV Rotavirus 10. Zawar V, Chuh A. Gianotti-Crosti syndrome Poxvirus in India is not associated with hepatitis B infection. Dermatol. 2004;208(1):87. Respiratory syncytial virus 11. Hergueta Lendínez R, Pozo García L, Alejo Mumps García A, Romero Cachza J, González Hachero Parainfluenza 2 J. Gianotti-Crosti syndrome due to a mixed infection produced by the mumps virus and the Worldwide, HBV and EBV are the most patient. For most patients and their parents, 3 parainfluenza virus type 2. An Esp Pediatr. 1996 commonly associated viruses. With widespread reassurance is all that is needed. If the patient Jan;44(1):65-6. HBV vaccination in developed countries, EBV complains of pruritus, supportive treatment has become the most commonly recognized in the form of oral antihistamines and topical 12. Sigmon JR, Venkatesh S, Lesher JL. Gianotti- associated virus. Ricci et al. described an antipruritics may be used, although these will not Crosti syndrome associated with hepatitis A and increased incidence of GCS in patients with shorten the duration of the eruption.3 Topical influenza vaccination. J Drugs Dermatol. 2012 a history of atopy, suggesting that preexisting corticosteroids are often of little benefit. In one Feb;11(2):260-1. immune dysregulation may play a factor in case of particularly disabling and long-lasting 13. Karakaş M, Durdu M, Tuncer I, Cevlik F. developing GCS following a viral infection or GCS, spontaneous resolution was observed after Gianotti-Crosti syndrome in a child following 4 8 immunization. Despite a possible association the initiation of ribavirin therapy. hepatitis vaccination. J Dermatol. 2007 between certain and GCS, a history In summary, GCS is a benign, self-limited Feb;34(2):117-20. of GCS should not serve as a contraindication 3 eruption of uncertain pathogenesis that is 14. Erkek E, Senturk GB, Ozkaya O, Bükülmez to receiving future vaccinations. Despite many commonly associated with a preceding viral G. Gianotti-Crosti syndrome preceded by oral potential causative agents, no significant clinical infection or immunization. It is most commonly polio and followed by varicella infection. or histological difference has been identified 1,3 observed in the pediatric population, and Pediatr Dermatol. 2001;18(6):516-8. regardless of the suspected causative agent. although its appearance may alarm parents, no 15. Silveira Cancela M, Valdés Tascón F, Pita The histopathological findings in GCS treatment is usually required. Carretero J, Montes Fontao M, Rico Bouza M. are relatively non-specific but may include Neonatal papular acrodermatitis (Gianotti- acanthosis accompanied by diffuse spongiosis and References Crosti) and Bartonella henselae infection. An vesicles. Langerhans cells are the dominant cell 1. Caputo R, Gelmetti C, Ermacora E, Gianni Esp Pediatr. 2000 Mar;52(3):299-300. appearing in the vesicle. There is a non-vesicular E, Silvestri A. Gianotti-Crosti syndrome: A variant in which the epidermis demonstrates retrospective analysis of 308 cases. J Am Acad 16. Draelos ZK, Hansen RC, James WD. modest acanthosis with focal parakeratosis and Dermatol. 1992 Feb;26(2):207-10. Gianotti-Crosti syndrome associated with spongiosis.3 One may also see a lymphohistiocytic infections other than hepatitis B. J Am Med perivascular infiltrate in the dermis with dilation 2. Chuh AAT. Truncal lesions do not exclude a Assoc. 1986 Nov 7;256(17):2386-8. of the dermal capillaries. A lichenoid pattern diagnosis of Gianotti-Crosti syndrome. Australas has also been described in one case of GCS.5 J Dermatol. 2003 Aug;44(3):215-6. When immunohistochemical stains and electron 3. Brandt O, Abeck D, Gianotti R, Burgdorf W. microscopy have been performed, they have Gianotti-Crosti syndrome. J Am Acad Dermatol. Correspondence: Travis Hamblin, Oakwood failed to identify viral antigens or particles in skin 2006 Jan;54(1):136-45. Southshore Medical Center, 5450 Fort St., biopsy specimens.6 4. Ricci G, Patrizi A, Neri I, Specchia F, Tosti Trenton, MI 48183; [email protected] GCS is self-limited, and spontaneous resolution G, Masi M. Gianotti-Crosti syndrome and usually occurs within three to four weeks although allergic background. Acta Derm Venereol. it may occasionally last up to eight weeks. In 2003;83(3):202-5. consideration of a differential diagnosis, one may 5. Stefanato CM, Goldberg LJ, Andersen WK, initially consider a viral , lichenoid drug Bhawan J. Gianotti-Crosti syndrome presenting eruption, , scabies, papular urticaria, as lichenoid dermatitis. Am J Dermatopathol. and . The clinician 2000 Apr;22(2):162-5. should conduct a thorough history to narrow the differential and screen for risk factors of serious 6. Smith KJ, Skelton H. Histopathologic features such as HBV. If clinically indicated, seen in Gianotti-Crosti syndrome secondary to laboratory tests for hepatitis or specific viral Epstein-Barr virus. J Am Acad Dermatol. 2000 agents may be obtained.7 With a benign physical Dec;43(6):1076-9. exam and the absence of serious risk factors, an 7. Mancini AJ, Shani-Adir A. Gianotti-Crosti asymptomatic patient does not require laboratory syndrome In: Bolognia JL, Jorizzo JL, Schaffer workup or treatment, as was the case with our JV, editors. Dermatology. 3rd ed. Elsevier; 2012; HAMBLIN, PORTELLA, GREKIN Page 39 Pyoderma Gangrenosum: A Case Report and Proposed Evidence-based Guidelines for Working-up the Condition

Steven Brooks, DO, MS,* Suzanne Sirota Rozenberg, DO, FAOCD**

*Dermatology Resident, 2nd Year, St. John’s Episcopal Hospital-Dermatology Residency Program, Far Rockaway, NY **Program Director, St. John’s Episcopal Hospital-Dermatology Residency Program, Far Rockaway, NY

Abstract Pyoderma gangrenosum (PG) is a relatively uncommon inflammatory skin disease. General incidence has been estimated at between 3 and 10 persons per million per year.1 It can initially present to any and have many clinical variations that make a timely diagnosis very difficult for the non-dermatologist. A delay in diagnosis can lead to severe scars, disfigurement, increased morbidity and mortality. Most cases are associated with an underlying systemic condition, such as inflammatory bowel disease (IBD), arthritis, and hematological malignancies. A skin biopsy is needed to exclude other skin conditions. First-line therapy is long-term immunosuppression, usually with high-dose prednisone. Evidence-based work-up guidelines are lacking in the current literature. This article discusses an interesting case presentation of pyoderma gangrenosum, briefly reviews the condition, and proposes evidenced-based guidelines in the work-up of PG. Case Report The patient was started on a slow prednisone A 44-year-old African American male presented taper beginning at 60 mg daily. Local wound to the dermatology clinic with a complaint of care instructions were given along with a “painful leg ulcer” present for several months. esomeprazole 40 mg daily for gastro-intestinal He stated the ulcer began as several small, red prophylaxis. The patient was subsequently bumps that progressively grew larger over several referred to gastroenterology to rule out recurrence days. The patient had a past medical history of of ulcerative colitis. He did extremely well over ulcerative colitis, status post partial colectomy and the next four months of follow-up, with near- colostomy in 2001, and had skin graft surgery over complete clearing of the ulceration (see Figures his right lateral leg in 2008. Physical examination 3-5). Soon after, the patient was lost to follow-up. was significant for a 6 cm by 4 cm erythematous, friable ulceration with rolled edges located over Pyoderma Gangrenosum his right lateral leg (Figure 1). Although the etiology of PG remains unclear, the current literature suggests there is a dysregulation of the immune system that leads to altered .2 Fifty percent of affected patients have an associated systemic condition, most commonly inflammatory bowel disease (IBD), followed by arthritis, hematologic malignancy, and paraproteinemia.3 It classically Figure 2. Mixed cellular inflammation with presents as an acute, painful ulceration with predominant neutrophils in the superficial and distinct rolled edges, typically on the lower deep dermis, vascular necrosis, and erythrocyte extremities, in adults 40 to 60 years old. Both extravasation. genders are affected; however, there is a slight female predominance. Many lesions begin at the A 5 mm punch biopsy was obtained, and the sites of previous trauma (pathergy). Patients often pathology results confirmed the diagnosis of complain of concomitant systemic symptoms PG, showing mixed cellular inflammation with such as fever, malaise, , and myalgia. predominant neutrophils in the superficial and PG can be subdivided into four distinct types: Figure 1. Initial presentation. deep dermis, vascular necrosis, and erythrocyte extravasation (Figure 2). classic (ulcerative), pustular, bullous, and

Figure 3. One month. Figure 4. Two months. Figure 5. Three months.

Page 40 PYODERMA GANGRENOSUM: A CASE REPORT AND PROPOSED EVIDENCE-BASED GUIDELINES FOR WORKING-UP THE CONDITION vegetative. The ulcerative and pustular types function studies.13 The cost-benefit analysis has malignancies, especially when the upper limbs or are usually more associated with IBD, while the yet to be studied, and the necessity of ordering a face is affected.15,16 Therefore, the initial work-up bullous types are more suggestive (up to 70% of complete set of laboratories when an associated is simply a CBC. cases) of an underlying hematologic malignancy. disease is already known remains unclear. Blindly The vegetative subtype, a superficial variant of the The differential diagnosis includes Sweet’s ordering dozens of lab tests in the wrong setting disease, seems to be the least-aggressive form of syndrome, traumatic ulceration, squamous cell can be detrimental to the patient’s care as well as PG. This type is usually not associated with any carcinoma, and Wegener’s granulomatosis. A drive up health care costs. underlying conditions, and patients are otherwise diagnosis of PG is generally made based on 15,16 4 healthy. These patients do not need an initial clinical and histopathologic findings. Histology Proposed Guidelines for work-up, and the lesions can be treated with will show massive dermal edema with epidermal local therapeutics. If systemic symptoms (fever, neutrophilic abscesses at the violaceous Initial Work-up of PG , and weight loss) are present, then an Our proposed guidelines are based on collective undermined border. Other findings include: initial work-up is warranted. mixed cellular infiltrates with predominant data obtained from numerous literature reviews neutrophils in the superficial and deep dermis; on PG. Once the diagnosis of PG is confirmed by leukocytoclastic vasculitis; vascular necrosis; and biopsy, the correct subtype should be established Conclusion erythrocyte extravasation. using clinical and histopathologic findings. A PG remains an intriguing inflammatory thorough history and should be dermatosis. Our proposed guidelines are intended Management of PG depends on the severity 5 ascertained. Then the provided algorithm (Figure to help the medical professional in the initial of disease and the underlying cause. First- 6) can be used as a guide. work-up of PG. The algorithm was developed line therapy for PG is systemic treatment with based on established associations between specific The classic or ulcerative subtype is the most high-dose corticosteroids alone or high-dose subtypes of PG and their respective conditions. common and often presents on the lower legs. corticosteroids with cyclosporine. Alternative Abnormalities in the initial work-up will prompt Most of these cases are associated with IBD, therapeutic options include , further studies and consultations. More research followed by seropositive or seronegative arthritis, mycophenolate mofetil, tacrolimus, thalidomide, is needed to validate and perfect our algorithm. ustekinumab, dapsone and plasmapheresis.6-9 followed by hematological malignancies. Patients usually respond well to high-dose Therefore, the initial work-up is tailored to systemic corticosteroids with up to 50% address these specific conditions. A complete References improvement in size of lesions within one month blood count (CBC) with differential would be 1. DermNet NZ [Internet]. Pyoderma of treatment. When managing a patient with essential to look for leukocytosis and anemia gangrenosum; 1998 [updated 8 June 2013, an established history of PG, it is important associated with IBD. Sending the patient for cited 30 Nov 2013]. Available from: http:// to discuss and avoid any unnecessary surgical colonoscopy is prudent as well. The CBC would www.dermnetnz.org/reactions/pyoderma- manipulation to help prevent new lesions from also show blood dyscrasias in the setting of gangrenosum.html. developing. The prognosis of PG is generally favorable. However, the disease may recur, and Figure 6 residual scarring is common.

Discussion Pyoderma gangrenosum is an interesting skin disease due to its known association with IBD and its propensity to develop at a site of skin trauma. Although the patient described in this case report meets the textbook description of PG, it is important to note that this may not always be the case. Besides IBD, PG has many other systemic associations, and while less common, they are equally important to rule out. Some of those associations include leukemia, myeloma, monoclonal gammopathy, polycythemia, polyarteritis nodosa, subcorneal pustular dermatosis, cryoglobulinemia and hepatitis C infection.10-12 Unfortunately, there hematological malignancies. Rheumatoid factor is a lack of consensus in the current literature to 2. Weenig RH, Bruce AJ, McEvoy MT, Gibson (RF) and erythrocyte sedimentation rate (ESR) the approach of working up PG, especially when LE, Davis MD. Neutrophilic dermatosis of the would be useful in establishing seropositive/ there is no clear underlying cause. This may lead hands: four new cases and review of the literature. seronegative arthritis. Although there are to an incorrect or untimely diagnosis and increase Int J Dermatol. 2004;43:95–102. other systemic conditions associated with the morbidity and mortality. A proposed solution classic subtype, they are extremely rare and are 3. Fernández A, Velasco A, Prieto V, Canueto J, is the development of evidence-based work-up mentioned sporadically in the current literature; Alvarez A, Rodriguez A. Response to infliximab guidelines. therefore they should not be initially addressed. in atypical pyoderma gangrenosum associated Currently, authors recommend numerous with ulcerative colitis. Am J Gastroenterol. The pustular form of PG is the rarest subtype, laboratory investigations to aid in identifying any 2008;103: 951-2. usually presenting on the trunk or extensor possible associated underlying diseases as well as surfaces of limbs. Since most of the pustular 4. Su WP, Davis MD, Weenig RH, Powell to rule out other conditions that mimic PG. These cases are associated with active IBD (specifically FC, Perry HO. Pyoderma gangrenosum: laboratory studies include: complete blood count, ulcerative colitis), initial work-up should include clinicopathologic correlation and proposed erythrocyte sedimentation rate, blood chemistry, a CBC and colonoscopy.14,15 diagnostic criteria. Int J Dermatol. 2004;43:790– coagulation profile (including antiphospholipid- 800. antibody), antineutrophil cytoplasmic antibodies, The bullous subtype of PG is also a relatively cryoglobulins, protein electrophoresis, chest rare subtype, and it has the worst prognosis. 5. Guenova E, Teske A, Fehrenbacher B, et , colonoscopy, and venous and arterial- This is most often associated with hematologic al. Interleukin 23 expression in pyoderma BROOKS, ROZENBERG Page 41 gangrenosum and targeted therapy with ustekinumab. Arch Dermatol. 2011 Oct;147(10):1203-5. A Basal Cell Carcinoma Simulator: 6. Eaton PA, Callen JP. Mycophenolate mofetil as therapy for pyoderma gangrenosum. Arch Case Report and Review of the Clinical, Dermatol. 2009 Jul;145(7):781-5. Dermoscopic and Reflectance Confocal 7. Kaur MR, Lewis HM. Severe recalcitrant pyoderma gangrenosum treated with infliximab. Microscopy Features of Br J Dermatol. 2005 Sep;153(3):689-91. 8. Mooij JE, van Rappard DC, Mekkes JR. Six Kimberly Hull, DO,* Theresa Cao, DO, ** Angela Combs, DO, *** Tracy Favreau, DO, **** Harold Rabinovitz, MD, ***** patients with pyoderma gangrenosum successfully treated with infliximab. Int J Dermatol. 2013 * Dermatology Resident, 1st year, Broward Health Medical Center/NSU-COM, Fort Lauderdale, Florida ** Mohs and Procedural Dermatology Fellow, Long Island Skin Cancer and Dermatologic Surgery, Smithtown, New York Nov;52(11):1418-20 *** Interim Program Director, Dermatology Residency, Broward Health Medical Center/NSU-COM, Fort Lauderdale, Florida 9. Ahmad K, Ramsay B. Pyoderma gangrenosum **** Associate Professor, Broward Health Medical Center/NSU-COM, Fort Lauderdale, Florida associated with subcorneal pustular dermatosis ***** Voluntary Clinical Professor, Skin and Cancer Associates, Plantation, Florida and IgA myeloma. Clin Exp Dermatol. 2009 Jan;34(1):46-8. Abstract 10. Branagan NM, Higgins SP, Halim SA, Le Sebaceous hyperplasia is a common mimicker of basal-cell carcinoma, particularly when it occurs on uncommon TH. Systemic polyarteritis nodosa mimicking locations of the body. Dermoscopy and reflectance confocal microscopy (RCM) help to differentiate between pyoderma gangrenosum in a rare association these different entities. with small lymphocytic leukemia/chronic lymphocytic leukemia. Clin Exp Dermatol. 2009 Case Report Figure3 Jul;34(5):e127-9. A 52-year-old Caucasian male with a past medical history of non-melanomatous skin 11. Namazi MR, Kerchner KR, Pichardo RO. cancer presented for a routine skin cancer Essential type II mixed cryoglobulinemia screening. He was otherwise healthy and took causing pyoderma gangrenosum-like ulcers. no medications regularly. On full-body skin ScientificWorldJournal. 2008;8:228. examination, he was found to have a 2 mm, skin- 12. Reichrath J, Bens G, Bonowitz A, Tilgen colored papule on his left mid flank (Figure 1). W. Treatment recommendations for pyoderma The patient was unaware of this lesion and denied gangrenosum: An evidence-based review of the any symptomatology. literature based on more than 350 patients. J Am Acad Dermatol. 2005;53(2):273–83. 13. Fenske NA, Gern JE, Pierce D, Vasey FB. Vesiculopustular eruption of ulcerative colitis. Figure 4 Arch Dermatol. 1983;119:664-9. 14. Powell FC, Collins S. Pyoderma gangrenosum. Clin Dermatol. 2000;18:283-93. 15. Hay CR, Messenger AG, Cotton DW, Bleehen SS, Winfield DA. Atypical bullous pyoderma gangrenosum associated with myeloid malignancies. J Clin Pathol. 1987;40:387-92. Figure 1. Clinical close-up, left mid flank 16. Wilson-Jones E, Winkelmann RK. Superficial granulomatous pyoderma: a localized vegetative On dermoscopy, the lesion lacked a pigmented form of pyoderma gangrenosum. J Am Acad network and displayed blue globules centrally as well as arborizing blood vessels suggestive of Dermatol. 1988;18:511-21. Figure 3. RCM images of sebaceous basal cell carcinoma. Conversely, there also was hyperplasia show collections of sebocytes an area of faint yellow coloration suggestive of and crown vessels as seen in sebaceous Correspondence: Steven J. Brooks, St. John’s hyperplasia. Episcopal Hospital, 327 Beach 19th St. Far Rockaway, NY 11691; [email protected] Figure 4. RCM images of pigmented BCC show peripheral palisading of tumor islands and spindle-shaped structures at the periphery of tumor islands (solid arrow), along with bright round cells within tumor islands (dashed arrow).

sebaceous differentiation. Clinical examination and dermoscopy did not yield a definitive diagnosis, and therefore reflectance confocal microscopy was performed. Figure 2. A dermoscopic image of the left mid- flank lesion demonstrates central blue globules, Reflectance confocal microscopy (RCM) allows peripheral yellow lobules and arborizing vessels for the in vivo evaluation of skin lesions. RCM suggestive of sebaceous differentiation. was performed using the Lucid VivaScope 1500.

Page 42 A BASAL CELL CARCINOMA SIMULATOR: CASE REPORT AND REVIEW OF THE CLINICAL, DERMOSCOPIC AND REFLECTANCE CONFOCAL MICROSCOPY FEATURES OF SEBACEOUS HYPERPLASIA This unit utilizes a diode laser, which emits a portion of the pilosebaceous unit surrounding Am Acad Dermatol. 2006 Apr;54(4):638-43. wavelength of 830 nm, allowing the visualization a follicular infundibulum. Sebaceous glands 10. Segura S, et al. Dendritic cells in pigmented of structures beneath the skin surface to can less frequently open directly to the skin basal cell carcinoma: a relevant finding by approximately 200 mm in depth. In sebaceous- surface, particularly in areas with modified skin reflectance-mode confocal microscopy. Arch gland hyperplasia, key features normally found such as on the lips and buccal Dermatol. 2007 Jul;143(7):883-6. on RCM include: 1) a dilated central follicular mucosa, Montgomery glands within the areolae, infundibulum; 2) clusters of round cells with Meibomian glands within the eyelids, and Tyson bright speckled cytoplasm and dark round nuclei glands in the clitoris and glans penis. Correspondence: Kimberly Hull, 3200 S corresponding to sebaceous lobules; and 3) vessels The number of sebaceous glands remains relatively University Drive, Fort Lauderdale, FL, 33314. around the periphery of the lobular structures, stable throughout life. Their size and activity can Phone number: (954)262-4100, fax number: which correlate with crown vessels described in 1-3 be altered by androgenic influence and age. High (954)262-3981. dermoscopic features of sebaceous hyperplasia. levels of circulating androgens are present during In comparison, the RCM features seen in puberty, resulting in increased sebaceous-gland pigmented basal cell carcinoma include: 1) tumor activity and size. With increasing age, androgen islands or silhouettes; 2) clefting around tumor levels begin to decline, leading to decreased islands; 3) presence of dendritic cells suggestive holocrine of sebocytes. Sebaceous- of melanocytes; 4) presence of bright round cells gland hyperplasia occurs as a result of decreased suggestive of melanophages; and 5) canalicular or sebocyte turnover and therefore an enlargement linear vessels.8,9 of the sebaceous-gland subunit with decreased sebum secretion. Based upon our findings clinically, dermoscopically and on reflectance confocal microscopy, our final diagnosis was sebaceous-gland hyperplasia. Conclusion There have been no reported cases of solitary A deep shave biopsy was performed for definitive sebaceous hyperplasia of the back in the diagnosis. Histopathology showed a collection literature to date. When an isolated lesion of of sebaceous lobules with normal morphology sebaceous hyperplasia occurs outside of the face, it can easily be mistaken for basal-cell carcinoma, prompting biopsy. With the use of dermoscopy and reflectance confocal microscopy, diagnostic accuracy may be improved.

References 1. Aghassi D, et al. Elucidating the pulsed-dye laser treatment of sebaceous hyperplasia in vivo with real-time confocal scanning laser microscopy. J Am Acad Dermatol. 2000;43:49-53. 2. Propperova I, Langley RG. Reflectance- mode confocal microscopy for the diagnosis of Figure 5. Hematoxylin and eosin, 40x sebaceous hyperplasia in vivo. Arch Dermatol. magnification thereby confirming the diagnosis 2007;143(1):134. of sebaceous hyperplasia 3. Gonzalez S, et al. Confocal imaging of within the papillary dermis. No basaloid sebaceous gland hyperplasia in vivo to assess proliferation was identified, thereby confirming efficacy and mechanism of pulsed dye laser the diagnosis of sebaceous hyperplasia. treatment. Lasers Surg Med. 1999;25:8-12 4. Belinchon I, et al. Areolar sebaceous Discussion hyperplasia: a case report. Cutis. 1996;58(1):63- Sebaceous hyperplasia is a common, benign 4. enlargement of sebaceous glands surrounding a 5. Ena P, Origa D, Massarelli G. Sebaceous follicular infundibulum. These lesions clinically hyperplasia of the foreskin. Clin Exp Dermatol. present as asymptomatic, yellowish, occasionally 2009;34(3):372-4. telangiectatic papules with a central depression and are most often found on the face. There 6. Al-Daraji WI, Wagner B, Ali RB. Sebaceous have been few reported cases of solitary tumors hyperplasia of the vulva: a clinicopathological of sebaceous hyperplasia occurring on the areola, case report with a review of the literature. J Clin genitals, and chest.4-7 Additionally, multiple Pathol. 2007;60(7):835-7. tumors with sebaceous hyperplasia can be seen 7. Hogan DJ. Sebaceous hyperplasia of the chest. in transplant patients on immunosuppressive Int J Dermatol. 1991 Apr;30(4):306 therapy with cyclosporine, as well as in certain 8. González, S., Gill, M., & Halpern, A. C. (eds.). genodermatoses such as Muir-Torre syndrome Reflectance Confocal Microscopy of Cutaneous and .8 Tumors: An Atlas with Clinical, Dermoscopic, Sebaceous glands are found throughout all and Histological Correlations. London: Informa surfaces of the skin except for the palms and Healthcare; 2008. soles. The largest number of sebaceous glands 9. Agero AL, et al. Reflectance confocal is found on the face, chest and back. Sebaceous microscopy of pigmented basal cell carcinoma. J glands exhibit holocrine secretion and exist as a

HULL, CAO, COMBS, FAVREAU, RABINOVITZ Page 43 Hypopigmented Mycosis Fungoides: Case Report and Review

Holly Kanavy, DO,* Angela Macri, BS,** Harleen Sidhu, MD,*** Craig Austin, MD****

* Dermatology Resident, 2nd year, St. Barnabas Hospital, Bronx, NY ** Medical Student, 4th year, Nova Southeastern University, Fort Lauderdale, FL *** Dermatopathology Fellow, Mount Sinai School of Medicine, New York, NY **** Dermatopathologist, St. Barnabas Hospital, Bronx, NY

Abstract Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma (CTCL). It is characterized by a malignant clone of CD4+ helper T-cells that homes to the skin. Several variants of MF have been described, including a hypopigmented subtype. Herein, we describe a case of hypopigmented MF in a 13-year-old Hispanic boy and review the current literature on the disease. We discuss some of the important challenges in diagnosis of the disease, with a focus on histopathologic findings and their clinical correlations. Introduction antifungal agents and completed a course of (Figures 2a [10x], 2b [40x]). Laboratory studies Mycosis fungoides (MF) is a cutaneous T-cell griseofulvin with no improvement. Review were performed, including a complete blood lymphoma (CTCL) involving a malignant clone of systems was positive for pruritus only. The count with differential, chemistry panel, and liver of CD4+ helper T-cells that homes to the skin. patient’s past medical history included asthma, function tests, all of which were within normal The majority of cases presents in the classical controlled with an albuterol inhaler, and seizure range. Treatment with narrow-band ultraviolet form, referred to as Alibert-Bazin disease, which disorder, stable without medication. His family light therapy has resulted in significant clearing. evolves clinically through three stages: patch, and social histories were non-contributory. He plaque and tumor.1 MF has been described was born in the United States, had no history of Epidemiology to present in several other forms as well, recent travel, and had no pets. Mycosis fungoides is the most common type of including hypopigmented, hyperpigmented, Physical examination revealed widespread, CTCL, representing nearly 50% of all primary erythrodermic, ichthyosiform, pityriasis hypopigmented, reticular patches with slight cutaneous lymphomas, and has an incidence rate 1,3 lichenoides-like, granulomatous, folliculotropic, scale affecting >75% of his body surface area of 4.5 per 1 million persons. It occurs most bullous, palmoplantar, pagetoid reticulosis, (Figures 1a,b,c). commonly in adults aged 50 to 60 years old, but 2 and granulomatous slack skin.2 This paper will can also be seen in children and young adults. Sensation in the affected areas was intact. No 2 specifically review hypopigmented mycosis The male-to-female ratio is approximately 2:1. lymphadenopathy or hepatosplenomegaly was fungoides and discuss some of the challenges Hypopigmented mycosis fungoides (HMF) appreciated. A 4 mm punch biopsy was obtained 4 surrounding diagnosis of the disease. was first described by Ryan et al. in 1973. It from the right posterior shoulder. On histological is an uncommon disease, but it may be under- examination, the dermis contained a dense reported due to the frequent delay in diagnosis lichenoid and superficial perivascular infiltrate Case and lack of recognition. It has a predilection A 13-year-old Hispanic male presented to our of lymphocytes with mild nuclear atypia, and for dark-skinned children of African American, office complaining of itchy white spots all over foci of exocytosis into the epidermis. Pigment West-Indian, and Asian origin, but has also been his body for seven years. He had previously incontinence was also seen, supporting the 5 reported in Caucasians. The average age of been treated with several topical steroids and diagnosis of hypopigmented mycosis fungoides onset of HMF is 29 years old, in comparison to

Figure 1a Figure 1b Figure 1c

Page 44 HYPOPIGMENTED MYCOSIS FUNGOIDES: CASE REPORT AND REVIEW profile evidenced by an increase in Diagnosis is often delayed due to the interferon-gamma and interleukins 2 and 12 in asymptomatic nature of most lesions and because 11 the skin. Histopathologically, both CD4+ and of the many similarities to other inflammatory 9 CD8+ T-cells are present. In contrast, late MF diseases.21 Histologic, immunophenotypic, has been shown to have more of a TH2 response and T-cell receptor (TCR) gene rearrangement with an increase in interleukins 4, 5, 10, and 13 studies are not entirely sensitive or specific and an increased number of CD4+ T-cells.11 It for MF, and many of the findings can also be has been suggested that the progression of MF demonstrated in inflammatory skin disorders, may be due in part to the loss of the CD8+ further complicating the diagnosis.21 There T-cells, which are known to mount an anti-tumor 9 is also poor histopathologic inter- and intra- response. Interleukins 15 and 16 and TH17 22 Figure 2a cytokines such as interleukins 17A, 21, and 22 observer agreement. 9 may also be expressed in MF. While classic MF Because of the heterogeneity in the diagnostic is characterized as having mostly CD4+ T-cells, findings of early MF, it is important to incorporate hypopigmented MF has an immunophenotype 12,13 clinical and diagnostic studies. Physical consisting of mostly CD8+ T-cells. The examination should evaluate total percentage of predominantly CD8+ T-cell immunophenotype body surface area involved and include checking in HMF may offer an important anti-tumor for lymphadenopathy and hepatosplenomegaly. response and possibly contribute to its indolent course. One punch biopsy should be taken for H&E and T-cell markers, and one shave biopsy for There are several mechanisms speculated to be T-cell receptor rearrangement studies.7 Multiple involved in the pathogenesis of hypomelanosis biopsies should be taken from different sites in HMF. Three mechanisms include atypical on the body, with topical treatments avoided mycosis cells causing abnormal melanogenesis, Figure 2b two to four weeks prior to avoid interference defects in melanosome transfer to keratinocytes, 21 and non-specific inflammation causing damage with the interpretation. Blood tests should 14,15 include a complete blood count with differential, the average age of onset of classical MF, which to melanocytes from cytotoxic CD8+ T-cells. chemistry panel, lactate dehydrogenase (LDH), has a mean of 63 years. Mycosis fungoides onset One other mechanism that may be involved in liver function tests, a blood TCR gene analysis in childhood is rare, representing 0.5% to 2.3% the hypomelanosis of HMF is the cytotoxic effect 6 to compare with tissue biopsies, and a Sézary of all MF patients. HMF represents up to 24% of CD8+ T-cells on the CD117 receptor. CD117 is a receptor on melanocytes that binds with cell count and/or flow cytometry to analyze any of childhood MF patients,and it displays a male 23 5 stem-cell factor to maintain melanocytes within abnormal lymphocytes. Pope et al. suggest predominance, similar to adult-onset disease. 16 the epidermis. Studies have found that there is assessing serology for EBV, HTLV-1 and 2, and 16 a decrease of CD117 in both vitiligo and HMF. HIV. 7 A chest X-ray should be taken for T1-2 Etiology and Pathogenesis N0 B0 patients with limited skin involvement The etiology of MF is unknown. Persistent and no organ-specific complaints, while a CT- antigeniºc stimulation has been proposed as Clinical Manifestations HMF typically presents with asymptomatic, scan of the chest, abdomen, and pelvis should an initial event in the disease, as MF has been hypopigmented macules, patches, and/or plaques be completed for all other groups.23 A lymph observed to be a disease of mature CD4+ memory distributed on the trunk and extremities, similar cells, but no specific antigen has been identified. node biopsy should be completed in lymph nodes to the areas of classic MF.2 It can occur as a sole Infectious agents have been implicated, including greater than 1.5 cm or if they are firm, irregular, manifestation or in combination with classic MF 23 human T-cell lymphotropic virus (HTLV)-1, clustered, or fixed. lesions such as erythematous patches, plaques, Epstein-Barr virus, and HIV; however, evidence or tumors.2 HMF may evolve to include the The common histologic criteria for diagnosing is lacking to support such associations.7 MF may peripheral blood, lymph nodes, and internal MF includes a lichenoid lymphoid infiltrate with be viewed as a disease of immune deregulation, organs.2 A differential diagnosis to consider lining up of atypical lymphoid cells at the DEJ; since tumor progression is associated with in HMF patients includes , epidermotropism (movement of lymphocytes decreased antigen-specific T-cell responses and , tinea versicolor, vitiligo, post- to the epidermis) with little spongiosis; Pautrier impaired cell-mediated cytotoxicity.8 inflammatory hypopigmentation, progressive microabscesses (collections of T-cells around The pathogenesis of MF is not completely macular hypomelanosis, lichen sclerosis et Langerhans cells); wiry collagen in the papillary understood but is believed to initially involve the atrophicus, pityriasis lichenoides chronica, dermis; and mild epidermal hyperplasia with presentation of an antigen to Langerhans cells morphea, sarcoidosis, syphilis, leprosy, and moderate lymphocytic exocytosis.16,24 The 2 in the skin. Langerhans cells carry the antigen onchocerciasis. lymphocytes in the epidermis are usually more to peripheral lymph nodes, where it is presented Chronic inflammatory diseases resistant to atypical (small-to-medium sized with convoluted to CD4+ helper T-cells. This presentation treatment should be suspicious for MF, and hyperchromatic nuclei and inconspicuous converts the helper T-cells into cutaneous T-cell 24 several reports of chronic inflammatory diseases nucleoli) than the ones in the dermis. Haloed lymphoma cells (CTCLs). These cells express 25 that have transformed into CTCL are reported. lymphocytes may also be present. cutaneous lymphoid antigen (CLA) on their Some reports suggest an increased risk of CTCL surface, which binds to E-selectin (CD26E) 17,18 These findings are not consistently observed, 9 in patients with atopic dermatitisand psoriasis. located on vascular endothelial cells in skin. Several cases have also been described in which however. A study by Massone et al. showed that Chemokines involved in the homing of CTCLs chronic inflammatory lesions, including those only 19% of MF cases demonstrated Pautrier to skin include CCR4, CXCR3, CXCR4, and microabscesses; atypical lymphocytes were 9,10 from contact dermatitis, inoculation injury, rhus CCR10. Once in the epidermis and dermis, dermatitis, and a chronic draining hematoma, present in only 9% of cases; and epidermotropism CTCLs have the potential to become chronically eventuated into MF.19,20 was completely missing in 4% of cases.26 In early activated, producing a dominant clone that may MF, the histology is often non-specific, showing ultimately expand, escape the surveillance of the a mild perivascular infiltrate in the upper dermis immune system, and progress beyond the skin.9 Diagnosis Diagnosis of early MF can be quite challenging. with no atypical lymphocytes or epidermotropism, Early MF expresses a predominantly TH1 just as in many inflammatory diseases.2,21 When KANAVY, MACRI, SIDHU, AUSTIN Page 45 lesions have evolved into the plaque stage, a defines CTLD as chronic conditions with: 1) narrowband-UVB (NB-UVB), with lower rates denser infiltrate with more atypical lymphocytes tendency to relapse after topical treatment; of relapse; however, NB-UVB has the benefit of can be found.2,24 Cho-Vegga et al. state that “it 2) an unknown triggering event with no re-pigmentation and lacks the side effects and is unusual to find marked spongiosis, vacuolar evidence of hypersensitivity, allergic reaction, carcinogenicity of psoralen.36-38 The long-term change, keratinocyte necrosis, or numerous associated connective-tissue disorder, or other effects of phototherapy and radiotherapy in eosinophils and/or neutrophils in classic MF.”24 lymphoproliferative conditions; 3) lack of children should be considered. overtly malignant cytomorphologic features; 4) The histological findings in HMF are similar monoclonality or oligoclonality; 5) clinical and to classic MF but also include an absent or pathological distinction from CTCL and the Conclusion decreased number of melanocytes and a decreased 32 Hypopigmented mycosis fungoides is an potential to progress to CTCL. number of melanosomes inside keratinocytes.14,27 uncommon variant of MF that can present a Shabrawi-Caelen et al. found that the most Histopathologic features of hypopigmented number of diagnostic challenges. The disease can common histological findings in their HMF CTLD lesions were described by Crowson et al. resemble many other inflammatory conditions, 29 patients were mild psoriasiform epidermal in 2008. They described these lesions as a low- and no studies are entirely sensitive or specific. hyperplasia, a lichenoid infiltrate of lymphocytes density, small-cell predominant, epitheliotropic Diagnostic algorithms used for classic MF, in the superficial dermis, and melanophages in lymphocytic infiltrate with colonization of the such as the revised ISCL algorithm, cannot be the papillary dermis with melanin incontinence.13 basal layer. The condition is unaccompanied applied to variants such as HMF. When the Koorse et al. found slight spongiosis, patchy by significant destructive epithelial changes, diagnostic criteria for MF cannot be met, a parakeratosis, and perieccrine lymphocytes in a distinguishing it from a true interface dermatitis. diagnosis of T-cell dyscrasia might be considered. majority of their HMF cases.25 They also describe a single-cell pattern of More explicit guidelines and/or specific disease lymphocyte migration in the upper epidermis, markers for HMF would greatly aid in diagnosis, Immunophenotypic studies of early MF show no presence of Pautrier microabscesses, and especially during the early stages of the disease. CD8+ and CD4+ T-cells; however, in later stages a cerebriform appearance of the cells in the of MF, there seems to be a loss of the CD8 epidermis. Immunophenotypic studies of 9 marker, leaving a CD4+ predominate phenotype. hypopigmented CTLD lesions show a significant References 1. Willemze R, Jaffe ES, Burg G, Cerroni L, HMF, on the other hand, typically shows a reduction in CD7 and CD62L expression, Berti E, Swerdlow SH, Ralfkiaer E, Chimenti S, predominance of CD8+ T-cells, although patients predominant expression of CD8+ T-cells Diaz-Perez JL, Duncan LM, Grange F, Harris with CD8-/CD4-, equal ratios of CD4+/CD8+, compared to CD4+ T-cells, and a restricted NL, Kempf W, Kerl H, Kurrer M, Knobler R, and predominantly CD4+ T-cells have also been oligoclonal T-cell repertoire.29 Early biopsies 6,28 Pimpinelli N, Sander C, Santucci M, Sterry W, found. T-cell markers in MF include CD2, of HMF may suggest a T-cell dyscrasia but will 34 Vermeer MH, Wechsler J, Whittaker S, Meijer CD3, CD5,CD7, and CD26, which are usually evolve into MF with time. lost with progression of disease. Loss of theses CJ. WHO-EORTC classification for cutaneous markers may be found in benign inflammatory lymphomas. Blood. 2005;105:3768–3785. 9 Staging/Prognosis diseases as well. Other T-cell markers include The staging of MF is based on a Tumor, Node, 2. Kazakov DV, Burg G, Kempf W. CD45R0, CD25, CD56, TIA1, and CD30 and Clinicopathological spectrum of mycosis 2,6,29 Metastasis (TNM) approach and uses a revised the cytotoxic markers CD56 and TIA. classification scheme from the International fungoides. J Eur Acad Dermatol Venereol. 2004 Sometimes, T-cell markers are not present in Society for Cutaneous Lymphomas (ISCL) and Jul;18(4):397-415. early MF, rendering immunophenotypic studies the European Organization for Research and 3. Wilson LD, Hinds GA, Yu JB. Age, 33 unreliable. For this reason, TCR-beta and Treatment of Cancer (EORTC). Stages IA, race, sex, stage, and incidence of cutaneous TCR-gamma gene-rearrangement studies are IB, and IIA are considered limited-stage disease, lymphoma. Clin Lymphoma Myeloma Leuk. 23,33 recommended. Approximately 50% of cases while stages IIB –IVB are advanced stages. 2012;12(5):291-296. display monoclonal rearrangement.30 In the HMF appears to have a slow progression and an 4. Ryan EA, Sanderson KV, Bartak P, early stages of MF and HMF, there is a T-cell excellent prognosis, with a 20-year overall and Samman PD. Can mycosis fungoides begin in malignant clone located mainly in the epidermis, 28,30 disease-specific survival of 98.6%. Progression the epidermis? A hypothesis. Br J Dermatol. whereas in later stages the clone is only located 13 2,31 to tumor stage or systemic involvement is rare. 1973;88:419-429. in the dermis. The clones can also be found Wain et al. reviewed 30 cases of HMF, 85% of 5. Wain EM, Orchard GE, Whittaker SJ, in the lymph nodes and blood. T-cell clonality is which (28/30) did not progress beyond stage Spittle M Sc MF, Russell-Jones R. Outcome not sensitive or specific for MF, as it has also been 1B disease.6 Because it is possible for patients in 34 patients with juvenile-onset mycosis demonstrated in benign inflammatory disorders to progress to systemic disease and develop fungoides: a clinical, immunophenotypic, and such as vitiligo, lymphomatoid papulosis, secondary malignancies, it is advised to monitor 16,32 molecular study. Cancer. 2003;98(10):2282-290. psoriasis, and pityriasis lichenoides. Negative patients throughout their lifetime. TCR studies may result if tested too early in the 6. Zackheim HS, McCalmont TH, Deanovic disease process due to paucity of malignant cells.16 Treatment FW, Odom RB. Mycosis fungoides with onset The International Society for Cutaneous Psoralen UV-A (PUVA), UV-B radiation, before 20 years of age. J Am Acad Dermatol. Lymphomas (ISCL) recognized the problems total skin electron irradiation, topical nitrogen 1997;36:557-562. associated with diagnosing early MF and mustard, carmustine, and corticosteroid creams 7. Pope E, Weitzman S, Ngan B, Walsh S, proposed an algorithm in 2005. The algorithm have all shown a good response in adults and Morel K, Williams J, Stein S, Garzon M, Knobler includes clinical, histologic, immunopathologic, children with HMF, with PUVA being the most E, Lieber C, Turchan K, Wargon O, Tsuchiya A. 33 and biomolecular criteria. However, variants of commonly described.12,30 There is no widely Mycosis Fungoides in the Pediatric Population: 12,21 MF, such as HMF, cannot be applied. accepted protocol pertaining to the treatment Report from an International Childhood Registry When there are not enough criteria to fulfill a of HMF in children, so they are managed in of Cutaneous Lymphoma. Journal of Cutaneous diagnosis of MF based on the ISCL algorithm, the same way as adults. Topical class 1 steroids Medicine and Surgery. 2010;14(1):1-6. have been shown to be effective in HMF.35 Guitart et al. suggest the term “cutaneous T-cell 8. Geskin LJ. Chapter 105. Cutaneous lymphoid dyscrasia” (CTLD). This algorithm PUVA was found to be more effective than T-Cell Lymphoma (Mycosis Fungoides and Page 46 HYPOPIGMENTED MYCOSIS FUNGOIDES: CASE REPORT AND REVIEW Sézary Syndrome). In: Prchal JT, Kaushansky 21. Furmanczyk PS, Wolgamot GM, Kussick SJ, Organization of Research and Treatment of K, Lichtman MA, Kipps TJ, Seligsohn U, eds. Sabath DE, Olerud JE, Argenyi ZB. Diagnosis Cancer (EORTC). Blood. 2007;110:1713. Williams Hematology. 8th ed. New York: of mycosis fungoides with different algorithmic 34. Chuang GS, Wasserman DI, Byers HR, McGraw-Hill; 2010. http://www.accessmedicine. approaches. J Cutan Pathol. 2010;37(1):8-14. Demierre MF. Hypopigmented T-cell dyscrasia com/content.aspx?aID=6137103. Accessed June 22. Olerud JE, Kulin PA, Chew DE, Carlsen evolving to hypopigmented mycosis fungoides 23, 2013. RA, Hammar SP, Weir TW, Patterson SD, during etanercept therapy. J Am Acad Dermatol. 9. Wong HK, Mishra A, Hake T, Porcu Bolen JW, Kadin ME, Barker E, et al. Cutaneous 2008;9(5 Suppl):S121-122 P. Evolving insights in the pathogenesis and T-cell lymphoma. Evaluation of pretreatment 35. Kim YH. Management with topical therapy of cutaneous T-cell lymphoma (mycosis skin biopsy specimens by a panel of pathologists. nitrogen mustard in mycosis fungoides. Dermatol fungoides and Sézary syndrome). Br J Haematol. Arch Dermatol. 1992;128(4):501-507. Ther. 2003;16(4):288-298. 2011 Oct;155(2):150-166. 23. Thomas BR, Whittaker S. A practical 36. Wongpraparut C, Setabutra P. Phototherapy 10. Kallinich T, Muche JM, Qin S, Sterry W, approach to accurate classification and staging of for hypopigmented mycosis fungoides in Asians. Audring H, Kroczek RA. Chemokine receptor mycosis fungoides and Sézary syndrome. Skin Photodermatol Photoimmunol Photomed. expression on neoplastic and reactive T cells in Therapy Lett. 2012;17(10):5-9. 2012;28(4):181-186. the skin at different stages of mycosis fungoides. 24. Cho-Vega JH, Tschen JA, Duvic M, Vega F. J Invest Dermatol. 2003;121:1045-1052. 37. Sezer E, Sezer T, Senayli A, Koseoglu D, Early-stage mycosis fungoides variants: case-base Filiz N. Hypopigmented mycosis fungoides in a 11. Saed G, Fivenson DP, Naidu Y, Nickoloff review. Ann Diagn Pathol. 2010;14(5):369-385. Caucasian child. Eur J Dermatol. 2006;16(5)584 BJ. Mycosis fungoides exhibits a Th1-type 25. Koorse S, Tirumalae R, Yeliur IK, Jayaseelan cell-mediated cytokine profile whereas Sézary 38. Onsun N, Kural Y, Su Ö, Demirkesen E. Clinicopathologic profile of hypopigmented syndrome expresses a Th2-type profile. J Invest C, Büyükbabani N. Hypopigmented Mycosis mycosis fungoides in India. Am J Dermatopathol. Dermatol. 1994;103:29-33. Fungoides Associated with Atopy in Two 2012;34(2):161-164. Children. Pediatr Dermatol. 2006;23(5):493- 12. Khopkar U, Doshi BR, Dongre AM, Gujral 26. Massone C, Kodama K, Kerl H, Cerroni L. 496. S. A study of clinicopathologic profile of 15 cases Histopathologic features of early (patch) lesions of hypopigmented mycosis fungoides. Indian J Dermatol Venereol Leprol. 2011;77(2):167-173. of mycosis fungoides: a morphologic study on 745 biopsy specimens from 427 patients. Am J Correspondence: Holly Kanavy, DO, St. 13. El-Shabrawi-Caelen L, Cerroni L, Medeiros Surg Pathol. 2005;29:550–560. Barnabas Hospital, 4451 3rd Ave., Bronx, NY LJ, McCalmont TH. Hypopigmented mycosis 10457; [email protected] fungoides: frequent expression of a CD8+ T-cell 27. Neuhaus IM, Ramos-Caro FA, Hassanein phenotype. Am J Surg Pathol. 2002;26(4):450- AM. Hypopigmented Mycosis Fungoides 457. in Childhood and Adolescence. Pediatric Dermatology. 2000;17(5):403. 14. Breathnach SM, McKee PH, Smith NP. Hypopigmented mycosis fungoides: report of 28. Uhlenhake EE, Mehregan DM. Annular five cases with ultrastructural observations. Br J hypopigmented mycosis fungoides: a novel ringed Dermatol. 1982;106(6):643-649. variant. J Cutan Pathol. 2012;39(5):535-539. 15. Lambroza E, Cohen SR, Phelps R, 29. Crowson AN, Magro CM, Mihm MC Jr. Lebwohl M, Braverman IM, DiCostanzo Interface Dermatitis. Arch Pathol Lab Med. D. Hypopigmented variant of mycosis 2008;132(4):652-666. fungoides: Demography, histopathology, and 30. Juhas E, English JC 3rd. Hypopigmented treatment of seven cases. J Am Acad Dermatol. patches on the skin. J Am Med Assoc. 1995;32(6):987-993. 2013;309(4):392-393. 16. Ngo JT, Trotter MJ, Haber RM. Juvenile- 31. Ardigó M, Borroni G, Muscardin L, Kerl H, onset hypopigmented mycosis fungoides Cerroni L. Hypopigmented mycosis fungoides in mimicking vitiligo. J Cutan Med Surg. Caucasian patients: a clinicopathologic study of 2009;13(4):230-233. 7 cases. J Am Acad Dermatol. 2003;49(2):264- 17. Van Haselen CW, Toonstra J, Preesman AH, 270. Van Der Putte SC, Bruijnzeel-Koomen CA, Van 32. Guitart J, Magro C. Cutaneous T-cell Vloten WA. Sézary syndrome in a young man lymphoid dyscrasia: a unifying term for idiopathic with severe atopic dermatitis. Br J Dermatol. chronic dermatoses with persistent T-cell clones. 1999;140: 704–707. Arch Dermatol. 2007;143(7):921-932. 18. Gelfand JM, Shin DB, Neimann AL, 33. Olsen E, Vonderheid E, Pimpinelli N, Wang X, Margolis DJ, Troxel AB. The risk of Willemze R, Kim Y, Knobler R, Zackheim lymphoma in patients with psoriasis. J Invest H, Duvic M, Estrach T, Lamberg S, Wood Dermatol. 2006;126(10)2194-2201. G, Dummer R, Ranki A, Burg G, Heald P, 19. Alloo A, DeSimone JA, Kupper TS. Pittelkow M, Bernengo MG, Sterry W, Laroche Mycosis fungoides presenting at the site of L, Trautinger F, Whittaker S, ISCL/EORTC. a transdermal estradiol patch. J Am Acad Revisions to the staging and classification Dermatol. 2012;67(5):e207-208. of mycosis fungoides and Sézary syndrome: a proposal of the International Society for 20. Paul LJ, Duvic M. Mycosis fungoides Cutaneous Lymphomas (ISCL) and the following skin trauma. J Am Acad Dermatol. cutaneous lymphoma task force of the European 2012;67(4):e148. KANAVY, MACRI, SIDHU, AUSTIN Page 47 Scalp Psoriasis Treated with Excimer Laser, Clobetasol Propionate Spray, and Calcitriol Ointment: A Case Report

Monica Huynh, BA,* Ethan Levin, MD,** John Koo, MD***

*Medical Student, Chicago College of Osteopathic Medicine, Downers Grove, IL **Psoriasis Fellow, Department of Dermatology, University of California at San Francisco, San Francisco, CA ***Professor, Department of Dermatology, University of California at San Francisco, San Francisco, CA

Abstract Psoriasis is a chronic dermatologic disease affecting 2% to 3% of the general population. The disease can remain stable over a person’s lifetime or gradually become more widespread. Given that there is currently no cure available, patients with psoriasis need long-term treatment. Scalp psoriasis presents a unique challenge since treatment may be limited, cumbersome, or ineffective. We present a case that demonstrates how combination therapy consisting of excimer laser therapy and topical therapy (clobetasol propionate spray and calcitriol ointment) can be a highly efficacious method of treating scalp psoriasis.

UVB light to the affected area.1-3 We present a For excimer therapy, the patient was started at Introduction case of scalp psoriasis treated with excimer laser, energy of 600 millijoules per square centimeter Psoriasis is a chronic dermatologic disease 2 affecting 2% to 3% of the general population. The clobetasol propionate 0.05% spray, and calcitriol (mJ/cm ). The dose was increased 25% on each disease can remain stable over a person’s lifetime ointment. subsequent visit to a maximum tolerable dose or gradually become more widespread. Given that of 1551 mJ/cm2. The maximum dose was determined by examination of blistering at the there is currently no cure available, patients with Case treatment site. After three weeks of combination psoriasis need long-term treatment. A 41-year-old Filipino man presented with therapy with excimer laser and clobetasol spray, a five-year history of generalized plaque-type Psoriasis can affect any area of the body. Scalp the patient demonstrated marked improvement psoriasis. He was in marked distress due to the psoriasis presents a unique challenge since on the entirety of his scalp and body, all similar visible disfigurement and physical discomfort treatment may be limited, cumbersome, or to that seen in Figure 2. The head PASI score from the psoriatic plaques. The patient failed ineffective. There is no universal guideline for the decreased to 0.6, less than one quarter the score multiple prior topical therapies, including treatment of scalp psoriasis. First-line therapy in at the baseline visit three weeks prior. With superpotent steroids. His past medical history treating scalp psoriasis includes topical treatment, continued treatment, the patient noted further was not significant for other medical illnesses or such as medicated shampoos, steroids, salicylic improvement, with total clearance of his scalp disorders. He had no history of photosensitivity acid, tars, calcipotriene/calcitriol, tazarotene, and psoriasis (PASI 0) by the end of the treatment or skin cancer. He was not on any psoriasis anthralin. For those patients with more severe (week 12). therapy at the time of presentation nor was he scalp disease or who need a faster response, taking any photosensitizing medication. Figure 2 treatment can include combination therapy (i.e. simultaneous use of a steroid agent and non- On physical examination, the patient presented steroid agent), more occlusive formulations, with indurated, well-demarcated erythematous keratolytics, and superpotent corticosteroids. If plaques with adherent silvery scale over the topical agents are not able to adequately treat upper and lower extremities bilaterally and the scalp psoriasis, the patient may benefit from the lower back, buttocks, and scalp (Figure 1). systemic therapy, ultraviolet phototherapy or Psoriasis involved more than 50% of the scalp. excimer laser therapy. Of these three therapies, The Psoriasis Area and Severity Index (PASI) excimer laser may present clear advantages over scores for the entire body and head were 12.9 the others. The risk of side effects from systemic and 2.8, respectively. The patient was started on medication is usually a deterrent for patients with twice-weekly excimer laser therapy for six weeks. isolated scalp disease. Though light therapy is a During the first month of excimer treatment the patient also used clobetasol propionate 0.05% well-established therapeutic option for psoriasis, The patient did not experience any side effects spray twice daily. During the second month, hair often prevents penetration of light to the on the scalp from laser therapy such as blistering, the patient used calcitriol ointment twice daily. psoriatic plaque. Since traditional phototherapy burning, hyperpigmentation, or erythema. After During the third month of treatment, the patient is administered in a nonspecific fashion and may two months without any subsequent therapy, the used both clobetasol spray and calcitriol ointment reach uninvolved skin, the therapeutic capacity is scalp psoriasis maintained clearance. twice daily. limited by the minimal erythema dose (MED). For these reasons, traditional phototherapy is Figure 1 Discussion often impractical and/or ineffective for treating Most algorithms for the treatment of scalp scalp psoriasis. psoriasis rely on topical therapy. One strategy, Ultraviolet B (UVB) 308 nm excimer laser is coined the “yin-yang” technique, uses sequential a novel approach for treating psoriasis and is clobetasol spray and calcipotriene ointment.4 unique in that it offers targeted phototherapy This strategy is based on treating two types that can be delivered specifically to the plaques of psoriatic inflammation that a patient may at fluences up to 8x the MED. There are reports experience: 1) acute and highly inflamed, and 2) describing its use in scalp psoriasis, including chronic and indolent. During the highly inflamed those that assess unique hair-parting devices to phase, treatment with clobetasol spray is used. separate the hair and allow easier penetration of In a placebo-controlled study of scalp psoriasis,

Page 48 SCALP PSORIASIS TREATED WITH EXCIMER LASER, CLOBETASOL PROPIONATE SPRAY, AND CALCITRIOL OINTMENT: A CASE REPORT 85% (35/41) of patients treated with clobetasol Conclusion 10. Gattu S, Pang M-L, Pugashetti R, Malick F, spray were “cleared” or “almost clear” at week 4, Like most psoriasis types, topical therapy is the Hong J, Bowers E, et al. Pilot evaluation of supra- compared to 13% (5/40) of patients in the placebo erythemogenic phototherapy with excimer laser 5 mainstay for treatment of scalp psoriasis. In group. During the chronic and indolent phase, recalcitrant cases, the addition of other therapeutic in the treatment of patients with moderate to the yin-yang strategy uses calcitriol ointment. In modalities such as excimer laser may be useful. severe plaque psoriasis. J Dermatolog Treat. 2010 one open-label study of patients cleared with four This case demonstrates that combination therapy Jan;21(1):54-60. weeks of clobetasol spray, 92% and almost 80% of consisting of excimer laser therapy and topical 11. Kagen M, Cao LY, Oyetakin-White P, patients maintained clearance at week 8 and week therapy (clobetasol propionate spray and calcitriol Tacastacas JD, Yan C, McCormick TS, et al. 12, respectively, with two months using calcitriol ointment) can be a highly-efficacious method of 6 Single administration of lesion-limited high-dose ointment. treating scalp psoriasis. The external approach of (TURBO) ultraviolet B using the excimer laser: Wong et al. proposed an updated algorithm for both excimer laser therapy and topical therapy clinical clearing in association with apoptosis of the treatment of scalp psoriasis, introducing the minimize the risk of systemic side effects. Larger epidermal and dermal T cell subsets in psoriasis. excimer laser as a viable option if the psoriasis is studies are needed to substantiate these findings, Photodermatol Photoimmunol Photomed. 2012 resistant to topical therapies or scalp involvement optimize the dosimetry of excimer laser therapy, Dec;28(6):293–8. 7 and evaluate for proper therapeutic technique in is severe. Targeted ultraviolet B (UVB) 308 nm 12. Asawanonda P, Anderson RR, Chang treating scalp psoriasis. excimer laser is at the cutting-edge of dermatologic Y, Taylor CR. 308-nm excimer laser for the therapies and may potentially change the use treatment of psoriasis: a dose-response study. of phototherapy for scalp psoriasis. In contrast References: Arch Dermatol. 2000 May;136(5):619–24. to traditional phototherapy, UVB excimer laser 1. Taylor CR, Racette AL. A 308-nm excimer delivers targeted transmission through a hand- laser for the treatment of scalp psoriasis. Lasers held device with a spot diameter of 14 mm to Surg Med. 2004;34(2):136–40. Correspondence: Monica Huynh, BS, 3950 N. 8 Lake Shore Dr., Chicago, IL 60613; (408)242- 30 mm. Since psoriatic plaques can tolerate 2. Gupta SN, Taylor CR. 308-nm excimer 7618; [email protected] much higher doses of light when compared laser for the treatment of scalp psoriasis. Arch to noninvolved skin, a much higher dose of Dermatol. 2004 May;140(5):518–20. energy can be delivered directly to the plaques than through traditional UVB phototherapy. 3. Morison WL, Atkinson DF, Werthman L. The resulting dose of energy is many times Effective treatment of scalp psoriasis using greater than the MED, thus delivering a supra- the excimer (308 nm) laser. Photodermatol erythemogenic dose.9 As a result, the psoriasis Photoimmunol Photomed. 2006 Aug;22(4):181– can be treated in fewer treatments with a faster 3. clearance compared to traditional phototherapy. 4. Bhutani T, Zitelli KB, Koo J. Yin-yang strategy: In addition, excimer laser therapy results in a long proposing a new, effective, repeatable, sequential duration of remission.10 Two studies showed that therapy for psoriasis. J Drugs Dermatol. 2011 a single dose of excimer laser at least eight times Aug;10(8):831–4. MED is sufficient to clear individual psoriatic 11,12 5. Sofen H, Hudson CP, Cook-Bolden FE, plaques. One of the studies reported that Preston N, Colón LE, Colón LE, et al. Clobetasol patients were still completely clear in the treated 12 propionate 0.05% spray for the management of area four months after the single treatment. moderate-to-severe plaque psoriasis of the scalp: Though there is concern that hair can inhibit results from a randomized controlled trial. J the penetration of the excimer laser to psoriatic Drugs Dermatol. 2011 Aug;10(8):885–92. plaques, a hair-parting device can be used to 6. Brodell RT, Bruce S, Hudson CP, Weiss JS, minimize interference. Such devices were used Colón LE, Johnson LA, et al. A multi-center, in two separate studies of excimer laser for scalp open-label study to evaluate the safety and psoriasis. In one prospective study, the modified efficacy of a sequential treatment regimen of PASI score decreased from 4 to 2.6 after 15 weeks clobetasol propionate 0.05% spray followed by of twice-weekly excimer scalp therapy using a Calcitriol 3 mg/g ointment in the management 1 hair-blowing device. In a retrospective study of plaque psoriasis. J Drugs Dermatol. 2011 using manual separation of the hair to increase Feb;10(2):158–64. scalp exposure, almost half of the patients 3 7. Wong JW, Kamangar F, Nguyen TV, Koo achieved complete clearance. A case of a woman JYM. Excimer laser therapy for hairline psoriasis: with a 20-year history of refractory scalp psoriasis a useful addition to the scalp psoriasis treatment had 90% improvement in PASI score after 11 algorithm. Skin Therapy Lett. 2012 May;17(5):6– weeks of treatment. The area that was treated with excimer laser continued to be clear 10 weeks 8. Gattu S, Rashid RM, Wu JJ. 308-nm excimer post-cessation of treatments.2 laser in psoriasis vulgaris, scalp psoriasis, and palmoplantar psoriasis. J Eur Acad Dermatol Clobetasol propionate spray and excimer Venereol. 2009 Jan;23(1):36–41. laser work by very different mechanisms, so combination therapy is likely to result in an 9. Hong J, Malick, Farah, Sivanesan P, Koo, John. additive therapeutic effect. Therefore, clobetasol Expanding the use of the 308nm excimer laser propionate spray is a worthwhile addition for for treatment of psoriasis. Practical Dermatology. excimer laser. Clobetasol propionate spray also 2007 Apr;13–6. provides the additional benefit of decreasing the risk of phototoxic reaction from the excimer laser.

HUYNH, LEVIN, KOO Page 49 : A Case Report and Review

Steffany B. Steinmetz, DO,* Stanley E. Skopit, DO, MSE, FAOCD**

*Third-year Dermatology Resident, Larkin Community Hospital/NSU-COM, South Miami, FL **Program Director, Dermatology Residency, Larkin Community Hospital/NSU-COM, South Miami, FL

Abstract Ichthyoses represent a large heterogeneous group of disorders of cornification. Lamellar ichthyosis affects approximately 1:200,000-300,000 in the United States.1 The majority of lamellar ichthyosis cases are of autosomal recessive inheritance caused by transglutaminase-1 deficiency resulting from mutations in both copies of the gene on chromosome 14. Transglutaminase-1 is necessary for the structural formation of the stratum corneum.2 When the skin barrier is ineffective, it stimulates epidermal hyperplasia and hyperkeratosis. This explains the classic phenotype of diffuse, large, brown, polygonal scales over the entire body. In more severe cases, ectropions, , scarring alopecia, palmoplantar keratoderma with hyperlinearity, dystrophic nails, and crumpled ears can be seen.3 We present a case report of two brothers with lamellar ichthyosis and then discuss lamellar ichthyosis in further detail.

Introduction prominent skin markings. The palms and soles Ichthyoses represent a large heterogeneous group demonstrated hyperkeratosis and hyperlinearity. of disorders of cornification. Classification Facial skin was taut with significant scales. schemes have been sought not only to aid in Bilateral lower congenital ectropions were present diagnosis and treatment options, but also to help in both brothers. Their nails showed exaggerated further research. The classification consensus curvature. Their hair, teeth, and auricular began in 2007 at the First World Conference on cartilage appeared normal. Other extracutaneous Ichthyosis in Germany. At the First Ichthyosis systems were normal. Intellectual and physical Consensus Conference in France in 2009, the development was also normal. proposed term “autosomal recessive congenital Diffuse, large, brown, polygonal scales noted in ichthyosis” was accepted as an umbrella term for two brothers with lamellar ichthyosis at initial the following subtypes: Harlequin ichthyosis, visit (a=Brother 1; b=Brother 2). lamellar ichthyosis, and congenital ichthyosiform 4 After a thorough history and physical and blood erythroderma. work, the patients were started on acitretin 25mg daily for one month. At their follow-up visit, the Case Report acitretin dose was increased to 50mg daily and Two brothers, ages 18 and 19 years, were referred they continue to improve at this dose with no to our dermatology clinic for evaluation and Figure 1a changes noted in their blood work (Figure 2). treatment of their . The boys were They also have been prescribed Drisdol 50,000 born in Dominican Republic and then moved to units once weekly to correct their low vitamin D the United States with their grandmother when levels with noted improvement in their levels at they were 6 months old for medical care. They subsequent follow-up visits. Furthermore, they were diagnosed clinically with lamellar ichthyosis have been applying Lac-Hydrin 12% lotion once at ages 3 and 4, respectively, per their history. to twice daily for keratolytic purposes. Of note, The two brothers are the only children of non- the patients noted that lotions and creams adhere consanguineous parents. They were born full- to the scales and leave their skin with white term. There was no recollection of any family residue. Ointments or gels would be the more members with ichthyosis or any other skin preferred vehicles if possible, based on availability, conditions. Their grandmother described the insurance coverage, and cost. classic presentation of a collodion membrane Improvement in appearance with significant at birth in both boys. The grandmother stated reduction of scale noted at three-month follow-up that the layer peeled away within a week, and with acitretin treatment (a=Brother 1; b=Brother then the boys had very thick pale skin with deep 2). red fissures. After several weeks, they began to develop the classic dark brown scales covering their entire bodies. The grandmother stated that Epidemiology According to the Foundation for Ichthyosis both boys had a very difficult time with feeding Figure 1b and Related Skin Types, autosomal recessive and growing with subsequent hospitalizations. congenital ichthyosis-lamellar ichthyosis type in high school. They have been living with Upon social history, the brothers admitted to past affects approximately 1:200,000 in the United their grandmother since 6 months of age. Their depression, but denied any current depressive States. The most frequently reported prevalence parents still reside in Dominican Republic. 1 symptoms. They both denied any current or is 1:200,000-300,000. Consanguinity of parents history of suicidal ideation. The elder brother left Physical examination revealed a generalized is present in about 8% of cases. Premature high school, is pursuing his GED, and is working distribution of large, dark brown, polygonal, birth occurs in 25% of individuals and 51% of as a mechanic. The younger brother is two adherent scales without apparent underlying siblings are affected. Lamellar ichthyosis is most years behind in school, currently a sophomore erythema (Figure 1). The flexural regions had commonly inherited as an autosomal recessive

Page 50 LAMELLAR ICHTHYOSIS: A CASE REPORT AND REVIEW Genetics vitamin D deficiencies, however, did not improve. As previously mentioned, lamellar ichthyosis Similarly, systemic medication that resolved vitamin D deficiencies did not improve skin is most commonly inherited in an autosomal- 8 recessive manner. The parents of the affected findings. Measurement of 25-hydroxyvitamin individual must carry a mutant allele. A sibling D in individuals with ichthyosis would allow for has a 25% chance of being affected, a 25% chance identification and treatment of those at risk for of being unaffected, and a 50% chance of being vitamin D deficiency, preventing development of a carrier. The offspring of an affected individual rickets, osteoporosis, or other conditions that may is a carrier, unless the partner is also a carrier, in develop or worsen due to low vitamin D levels. which case the offspring has a 50% chance of being a carrier or a 50% chance of being affected. Diagnosis Once the mutation of the affected individual has The diagnosis of lamellar ichthyosis can be been identified, carrier testing for at-risk relatives established by a thorough history and physical and prenatal testing for pregnancies at increased examination. Skin biopsy is not necessary to risk can be done.3 Young adults who are affected, establish the diagnosis. 3 Histologic findings any person identified as a carrier, or any person at in lamellar ichthyosis are nonspecific with risk for being a carrier should be offered genetic massive compact hyperkeratosis covering an counseling. Genetic counseling provides these underlying acanthotic epidermis. 2 The Ichthyosis individuals an understanding and awareness Consensus Conference stated, “Diagnosis of the condition as well as the risks inherent in is based on dermatologic evaluation, careful being a carrier. Furthermore, the availability of family and medical history, and can be strongly prenatal testing can be discussed if a patient is supported by directed morphologic examinations Figure 2a considering reproduction.3 and other special analyses. If available, molecular analyses are suggested to confirm diagnosis, and allow for testing of family members and prenatal Clinical Findings 4 Neonates with lamellar ichthyosis typically diagnosis.” present with a collodion membrane at birth. The membrane dries and peels away within the Management first few days to weeks of life. The skin then Bathing is recommended at least once daily. develops diffuse, large, brown, polygonal scales Exfoliation should be done after soaking with over the entire body. The skin manifestations sponge, microfiber cloth, or pumice stone. are unremitting and persist throughout Propylene glycol, vitamin E, and glycerol are life. Ectropion, eclabium, scarring alopecia, emollients that should be reapplied throughout palmoplantar keratoderma with hyperlinearity, the course of the day. Pure sodium bicarbonate dystrophic nails, and crumpled ears can be seen has been successfully used as a bath additive to in severe cases. Erythroderma is mild if at all mechanically remove scale.9 present.3 is not uncommon and During the neonatal period, temperature, fluids, temperature regulation/monitoring is critical. and electrolytes need to be regulated. Risk During the neonatal period, they can have of infection needs to be closely monitored. significant transepidermal water loss, fluid and Environment needs to provide humidity/ electrolyte disturbances, and are at an increased moisture. Urea cream is commonly avoided in risk for infection and sepsis.3 neonates. Dexpanthenol 5% is an alternative to Ophthalmologic involvement is a significant urea that is safe to use during infancy. Salicylic comorbidity among lamellar ichthyosis acid is contraindicated in neonates or infants. 9 individuals. Ocular manifestations can include In children and adults, keratolytic agents such as exposure keratitis secondary to ectropion, urea, lactic acid, salicylic acid, and alpha-hydroxy Figure 2b unilateral megalocornea, enlarged corneal acid may help thin the stratum corneum and nerve, blepharitis, absent Meibomian gland, induce peeling. Topical or oral retinoid therapy trichiasis, madarosis, and absence of lacrimal trait, but autosomal dominant transmission has is recommended for those with severe skin 2 puncta. Corneal ulcerations can occur. With been observed. involvement. Acitretin is efficacious, especially in prolonged excessive dryness, patients can develop lamellar ichthyosis and congenital ichthyosiform bilateral cicatricial ectropions with subsequent erythroderma. Isotretinoin may be preferred Pathogenesis contractures. Late presentation can lead to severe, The majority of cases of lamellar ichthyosis are 6 in female patients due to shorter duration of sight-threatening complications. caused by transglutaminase-1 deficiency resulting teratogenicity risk after taking the medication. 9 from mutations in both copies of the gene on Hypovitaminosis D in individuals with ichthyosis For individuals with ectropion, prevention of chromosome 14. Transglutaminase-1 is expressed and other disorders of keratinization have been cornea dessication is through use of lubrication in the upper layers of the epidermis, facilitating reported, which is consistent with the case we with artificial tears or prescription ophthalmic 3 the formation of the stratum corneum through present, and is most likely due to the impaired ointments. synthesis in the skin. Vitamin D is essential for a cross-linking structural proteins and attaching An up and coming treatment is the new class 2 healthy . Deficiency can lead to rickets in the lipid envelope. This ineffective barrier, in of retinoic acid metabolism-blocking agents, children and osteoporosis in adults. Vitamin D has a means to correct itself, stimulates epidermal otherwise known as RAMBAs. This class of also been shown to be a potent antiproliferative hyperplasia and hyperkeratosis. Hence, the medications inhibits catabolism of endogenous and prodifferentiation mediator.7 One study clinical phenotype of lamellar ichthyosis is a all-trans-retinoic acid. The pharmacokinetic involving children with ichthyosis showed reflection of the underlying physiologic cascade profile is promising as the effects of retinoic improvement of skin with topical application of in the epidermis in an attempt to normalize acid on epidermal growth and differentiation 5 calcipotriene, a vitamin D analog. Their systemic barrier function. are indirectly achieved and with better

STEINMETZ, SKOPIT Page 51 tissue specificity. Therefore, the retinoic acid themselves. In certain areas of the world, families References metabolism-blocking agents offer the possibility believe socialization of their affected child will 1. Hernández-Martín A, Garcia-Doval I, of reduced side effects and reduced potential for result in severe castigation for the whole family. Aranegui B, de Unamuno P, Rodríguez-Pazos L, teratogenicity when compared with synthetic Affected individuals are treated as outcasts and 10 et al. Prevalence of autosomal recessive congenital retinoids. A recent phase II/III, randomized, marriage is not acceptable due to poor genetics. A ichthyosis: A population-based study using the double-blind, controlled study indicated that case report of two sisters with lamellar ichthyosis capture-recapture method in Spain. J Am Acad liarozole at a daily dose of 150mg is equally from sub-Saharan Africa discusses the isolation Dermatol. 2012;67:240-244. effective as treatment with acitretin. In a study that individuals with such conditions endure. The involving a patient with lamellar ichthyosis girls in this report were removed from society, 2. Bolognia J, Jorizzo J, Rapini R. Lamellar treated with liarozole 150mg daily, significant denied an education, and medical treatment was Ichthyosis. Dermatology. Edinburgh: Mosby, reduction in scale was noted. Liarozole has been withheld.13 Inc; 2008. p. 755. granted orphan drug status for the treatment of Affected individuals and their families should 3. Richard G, Bale SJ. Autosomal Recessive congenital ichthyosis by the European Medicines be guided to educational and supportive groups Congenital Ichthyosis. GeneReviews. 2012. 9 Such drugs as Agency and the US FDA. such as FIRST, Foundation for Ichthyosis liarozole may become the treatment of choice for 4. Oji V, Tadini G, Akiyama M, Blanchet-Bardon and Related Skin Types. The FIRST Skin cases of ichthyosis that warrant systemic therapy. C, Bodemer C, et al. Revised nomenclature and Foundation states, “Our mission is to educate, classification of inherited ichthyoses: results of the Another medication of interest is the inspire, and connect those touched by ichthyosis First Ichthyosis Consensus Conference in Soreze compounded combination of topical 10% and related disorders through emotional support, 2009. J Am Acad Dermatol. 2010;63:607–641. N-acetylcysteine and 5% urea emulsion. A information, advocacy, and research funding for report of five children with lamellar ichthyosis better treatments and eventual cures. Governed 5. Elias PM, Williams ML, Holleran WM, et al. being treated with this medication describes by a Board of Directors and guided by a Medical Pathogenesis of permeability barrier abnormalities marked overall improvement in the appearance & Scientific Advisory Board, FIRST provides in the ichthyoses: inherited disorders of lipid of their skin with noteworthy reduction of scale. accurate and timely information to meet the metabolism. J Lipid Res. 2008;49:697–714. N-acetylcysteine has been shown to inhibit medical, social, and educational needs of our 6. Chakraborti C, Tripathi P, Bandopadhyay G, the proliferation of keratinocytes, and when community.” Patients should also be encouraged Mazumder DB. Congenital bilateral ectropion combined with a commonly used keratolytic to review and enroll in the National Registry for in lamellar ichthyosis. Oman J Ophthalmol. such as urea, significant benefit was noted with Ichthyosis and Related Disorders. This source was 2011;4:35–6. effectiveness that was greater than that seen with created to encourage research into the diagnosis 7. Holick MF. Noncalcemic actions of each entity separately. The emulsion was applied and treatment of the ichthyosis and remains a 1,25-dihydroxyvitamin D3 and clinical twice daily for 6 weeks and then continued once resource for investigators. Information regarding applications. Bone. 1995;17:S107–S111. daily. The drug was well tolerated, efficacious, and the FIRST Skin Foundation and the National safe. 11 Registry for Ichthyosis and Related Disorders 8. Thacher T, Fischer P, Pettifor J, Darmstadt G. Nutritional rickets in ichthyosis and response to Genetic counseling should be offered to can be found at http://www.firstskinfoundation. calcipotriene. Pediatrics. 2004;114:e119–e123. affected individuals and their families. The org. comprehension of their condition is a central 9. Oji V, Traupe H. Ichthyosis: clinical part of their care and should be a standard in the Conclusion manifestations and practical treatment options. management of such conditions. Genetic testing Classic lamellar ichthyosis is most notably due Am J Clin Dermatol. 2009;10:351-364. and counseling enables patients to seek answers to mutations in the transglutaminase-1 gene. 10. Van Steensle MAM. Emerging drugs to their many questions regarding the nature of This is most likely the situation in this case we for ichthyosis. Expert Opin Emerg Drugs. the disorder, inheritance pattern, and probability report. TGM1 is crucial for the formation of 2007;12:647-656. of affected family members or offspring. 4 Further the cornified cell envelope, which provides the information can be found at the Gene Tests barrier function of the skin. Current treatment 11. Bassotti A, Moreno S, Criado E. Successful Clinic Directory website, www.ncbi.nlm.nih.gov/ is symptomatic and is largely directed towards Treatment with Topical N-Acetylcysteine in sites/GeneTests/clinic. 3 The Gene Tests Clinic improving the appearance of the skin by reducing Urea in Five Children with Congenital Lamellar Directory is a voluntary list of United States and scaling. This, however, defeats the body’s natural Ichthyosis. Pediatr Dermatol. 2011;28:451–455. international genetics clinics. protective compensation for a defective stratum 12. Paller AS, van Steensel MAM, Rodriguez- corneum. Furthermore, due to the dysfunctional Martín M, Sorrell J, Heath C, et al. barrier, there is an increased risk for systemic Pathogenesis-Based Therapy Reverses Cutaneous Additional Concerns and absorption and toxicity, especially during infancy. Abnormalities in an Inherited Disorder of Distal Patient Resources Significant research of the underlying genetic Cholesterol Metabolism. J Invest Dermatol. Social and psychological support for the and biochemical mechanisms has lead to a 2011;131:2242–2248. management of such chronic skin diseases is a greater understanding of this disease, furthering 13. Ibekwe PU, Ogunbiyi AO, Ogun OG, crucial entity of care. The negative impact on the progress and development of more targeted 12 George AO. Social stigmatization of two sisters the quality of life is immense. The burden of therapies. with lamellar ichthyosis in Ibadan, Nigeria. Int J daily skin care alone is significantly cumbersome The website www.clinicaltrials.gov is a database Dermatol. 2012;51:67–68. and laborious. Patients commonly spend hours of registries and results of publicly and privately caring for their skin, with little to no visible supported clinical studies. This service is provided improvement. Furthermore, patients commonly by the U.S. National Institutes of Health. This Correspondence: Steffany B. Steinmetz, DO, 450 suffer from severe psychological stress and th can provide access to information on clinical NE 5 St, Unit # 145, Fort Lauderdale, Florida depression. In many cases, parents are hesitant studies and trials for this particular disorder. 33301 (1-405-414-7211; steffanybrooke@ or fearful to touch their children, depriving them hotmail.com) of the need for human touch and emotional connection. Later in life, affected individuals experience constant ridicule and mockery. They have difficulty finding a life partner.10 This social stigmatization is endless and only deepens their insecurity and prevents their acceptance of

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It’s true. Rosacea is complex and it’s with them for life. Finacea® treats the papules and pustules with associated erythema of mild to moderate rosacea. Although some reduction of erythema which was present in patients with papules and pustules of rosacea occurred in clinical studies, effi cacy for treatment of erythema in rosacea in the absence of papules and pustules has not been evaluated. You have made Finacea® the #1 Dermatologist-prescribed topical brand.1

INDICATION & USAGE Finacea® (azelaic acid) Gel, 15% is indicated for topical treatment of infl ammatory papules and pustules of mild to moderate rosacea. Although some reduction of erythema which was present in patients with papules and pustules of rosacea occurred in clinical studies, effi cacy for treatment of erythema in rosacea in the absence of papules and pustules has not been evaluated.

IMPORTANT SAFETY INFORMATION Skin irritation (e.g. pruritus, burning or stinging) may occur during use with Finacea®, usually during the fi rst few weeks of treatment. If sensitivity or severe irritation develops and persists during use with Finacea®, discontinue use and institute appropriate therapy. There have been isolated reports of hypopigmentation after use of azelaic acid. Since azelaic acid has not been well studied in patients with dark complexion, monitor these patients for early signs of hypopigmentation. Avoid contact with the eyes, mouth, and other mucous membranes. In case of eye exposure, wash eyes with large amounts of water. Wash hands immediately following application of Finacea®. Avoid use of alcoholic cleansers, tinctures and astringents, abrasives and peeling agents. Avoid the use of occlusive dressings or wrappings. In clinical trials with Finacea®, the most common treatment-related adverse events (AE’s) were: burning/stinging/tingling (29%), pruritus (11%), scaling/dry skin/xerosis (8%) and erythema/irritation (4%). Contact dermatitis, edema and acne were observed at frequencies of 1% or less. Finacea® is for topical use only. It is not for ophthalmic, oral or intravaginal use. Patients should be reassessed if no improvement is observed upon completing 12 weeks of therapy. Please see Brief Summary of full Prescribing Information on adjacent page. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch, or call 1-800-FDA-1088. 1. According to IMS NPATM (National Prescription Audit) July 2010-August 2013 © 2013 Bayer HealthCare Pharmaceuticals. Bayer, the Bayer Cross and Finacea® are registered trademarks of Bayer. All rights reserved. FIN-10-0001-13b | AUGUST 2013 JAOCD 8.5 X 11 in

6.2 Post-Marketing Experience The following adverse reactions have been identified post approval of FINACEA Gel. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure: Eyes: iridocyclitis upon accidental exposure of the eyes to FINACEA Gel Finacea® 7 DRUG INTERACTIONS There have been no formal studies of the interaction of FINACEA Gel with other drugs. (azelaic acid) Gel,15% 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Teratogenic Effects: Pregnancy Category B For Dermatologic Use Only–Not for Ophthalmic, Oral, or Intravaginal Use There are no adequate and well-controlled studies in pregnant women. Therefore, FINACEA Gel should Rx only be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. BRIEF SUMMARY Dermal embryofetal developmental toxicology studies have not been performed with azelaic acid, CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION 15% gel. Oral embryofetal developmental studies were conducted with azelaic acid in rats, rabbits, 1 INDICATIONS AND USAGE and cynomolgus monkeys. Azelaic acid was administered during the period of organogenesis in all FINACEA® Gel is indicated for topical treatment of the inflammatory papules and pustules of mild to three animal species. Embryotoxicity was observed in rats, rabbits, and monkeys at oral doses of moderate rosacea. Although some reduction of erythema which was present in patients with papules azelaic acid that generated some maternal toxicity. Embryotoxicity was observed in rats given 2500 and pustules of rosacea occurred in clinical studies, efficacy for treatment of erythema in rosacea in mg/kg/day [162 times the maximum recommended human dose (MRHD) based on body surface the absence of papules and pustules has not been evaluated. area (BSA)], rabbits given 150 or 500 mg/kg/day (19 or 65 times the MRHD based on BSA) and cynomolgus monkeys given 500 mg/kg/day (65 times the MRHD based on BSA) azelaic acid. No 5 WARNINGS AND PRECAUTIONS teratogenic effects were observed in the oral embryofetal developmental studies conducted in rats, 5.1 Skin Reactions rabbits and cynomolgus monkeys. Skin irritation (i.e. pruritus, burning or stinging) may occur during use of FINACEA Gel, usually during An oral peri- and post-natal developmental study was conducted in rats. Azelaic acid was administered the first few weeks of treatment. If sensitivity or severe irritation develops and persists, discontinue from gestational day 15 through day 21 postpartum up to a dose level of 2500 mg/kg/day. Em- treatment and institute appropriate therapy. bryotoxicity was observed in rats at an oral dose of 2500 mg/kg/day (162 times the MRHD based There have been isolated reports of hypopigmentation after use of azelaic acid. Since azelaic acid has on BSA) that generated some maternal toxicity. In addition, slight disturbances in the post-natal not been well studied in patients with dark complexion, monitor these patients for early signs of development of fetuses was noted in rats at oral doses that generated some maternal toxicity hypopigmentation. (500 and 2500 mg/kg/day; 32 and 162 times the MRHD based on BSA). No effects on sexual 5.2 Eye and Mucous Membranes Irritation maturation of the fetuses were noted in this study. Avoid contact with the eyes, mouth and other mucous membranes. If FINACEA Gel does come in 8.3 Nursing Mothers contact with the eyes, wash the eyes with large amounts of water and consult a physician if eye It is not known whether azelaic acid is excreted in human milk; however, in vitro studies using equilibrium irritation persists [see Adverse Reactions (6.2)]. dialysis were conducted to assess the potential for human milk partitioning. The studies demonstrated 6 ADVERSE REACTIONS that, at an azelaic acid concentration of 25 µg/mL, the milk/plasma distribution coefficient was 0.7 6.1 Clinical Trials Experience and the milk/buffer distribution was 1.0. These data indicate that passage of drug into maternal milk Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed may occur. Since less than 4% of a topically applied dose of 20% azelaic acid cream is systemically in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug absorbed, the uptake of azelaic acid into maternal milk is not expected to cause a significant change and may not reflect the rates observed in practice. from baseline azelaic acid levels in the milk. Nevertheless, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. In two vehicle-controlled and one active-controlled U.S. clinical trials, treatment safety was monitored in 788 subjects who used twice-daily FINACEA Gel for 12 weeks (N=333) or 15 weeks (N=124), or 8.4 Pediatric Use the gel vehicle (N=331) for 12 weeks. In all three trials, the most common treatment-related adverse Safety and effectiveness of FINACEAGelin pediatric patients have not been established. events were: burning/stinging/tingling (29%), pruritus (11%), scaling/dry skin/xerosis (8%) and 8.5 Geriatric Use erythema/irritation (4%). In the active-controlled trial, overall adverse reactions (including burning, Clinical studies of FINACEA Gel did not include sufficient numbers of subjects aged 65 and over to stinging/tingling, dryness/tightness/ scaling, itching, and erythema/irritation/redness) were 19.4% determine whether they respond differently from younger subjects. (24/124) for FINACEA Gel compared to 7.1% (9/127) for the active comparator gel at 15 weeks. 17 PATIENT COUNSELING INFORMATION Table 1: Adverse Events Occurring in ≥1% of Subjects in the Rosacea Trials by Treatment Group Inform patients using FINACEA Gel of the following information and instructions: and Maximum Intensity* I N FACEA Gel, 15% e hVicle Use only as directed by your physician. = 4N57 (100%) = N331 (100%) •For external use only. iMld Moderate Severe Mild Moderate Severe •Before applying FINACEA Gel, cleanse affected area(s) with a very mild soap or a soapless cleansing = n99 n=61 n=27 n=46 n=30 n=5 lotion and pat dry with a soft towel. 2 2(%) (13%) (6%) (14%) (9%) 2(%) •Avoid use of alcoholic cleansers, tinctures and astringents, abrasives and peeling agents. Burning/ 71 (16%) 42 (9%) 17 (4%) 8 (2%) 6 (2%) 2 (1%) •Avoid contact with the eyes, mouth and other mucous membranes. If FINACEA Gel does come in stinging/ contact with the eyes, wash the eyes with large amounts of water and consult your physician if eye tingling irritation persists. •Wash hands immediately following application of FINACEA Gel. Pruritus 92 (6%) 18 (4%) 5 (1%) 9 (3%) 6 (2%) 0 (0%) •Cosmetics may be applied after the application of FINACEA Gel has dried. Scaling/ 21 (5%) 10 (2%) 5 (1%) 31 (9%) 14 (4%) 1 (<1%) •Avoid the use of occlusive dressings or wrappings. dry skin/ •Skin irritation (e.g., pruritus, burning, or stinging) may occur during use of FINACEA Gel, usually xerosis during the first few weeks of treatment. If irritation is excessive or persists, discontinue use and Erythema/ 6 (1%) 7 (2%) 2 (<1%) 8 (2%) 4 (1%) 2 (1%) consult your physician. irritation •Report abnormal changes in skin color to your physician. Contact 2 (<1%) 3 (1%) 0 (0%) 1 (<1%) 0 (0%) 0 (0%) •To help manage rosacea, avoid any triggers that may provoke erythema, flushing, and blushing. dermatitis These triggers can include spicy and thermally hot food and drinks such as hot coffee, tea, or alcoholic Edema 3(1%) 2 (<1%) 0 (0%) 3 (1%) 0 (0%) 0 (0%) beverages. Acne 3(1%) 1 (<1%) 0 (0%) 1 (<1%) 0 (0%) 0 (0%) © 2012, Bayer HealthCare Pharmaceuticals Inc. All rights reserved. * Subjects may have >1 cutaneous adverse event; thus, the sum of the frequencies of preferred terms may exceed the number of subjects with at least 1 cutaneous adverse event. In patients using azelaic acid formulations, the following adverse events have been reported: worsening of asthma, vitiligo, depigmentation, small depigmented spots, hypertrichosis, reddening (signs of Manufactured for: pilaris) and exacerbation of recurrent . Local Tolerability Studies FINACEA Gel and its vehicle caused irritant reactions at the application site in human dermal safety studies. FINACEA Gel caused significantly more irritation than its vehicle in a cumulative irritation Bayer HealthCare Pharmaceuticals Inc. Wayne, NJ 07470 study. Some improvement in irritation was demonstrated over the course of the clinical trials, but this improvement might be attributed to subject dropouts. No phototoxicity or photoallergenicity were Manufacture d in Italy reported in human dermal safety studies. 6706805BS