Elastosis Perforans Serpiginosa Secondary to D-Penicillamine Therapy with Coexisting Cutis Laxa

Elastosis Perforans Serpiginosa Secondary to D-Penicillamine Therapy With Coexisting Cutis Laxa Les B. Rosen, MD; Matthew Muellenhoff, DO; Thi T. Tran, DO; Michelle Muhart, MD Elastosis perforans serpiginosa (EPS) is a rare The patient presented to dermatology with a new complication of D-penicillamine therapy. EPS has onset eruption involving the back, axillae, chest, been reported in patients with Wilson disease, upper arms, and legs bilaterally. She stated this erup- cystinuria, and rheumatoid arthritis after many tion was sensitive to touch and contact with cloth- years of high-dose therapy. We report a case of ing. Findings from a physical examination showed D-penicillamine–induced EPS with coexisting loose hyperextensible skin on the trunk and extrem- acquired cutis laxa in a patient with cystinuria. ities with overlying grouped keratotic erythematous Although both EPS and acquired cutis laxa can papules arranged in a serpiginous pattern (Figure 2). be associated with D-penicillamine therapy, few Results of a 3-mm punch biopsy revealed short, cases have been reported with overlapping clin- thick, eosinophilic fibers with transepidermal elimi- ical presentations, and previously only in nation of elastin (Figure 3). The Verhoeff-van patients with Wilson disease. We review the Gieson stain highlighted elastic fibers with nodular characteristic clinical and histologic features of protrusions, giving a “zipperlike” pattern throughout EPS and discuss the potential dermatologic the dermis (Figure 4). Foreign body–type giant cell manifestations of D-penicillamine therapy. reaction to the elastic fiber was present. Cutis. 2005;76:49-53. The patient’s history and clinical and histologic findings supported the final diagnosis of elastosis perforans serpiginosa (EPS) secondary to D-penicillamine Case Report therapy with coexisting acquired cutis laxa. A 59-year-old white woman with cystinuria diagnosed D-penicillamine therapy was discontinued. At the at 20 years of age who had been on D-penicillamine patient’s request, conservative therapy was started therapy for more than 25 years, developed acquired with topical corticosteroids and antibiotics with dress- cutis laxa a few years after starting therapy (Figure 1). ings to open wound areas. However, her EPS has con- The loose skin folds were asymptomatic over the tinued to progress, with skin breakdown on the hips years, but recently she reported symptoms of dyspha- and thighs leading to chronic ulcerations that cur- gia and was found to have pulmonary fibrosis. She rently are being managed by wound care specialists. denied a history of joint involvement or cardiac symptoms. The patient developed inoperable kidney Comment stones with worsening renal function (attributed to Elastosis Perforans Serpiginosa—EPS, one of 4 essen- her cystinuria) and was placed on hemodialysis tial perforating disorders, including reactive perfo- 6 months prior to presentation. rating collagenosis, perforating folliculitis, and Kyrle disease, is characterized by extrusion of coarse, fragmented elastic fibers from the papillary Accepted for publication May 5, 2004. Dr. Rosen is in private practice, Fort Lauderdale, Florida. dermis through narrow epidermal channels result- Drs. Muellenhoff and Tran are from NOVA Southeastern ing clinically in umbilicated papules arranged in a University/Sun Coast Hospital, Largo, Florida. Dr. Muhart is in serpiginous pattern.1 private practice, Lake Worth, Florida. The primary lesions of EPS are described as dis- The authors report no conflict of interest. crete or grouped, flesh- to red-colored papules that Reprints: Matthew Muellenhoff, DO, NOVA Southeastern University/ Sun Coast Hospital, Dermatology Residency program, form arcuate or serpiginous patterns on the skin. A 1559 Indian Rocks Rd, Largo, FL 33770 central plug is seen that, if removed, can result in (e-mail: [email protected]). bleeding. Distribution is primarily on the face, VOLUME 76, JULY 2005 49 Elastosis Perforans Serpiginosa Figure not available online Figure 1. Loose skin folding associated with acquired cutis laxa. Figure 2. Serpiginous papules of elastosis perforans serpiginosa on the upper back of a patient with acquired cutis laxa. neck, upper trunk, and extremities and is some- The precise mechanism of D-penicillamine– times strikingly symmetrical. Although the clinical induced EPS is unclear. The drug has been shown features of EPS are quite distinct, the differential to directly inhibit cross-linking of elastin, resulting diagnosis includes granuloma annulare, tinea cor- in the deposition of abnormal elastin fibers. At poris, sarcoidosis, porokeratosis, and the above- higher doses, D-penicillamine also chelates copper, mentioned perforating disorders.1 thereby indirectly inhibiting the action of lysyl oxi- The classic histologic changes to elastin associ- dase, a copper-dependent enzyme required for cross- ated with D-penicillamine therapy have been linking collagen and elastin fibers.2,4 Supporting this described as “lumpy-bumpy,” “saw-toothed,” or theory, reports show that experimentally induced “bramble-bushlike” changes to thickened dermal copper deficiency has led to production of struc- elastic fibers. These changes, which can be seen turally and functionally deranged elastin.1,5 Exces- with hematoxylin-eosin (H&E) stain, accentuated sive buildup of abnormal elastic fiber promotes by Verhoeff-van Gieson elastic stain, or imaged by foreign body–type reaction and transepidermal elim- electron microscopy, are distinctive and specific for ination manifesting clinically as EPS. Considering the D-penicillamine–induced variety of EPS.2 both the rarity of EPS (even in the presence of long- Doses of 1 g daily for more than 5 years have been term D-penicillamine therapy) and the absence of suggested as the likely dose/duration prior to dis- EPS in copper-deficient patients with Menkes syn- playing these “classic” histologic changes.3 drome (kinky-hair disease), additional unidentified 50 CUTIS® Elastosis Perforans Serpiginosa Figure 3. Lesional biopsy of elastosis perforans serpiginosa showing epidermal hyperplasia with transepidermal elimination of elastin (H&E, original magnification ϫ100). Figure 4. Elastic fibers exhibiting the classic “lumpy- bumpy” or “zipperlike” nodular protrusions associated with penicillamine- induced elastosis perforans serpiginosa (Verhoeff-van Gieson stain, original magnification ϫ400). factors besides the effects of D-penicillamine are in patients receiving treatment for Wilson dis- likely needed to cause EPS to manifest.1 ease.6,7 To our knowledge, we report the first case of Development of EPS, though rare, is well des- D-penicillamine–induced cutis laxa and EPS in a cribed in cases of Wilson disease and is presumably patient with cystinuria. due to the longer treatment courses and the higher Therapeutic management of EPS can be chal- doses of D-penicillamine required. Even fewer lenging; only a few treatment options are reported reports exist documenting the coexistence of EPS in the literature. Successes with isotretinoin and and acquired cutis laxa, with both cases occurring pulsed dye laser have been reported, as well as VOLUME 76, JULY 2005 51 Elastosis Perforans Serpiginosa spontaneous resolution 36 months after cessation of capsules, these reports are far outnumbered by D-penicillamine therapy.8 In our case, outside of stop- EPS as a sole entity. Hill et al6 reported a 36-year- ping D-penicillamine, the patient opted to forego sys- old woman with EPS and acquired cutis laxa from temic treatment because of existing comorbidities. long-term D-penicillamine therapy for Wilson Acquired Cutis Laxa—Acquired cutis laxa is disease. She also had pharyngeal and tongue also a well-described complication of long-term weakness with ineffective cough reflex, which D-penicillamine therapy. Defined by loose sagging the authors believed represented upper respira- skin with decreased elasticity, acquired cutis laxa tory involvement of D-penicillamine–induced occurs as a localized or generalized eruption. elastolytic change.6 Inflammatory conditions (eg, urticaria, Sweet Price and Prentice2 reported another patient syndrome, erythema multiforme, nephrotic syn- with Wilson disease who received D-penicillamine drome), hematologic disorders (eg, myeloma), Borrelia infections, and long-term D-penicillamine therapy are a few conditions associated with disease onset.9 Proposed mechanisms include the release of activated elastases from inflammatory Table 1. cells into the extracellular compartment, leading to proteolytic degradation of elastic fibers.10 In Adverse Reactions Associated With D-penicillamine–induced cutis laxa, the drug is D-Penicillamine Therapy11,12 thought to directly and indirectly interfere with elastin cross-linking, as described with EPS, result- Adverse Reactions Incidence, % ing in poorly stable elastic fibers and the clinical manifestations of loose sagging skin.9 Cutaneous reactions 25–50 D-Penicillamine—D-penicillamine has been used Gastrointestinal symptoms in the treatment of Wilson disease, cystinuria, and (anorexia, epigastric pain, juvenile rheumatoid arthritis. Cutaneous side effects include immediate hypersensitivity reaction, pemphi- nausea, vomiting, diarrhea) 17 gus, and morphea; at higher doses, side effects include Dysgeusia 12 drug-induced dermatopathy, EPS, cutis laxa, and pseudoxanthoma elasticum. A comprehensive listing Proteinuria/hematuria 6 of adverse events associated with D-penicillamine Thrombocytopenia 4 therapy is noted

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