Delineating the Perforating Dermatoses: Case Reports and a Review of the Literature

Richard Limbert, DO,* Rachel White, BA,** Richard Miller, DO, FAOCD***

*Dermatology Resident, 3rd year, Nova Southeastern / Largo Medical Center, Largo, FL **Medical Student, 4th year, Philadelphia College of Osteopathic Medicine, Philadelphia, PA ***Program Director, Dermatology Residency, Nova Southeastern / Largo Medical Center, Largo, FL

Abstract Perforating dermatoses (PD) are a rare group of papulonodular skin diseases with a distinct central keratotic core representing the transepidermal elimination of an altered dermal substance. Diagnosis is established via biopsy and histopathologic evaluation. The primary PD are best categorized into four groups: reactive perforating collagenosis (RPC), acquired perforating dermatosis (APD), elastosis perforans serpiginosa (EPS), and perforating calcific elastosis (PCE). The primary PD can be differentiated based on the perforating substance, the distribution of the lesions, and their unique associations. Diagnosis of a PD should prompt screening for underlying systemic disease. Treatment of the PD is often difficult, but numerous reports have shown success. Here we present our case reports and a thorough literature review incorporating all identified case reports and studies found on PubMed as of July 2015. Introduction follicular structures. Special stains may be used to Perforating dermatoses (PD) represent a rare help identify the perforating substance. group of papulonodular skin diseases with a The precise pathogenesis of the PD is unknown. It distinct central keratotic core. The core represents is postulated that the primary PD may be due to the transepidermal elimination of an altered abnormal dermal substances, whether genetically 1 dermal substance. Diagnosis is established altered or acquired. Other theories question via biopsy and histopathologic evaluation. whether the PD represent a unique pathologic Whereas primary PD are diseases chiefly process or are simply a result of mechanical characterized by transepidermal elimination, exposure of dermal substances.1 secondary PD are a group of unrelated Various classifications of the PD have been used disorders in which transepidermal elimination 1 in the literature, and various names have been is a minor phenomenon of another disorder. reported for each entity. This has led to ambiguity The primary PD are best categorized into four and confusion. A useful classification scheme of Figure 1. Dome-shaped papules with keratotic groups: reactive perforating collagenosis (RPC), 2 all PD was proposed by Patterson in 1984: core overlying the knuckles. acquired perforating dermatosis (APD), elastosis perforans serpiginosa (EPS), and perforating 1. Perforation as an incidental histologic finding calcific elastosis (PCE). The primary PD can be 2. Perforation associated with other cutaneous differentiated based on the perforating substance, and systemic disorders (secondary PD) the distribution of the lesions, and their unique associations (Table 1).1 Diagnosis of a PD 3. Disorders chiefly characterized by perforation should prompt screening for underlying systemic (primary PD) disease. Treatment of the PD is often difficult, but Even more numerous are the variations of the numerous reports have shown success. primary PD in the literature. The authors feel the Amongst the PD, a shared histopathologic best classification is outlined in Table 1 and will sequence occurs, and findings depend on the be discussed in this review. stage of evolution.1 First, a hyperkeratotic plug or crust forms. The plug enlarges, inducing Case Reports surrounding epidermal hyperplasia and occasional Case 1 dyskeratosis. Inflammatory cell aggregates may A 17-year-old Hispanic male presented with be seen in the plug and adjacent dermis. In Figure 2. Dome-shaped papules with keratotic a three-year history of spreading “.” He well-developed lesions, the plug contains the core overlying the elbow. denied pain, pruritus, or manipulation of lesions perforating substances: collagen, elastic fibers, and requested treatment for cosmetic concerns. amorphous degenerated material, and/or altered allergic rhinitis, and medulloblastoma. He Past medical history was significant for asthma, had attempted numerous over-the-counter Table 1. Primary perforating dermatoses treatments, including topical salicylic acid and Perforating Substance Location Associations cryotherapy, with no improvement. Reactive perforating Collagen Extremities, overlying None Physical exam revealed skin-toned, dome-shaped collagenosis sites of trauma papules with a central keratotic core concentrated over the dorsal hands (Figure 1), elbows (Figure Acquired Collagen, elastic fibers, Lower extremities or Pruritus, diabetes, 2), and knees. perforating or necrotic material generalized renal failure, liver dermatosis disease, malignancies, A punch biopsy of a representative lesion on the endocrinopathies elbow was taken (Figure 3). There was a cup- Elastosis perforans Elastic fibers Lateral neck, flexures Genetic diseases, shaped invagination of acanthotic epidermis with serpiginosa penicillamine a plug of keratin, collagen, and inflammatory debris. High magnification revealed Perforating calcific Calcified elastic fibers Abdomen, periumbilical, Multiparity, obesity vertically oriented collagen fibers undergoing elastosis areolar transepidermal elimination. Verhoeff-van

Page 20 DELINEATING THE PERFORATING DERMATOSES: CASE REPORTS AND A REVIEW OF THE LITERATURE A punch biopsy was taken from the lower leg, RPC is histologically characterized by a cup- screening labs were ordered, and the patient shaped invagination of acanthotic epidermis was started on desoximetasone 0.25% ointment containing a plug of vertically oriented collagen bid. The biopsy revealed a channel through fibers, keratin, and inflammatory debris. The an acanthotic epidermis filled with a plug of connective tissue surrounding the plug is amorphous, degenerated material with overlying typically unremarkable.6 After the plug falls off, parakeratosis and underlying neutrophils the epidermis atrophies.There is no gold standard (Figure 6). Verhoeff-van Gieson stain failed of treatment for RPC. Treatment is not necessary to demonstrate perforating elastic fibers. Labs since lesions may spontaneously resolve and are revealed a low hemoglobin and elevated alkaline largely asymptomatic.1 Yasmeen et al. compared phosphatase, AST, and ALT. treatment between 10 patients with RPC and report the most successful responses were with oral and topical tretinoin combined Figure 3. Invagination of acanthotic with emollients.5 Other treatments reported epidermis with a plug of keratin, collagen, and with varying levels of success include: topical inflammatory debris (H&E). steroids under occlusion, photochemotherapy, UVB phototherapy, cryotherapy, allopurinol, Gieson stain failed to demonstrate perforating methotrexate, and electrical nerve stimulation.1,8 elastic fibers. A diagnosis of reactive perforating Despite all treatment regimens, RPC often collagenosis was made. recurs.8 The patient was started on topical tretinoin 0.1% Acquired Perforating Dermatosis cream daily. He returned after three months for APD is overwhelmingly the most common follow-up and displayed moderate improvement, PD. This category includes all PD arising in but smooth papules remained. The patient noted adults that have been previously reported as that the lesions tended to recur and decided Figure 6. A channel through acanthotic acquired RPC, acquired EPS, Kyrle’s disease, against further treatment. 1 epidermis filled with a plug of amorphous and perforating folliculitis, among others. degenerated material (H&E). Case 2 The splitting of this group reflects the variable A 42-year-old African American male presented histologic morphologies found in lesions of APD depending on the stage of development. A biopsy with an extremely pruritic, widespread eruption A diagnosis of acquired perforating dermatosis may reveal perforating collagen, elastic fibers, that had been worsening over three weeks. was established. The patient was referred to his amorphous degenerated material, and/or altered He tried over-the-counter itch creams and gastroenterologist for evaluation and treatment 9 follicular structures. emollients with no benefit. Past medical history of his anemia and hepatitis and was subsequently was significant for alcoholic hepatitis. He lost to follow-up. The classification of APD has changed over time, reported a similar eruption several years ago that and disagreement remains amongst authors. was successfully cleared with phototherapy. Discussion Kyrle’s disease was first described by Kyrle in Physical exam revealed hyperpigmented, 1916 as “follicular et parafollicularis in cutem keratotic papules scattered on the face, trunk, and Reactive Perforating Collagenosis penetrans” in a diabetic female with generalized RPC was first reported in a 6.5-year-old female hyperkeratotic nodules.10 Kyrle’s disease is extremities (Figure 4). Some lesions displayed a 3 strikingly linear pattern (Figure 5). by Mehregan et al. in 1967. It is a very rare, sometimes used synonymously with APD, and inherited disease thought to be caused by a genetic some describe it as the end stage of excoriated abnormality of collagen. Attempts to isolate the hyperplastic nodules of folliculitis. Patterson specific genetic defect have been unsuccessful et al. propose that perforating folliculitis and to date. RPC occurs in an autosomal-recessive acquired RPC are subsets of Kyrle’s disease.2 pattern, although there have been isolated reports Others suggest perforating folliculitis is not a 4 of autosomal-dominant inheritance. Onset is in specific disease, as perforation of follicles can childhood, with a mean age of 5.3 years, and there occur in any folliculitis regardless of the etiology. 5 is no gender or racial predilection. The term “acquired perforating dermatosis” was 10 Lesions present as 5 mm to 8 mm, flesh-colored first used by Rapini et al. in 1989. Kim et al. papules with a central keratotic core. They grow characterize the various APD lesions in a study over three to four weeks and may spontaneously of 30 cases as follows: KD-like hyperkeratotic resolve over six to 10 weeks, though some papules, PF-like follicular infiltrating papules, Figure 4. Keratotic papules scattered on the persist.1,6 Some lesions can grow up to 2 cm with EPS-like serpiginous hyperkeratotic papules, or trunk. increased age and a lack of treatment.4 There RPC-like keratotic plugged umbilicated papules 11 may be only a few localized lesions, or lesions (most common: 66.7%). can be more widespread and numerous. RPC APD occurs in middle-aged adults, with no can remain quiescent for long periods of time, 1,11 7 gender or geographic predilection. In the but a relapsing-remitting course is common. largest study to date, Kim et al. report a mean age RPC occurs in areas of superficial trauma and of onset of 55.5 years.11 APD generally presents Koebnerizes more than any other PD.2,5 The most as umbilicated papules and nodules with a central frequently affected areas include the dorsal hands, white keratotic core. The core is sometimes forearms, elbows, and knees.3,5,6 Some reports picked and physically removed by patients. Giant have associated exacerbations with cold weather variants have been reported where lesions are 2 in the winter months. It is postulated that the 12 cm. Lesions can be found on any cutaneous cold may induce degeneration of collagen and 5,8 surface, but the extensor lower legs are most Figure 5. Linear keratotic papules on the leg. thinning of the epidermis. Pruritus is not common, and many cases are generalized and prominent but has been reported in less than half 5 diffuse. Koebner’s phenomenon is occasionally of patients.

LIMBERT, WHITE, MILLER Page 21 seen, resulting in a linear configuration.11 Mucous four patients with APD. Schreml et al. agree that hydroxyapatite, or silicon, and metabolic membranes, palms, and soles are generally spared, all APD have similar pathogeneses because all disturbances leading to alteration of fibers, but there has been a report of conjunctival and eliminated materials, including collagen, elastin prompting their elimination.1,11 Another theory buccal involvement.11 Lesions persist anywhere and keratin, have been noted in one patient.17 proposes a role of abnormal vitamin A or D.6 from one month to five years, with an average On the contrary, Saray et al. propose that APD Anecdotal success of antibiotics for treatment has duration reported by Kim et al. of 7.8 months. represent a broad spectrum and are not variants led to the idea of a possible infectious etiology.23,24 13 The most common reported associated symptom of the same process. Kim et al. also did not There are also familial reports of APD. One is pruritus, and few report pain.11 Rarely, a observe overlapping histologic features in the 11 family in India has 22 members afflicted with secondary infection may occur from bacteria (S. same patient. 25 so-called Kyrle’s disease over five generations. aureus), atypical mycobacteria (M. abscessus), or There is also debate as to whether perforation Unique features are also noted within the affected fungi (Mucor sp.).1 actually exists. Schreml et al. point out that family members, including eye changes and APD is most commonly associated with diabetes scratching may lead to epidermal gaps that expose palmoplantar lesions.There are no clinical studies or chronic renal failure (CRF). APD is also subepithelial contents, which may appear as conducted regarding treatment for APD, and associated with numerous other underlying perforation.17 Therefore, they advocate obtaining therefore there is no gold standard. Conventional systemic diseases, particularly ones that cause continuous imaging of the evolving lesions to treatments have been derived from case reports. pruritus.1 Saray et al. report that 86.4% of APD guide understanding of the pathohistologic Kim et al. report 93.3% of patients responding patients have at least one systemic disease.13 An mechanism; however, that is not possible at this to topical steroids and 80% responding to estimated 90.9% of diabetic patients with APD point.APD is proposed to originate from pruritus antihistamines to decrease pruritus.11 Control of have an associated nephropathy, but non-diabetic resulting in chronic scratching and epidermal pruritus and treating any underlying disease is CRF has been reported as well. Further, most hyperplasia. A similar is process is seen in prurigo the key to treatment. Other commonly reported patients with CRF are on dialysis, but it can nodularis, a common concomitant condition treatments include intralesional steroids and occur earlier in the disease course prior to dialysis seen with APD.11 This theory is supported by topical retinoids. Other reported treatments initiation. Approximately 10% of dialysis patients the presence of Koebnerization. Fujimoto et al. include: UVB, PUVA, oral retinoids, and develop APD. 11 Other reported associations propose that scratching exposes keratinocytes to methotrexate.11 Some dialysis patients have been include liver disease (primary biliary cirrhosis, advanced glycation end product (AGE)-modified cured of disease after transplant.27 hepatitis, alcoholic cirrhosis), malignancies extracellular matrix proteins, specifically collagen Allopurinol has recently emerged as a useful 18 The interaction leads to terminal (Hodgkin’s lymphoma, hepatocellular carcinoma, types I and III. treatment of APD. Hoque et al. successfully differentiation of keratinocytes via AGE receptor thyroid cancer, acute leukemia), endocrinopathies treated four patients with a giant variant with (CD 36) and results in keratinocytes along 12 (hypothyroidism, hyperparathyroidism), allopurinol. The theory behind the use of a infections/infestations (, aspergillosis, with glycated collagen moving upward through xanthine oxidase inhibitor is that it reduces herpes zoster, ), congestive heart epidermis. oxygen free radicals, which cause collagen damage failure, neurodermatitis, , and 1 Other studies suggest that the interaction of and skin necrosis. Allopurinol is also reported to Kim et al. reported a pregnant APD 28 AIDS. keratinocytes with altered structural proteins inhibit neutrophil activity. case with no associated DM, CRF or previous plays a role. Fibronectin is increased in both the cutaneous disease.11 APD has also associated with Antibiotics have been used to treat culture- serum and lesional skin of diabetic and renal- negative APD. Clindamycin is reported to have TNF alpha inhibitors, bevacizumab, sirolimus, 18 Fibronectin is an 13 failure patients with APD. cleared a case after Kasiakou et al. noted the and indinavir. extracellular matrix protein involved in epithelial inflammatory histologic findings and suspected An extremely rare variant of APD called cell signaling, movement, and differentiation. It an infectious cause, thought to be anaerobic verrucous perforating collagenomas is reported binds collagen IV and keratinocytes and may 24 bacteria. Doxycycline has also been used in the literature but not well understood. It induce epithelial proliferation and transepidermal successfully in cases of APD.29 Metronidazole 19 One study identified type IV is characterized by verrucous papules with elimination. was successfully used in another case in which collagen from the basement membrane as transepidermal elimination of collagen. It occurs biopsy showed inflammatory infiltration in the 9 the specific type of collagen eliminated.20 after severe trauma. lesion. As opposed to clindamycin, metronidazole Other proteins overexpressed in APC include: Acquired perforating calcific collagenosis is an β does not have any anti-inflammatory properties, transforming growth factor beta-3 (TGF -3), 23 APD variant that develops after topical calcium which supports an infectious etiology. ) exposure. In certain cultures, matrix metalloproteinase-1 (MMP-1), and tissue chloride (CaCl2 A vitamin D3 synthetic analogue, tacalcitol, used CaCl is used to treat dermatitis and pruritus. inhibitor of metalloproteinase-1 (TIMP-1); 2 however, this may simply reflect normal wound in the treatment of has also been used to Lee et al. report two patients exposed to a CaCl - 30 2 17,21 treat APD. Tacalcitol inhibits the proliferation containing emulsion, used to produce bean curd, healing in these sites. 14 of keratinocytes and simultaneously modifies who developed coalescing umbilicated papules. An abundance of neutrophil remnants has inflammatory mediators. Since APD lesions Histologically, the lesions show transepidermal been found in early lesions of APD, leading contain significant inflammation and epidermal elimination of calcified collagen and elastic tissue. some to believe that proteolytic enzymes, such hyperplasia-like psoriatic lesions, Escribano- 17 The The authors were able to experimentally induce as collagenase and elastase, play a role. Stablé et al. decided to use this treatment on a case enzymes may transgress the epidermis and digest 30 similar phenomena in guinea pigs. Patel et al. refractory to topical steroids and antihistamines. extracellular matrix components, leading to report similar findings in a patient exposed to They report achieving complete remission after 14-16 It also destruction of anchoring fibrils and collagen IV, rock salts containing calcium chloride. two months. has been described in oil field workers exposed to ultimately resulting in their elimination.Another the chemical.14 theory pinpoints diabetic microvasculopathy 11,22 Elastosis Perforans Serpiginosa Histologically, APD shows cup-shaped as the culprit. Microvasculopathy leads to Lutz first described EPS in 1953 and termed the dermal necrosis by hypoxia. This would incite the invagination of epidermis plugged with disease “ follicularis serpiginous” based 31 amorphous, degenerated material and elimination of the necrotic dermal material.This on the unique configuration. In 1955, Miescher inflammatory cell debris.10 Rapini et al. originally mechanism is supported by positive periodic acid- characterized the specific pathologic finding of proposed that the histologic findings represent Schiff staining of thickened blood vessel walls in perforating elastic fibers and termed the disease 32 different stages or different types of lesions the upper dermis in diabetic patients with APD. “elastoma intrapapillare perforans verruciform.” within the same pathologic process.10 They report Other proposed hypotheses involve deposition Dammert and Putkonen coined the current name 33 elimination of both collagen and elastic fibers in of substances such as calcium salts, uric acid, in 1958. EPS can either be idiopathic (most

Page 22 DELINEATING THE PERFORATING DERMATOSES: CASE REPORTS AND A REVIEW OF THE LITERATURE common), drug-induced, or reactive. There are influence the differentiation of keratinocytes.42 calcified elastic fibers in the upper reticular and also few familial reports of EPS.34,35 They propose that altered elastic fibers papillary dermis.48 The pathogenesis of PCE is It is reported that 40% of EPS patients have an accumulate in the dermis and induce upward unknown. Pruzan et al. propose lesions originate movement and differentiation of keratinocytes from repeated stretching of the skin from underlying genetic disorder involving fibrous 46 tissue including: Down syndrome, Ehlers- via elastin-receptor protein, 67 kDa. Expression multiparty, obesity, ascites, or surgery. Danlos syndrome, osteogenesis imperfecta, of 67 kDa elastin-binding protein has not been No successful treatments have been identified for Marfan syndrome, pseudoxanthoma elasticum reported in normal epidermal keratinocytes but PCE. Failed treatments include topical tretinoin (PXE), , Rothmund-Thomsonis overexpressed in elastin-rich connective tissue. and topical steroids.48,52 1,33 Other reports have implicated immunologic syndrome, acrogeria, and Moyamoya disease. 33 An extensive history and physical exam should dysfunction like that seen in Down syndrome. Secondary Perforating Dermatoses be performed when establishing the diagnosis. Reports of EPS implicating dysfunctional Secondary perforating dermatoses are a group However, pediatric dermatologists collectively do epidermal barrier from mechanical trauma, of unrelated disorders in which a substance not routinely perform genetic testing on the sole chemicals like calcium chloride salt water, and is transepidermally eliminated as a minor basis of EPS in an otherwise healthy child.36 scabies are best classified as APD.14,15,33 phenomenon of another disorder. As with the primary PD, the epidermis becomes hyperplastic, EPS has a predilection for males in a 4:1 ratio As with other perforating disorders, there are surrounds the substance being eliminated, and and most commonly occurs in the second decade no clinical trials or gold standards for treatment. 33,37 causes the upward extrusion via keratinocyte of life. EPS is characterized by 2 mm to 5 Several treatments are described with mixed 1 maturation. Secondary PD include substances mm, keratotic papules in a serpiginous or annular efficacy and poor long-term success. Destructive that are endogenous (chondrodermatitis 1 Rings of papules may be up to configuration. modalities attempted include cryotherapy, nodularis helicis, hematomas, , several centimeters in diameter. Lesions are most curettage, electrocautery, dermabrasion, excision, lichen nitidus, papular mucinosis, amyloidosis), commonly located on the lateral neck but can also tape stripping, topical salicylic acid, and CO2 exogenous foreign materials (silica, wood, suture), appear on the face and flexural extremities.1 There laser.1 Caution is advised, as there is risk of infectious organisms (chromoblastomycosis, are isolated case reports of EPS on the axilla and scarring with these modalities. Furthermore, 33 leprosy, schistosomiasis, tuberculosis, glans penis. EPS is typically asymptomatic. treatment is not necessary, as EPS remains leishmaniosis), ( annulare, Diagnosis is established through biopsy. EPS localized and asymptomatic. Mixed results are lipoidica, sarcoidosis, rheumatoid lesions show eosinophilic elastic fibers and also reported using topical and intralesional nodules, tophaceous gout), and neoplastic cells steroids, UVB, erbium-doped yttrium aluminium other basophilic debris filling tortuous channels 43 (melanoma, Paget’s disease, mycosis fungoides, Successful 1,53 that span from the papillary dermis to the (Er-YAG) laser, and pulsed dye laser. pilomatricoma, nevus sebaceous). Perforation case reports are described using topical epidermis. In adjacent dermal tissue there are in these dermatoses is best considered an imiquimod, topical calcipotriene ointment, and many inflammatory cells including lymphocytes, incidental finding. systemic isotretinoin.43 Topical tazarotene was macrophages, and multinucleated giant cells and 33 used with remission of lesions that recur when also altered elastic tissue. Elastic fibers are best highlighted by special stains like Verhoeff-van medication was discontinued. Phenytoin was Conclusion tried in one case with no success.33 There are also The PD have been classified and named in Gieson, which stains elastin black. reports of successful treatment of resistant cases numerous ways in the literature, which has led Pass et al. documented the first drug-induced with photodynamic therapy and topical allium to confusion. This thorough literature review EPS in a patient with Wilson’s disease on cepa-allantoin-pentaglycan gel.43 attempts to compile all available case reports long-term treatment with penicillamine.38 EPS and studies of the PD from PubMed. The has also been documented in patients taking Perforating Calcific Elastosis primary PD are best organized into four groups. penicillamine for cystinuria. Thirty-three percent PCE is an exceedingly rare disease and is both Diagnosis of a PD should prompt the evaluation of patients on high-dose therapy will develop histologically and clinically similar to PXE. for underlying disease. Further studies are needed EPS.39 EPS has also been recognized in patients Some authors argue PCE is a localized form of to elucidate effective treatment options. on low-dose treatment for rheumatoid arthritis, PXE, while others say it is a separate entity.44 primary biliary cirrhosis, and scleroderma. Still, PCE is acquired and localized, whereas PXE is penicillamine-induced EPS accounts for only an autosomal-recessively inherited, multi-organ References 40 1. Bolognia JL, Jorizzo JL, Schaffer JV, editors. 1% of all EPS cases. The elastic fibers seen in systemic disease. PCE has also been reported Dermatology. 3rd rev. ed. Philadelphia: Elsevier 46 these cases have a distinct lumpy appearance as “periumbilical perforating PXE.” The first Limited; 2012. p. 1599. with lateral buds. Penicillamine is hypothesized case of PCE was diagnosed as EPS with PXE 47 2. Patterson JW. The perforating disorders. J Am to disrupt desmosine crosslinks within elastin by Schutt in 1965. Lund and Gilbert reported 40 Acad Dermatol. 1984 Apr;10(4):561-81. by inhibiting the enzyme lysyl oxidase. The PCE as a separate entity in 1976, terming it damaged elastic tissue is then eliminated through “perforating PXE,” and Lever and Schaumburg- 3. Mehregan AH, Schwartz OD, Livingood CS. the epidermis. Theories regarding the role of Lever coined the term “PCE” in 1989.48,49 Reactive perforating collagenosis. Arch Dermatol. 1967 Sep;96(3):277-82. copper metabolism in EPS are debunked by the PCE occurs most commonly in middle-aged, presence of EPS in patients taking penicillamine obese, multiparous African-American females.1 4. Kumar V, et al. Familial reactive perforating for diseases other than Wilson’s. Penicillamine Woo and Rasmussen reviewed 22 cases of PCE collagenosis. J Dermatol. 1998 Jan;25(1):54-6. has also been shown to cause other cutaneous and reported an 82% female preponderance with 5. Bhat YJ, Manzoor S, Qayoom S, Wani R, Baba changes like pseudo-PXE and acquired cutis a mean age of onset of 43 years.50 PCE presents AN, Bhat AH. Familial Reactive Perforating 33,39 Furthermore, laxa by damaging elastic tissue. as yellowish verrucous plaques with keratotic Collagenosis. Indian J Dermatol. 2009;54(4):334- penicillamine has been found in the skin of an papules scattered at the periphery. Lesions are 7. EPS patient 25 years after discontinuation of usually exclusively distributed on the abdomen, the drug. This may explain why discontinuing 6. James WD, Elston DM, Berger TG, Andrews especially periumbilically; however, there is a GC, editors. Andrews’ Diseases of the skin: Clinical penicillamine does not prevent more EPS lesions 41 report of lesions on periareolar skin in one patient Dermatology. London: Saunders/Elsevier; 2011. p. from developing. 45,50,51 and on the axilla of another. 497-505. Most theories for EPS pathogenesis focus on Histologically, PCE shows short, thick, 7. Ramesh V, Sood N, Kubba A, Singh B, Makkar altered elastic fibers. A hypothesis presented basophilic, calcified elastic fibers residing in R. Familial reactive perforating collagenosis: a by Fujimoto et al. through in vitro studies the lower dermis. EPS, in contrast, reveals non- clinical, histopathological study of 10 cases. J Eur demonstrated that elastic fibers interact with and

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J Dermatol. 2010 beta3 and extracellular matrix proteins in acquired IH. Elastosis perforans serpiginosa during Jul;37(7):585-92. reactive perforating collagenosis. J Am Acad penicillamine therapy for Wilson disease. Arch Dermatol. 2009 Mar;60(3):463-9. Dermatol. 1973 Nov;108(5):713–5. Correspondence: Richard Limbert, DO; 22. Akoglu G, Emre S, Sungu N, Kurtoglu G, 39. Iozumi K, Nakagawa H, Tamaki K. Penicillamine induced degenerative dermatoses: Report of a case [email protected] Page 24 DELINEATING THE PERFORATING DERMATOSES: CASE REPORTS AND A REVIEW OF THE LITERATURE