Dermatology Online Journal
D-penicillamine elastosis perforans serpiginosa: Description of two cases and review of the literature
- Author(s): Atzori, Laura
- Pinna, Anna Luisa
- Pau, Monica
- Aste, Nicola
- et al.
D-penicillamine elastosis perforans serpiginosa: Description of two cases and review of the literatureDermatology Departments of Cagliari University, Italy
Laura Atzori, Anna Luisa Pinna, Monica Pau, Nicola Aste
Dermatology Online Journal 17 (4): 3
Long term D-penicillamine (DPA) therapy to treat Wilson disease can induce elastosis perforans serpiginosa (EPS), a very rare degenerative skin disease characterized by a transepidermal elimination of elastic fiber aggregates. The iatrogenous disease depends on DPA capacity to chelate copper and cause its depletion. Lysyl-oxidase is a copper dependent enzyme crucial to the dermal elastic fiber cross-linking, which is strongly affected by DPA copper depletion. Direct binding of the drug to collagen precursors also affects elastic fiber assemblage and maturation. The abnormal elastin accumulates into the middle dermis and produces a characteristic bramble brush or “lumpy-bumpy” appearance. In this way it acts as a foreign body and is progressively extruded through the epidermis. Clinically, the disease presents with multiple firm keratotic papules and nodules arranged in annular plaques over the neck, axillae, antecubital fossae, and forearms. The rarity of the disease frequently causes misdiagnoses and the process continues unabated causing concerns about systemic elastopathy.
Elastosis perforans serpiginosa (EPS) is a rare condition affecting the skin elastic tissue. In 30 percent of the cases it is associated with systemic diseases, such as Down syndrome, Ehlers-Danlos syndrome, osteogenesis imperfecta, pseudoxanthoma elasticum, or Marfan syndrome [1, 2]. There are a few reports of a familial occurrence . The acquired form secondary to long-term treatment with D-penicillamine (DPA) was first reported in 1972 . The mechanism relates to the capacity of DPA to interfere with elastin cross-linking through the inhibition of a copper-dependent enzyme, the lysyl oxidase, or by formation of complexes with the collagen cross-linked precursors, impairing a normal maturation of elastic fibers . Iatrogenic EPS is extremely rare [6, 7], even though DPA has been used for several conditions including cystinuria and rheumatoid arthritis . The majority of cases are associated with Wilson disease treatment [4, 5, 6], probably because copper chelating and elimination is pushed to the maximum, requiring constant high levels of the drug for years. Skin lesions actually appear after several years of drug intake and slowly regress after the drug discontinuation. The disease occurs in young adults, mainly in the second decade of life. Scarring and skin atrophy is the rule after prolonged illness.
We describe two patients with DPA elastosis perforans serpiginosa seen at our clinic and review the clinical, pathological, and ultrastructural features of this uncommon degenerative disease. Misdiagnosis prolongs the illness and delays discontinuation of the drug. Although no fatal complication of DPA-induced EPS has been reported so far, a matter of concern is the documentation of morphologic changes of the elastic fibers in other tissues, especially arteries and lungs [9, 10, 11]. The potential to develop consequences of the subclinical systemic elastopathy is time and dose-dependent, and should be of concern.
A 28-year-old patient was diagnosed with Wilson disease at the age of 18 years. From that moment on, treatment with DPA at a daily dosage of 1-1.5 g has been prescribed. The patient consulted our clinic for a 3 year-history of progressive skin eruptions, characterized by hyperkeratotic annular and serpiginous lesions on the neck (Figure 1) and antecubital, and flexural surface of the right fore-arm (Figure 2). Lesions were 1-2 mm in diameter, red-violaceous in color, centered with a yellowish hyperkeratotic plug, firm in consistency, arrayed in serpiginous lines, sometimes completely annular. Central scarring of the skin within the circinate lesions was quite severe. The patient had been treated for tinea corporis by several physicians and received courses of systemic and topical anti-fungal medications without any improvement. A diagnosis of granuloma annulare was also suggested and treated with corticosteroids.
Skin biopsy showed acanthosis, keratotic plugs, and irregular, broadened rete ridges. Roundish aggregates of basophilic material were present in the papillary dermis, proximal to or surrounded by epidermal invaginations, sometimes opening to the skin surface and configuring perforating channels (Figure 3). A mixed inflammatory infiltrate with scattered giant cells was seen in the papillary dermis, denser at the base of the perforating channels. At higher magnification the dermal aggregates were made of rare eosinophilic fibrils, abundant basophilic fibers, and granular cellular debris (Figure 4). Basophilic changes of the collagen were also seen in the dermis. The specific elastic fiber stain revealed course, tortuous elastic fibers (Figure 5).
Electron microscopy was performed to document the typical alteration of the elastic fibers, showing an inner core surrounded by a wide electron-lucent coat, with lateral irregular sac-like protrusions (Figure 6).
Physical examination was otherwise unremarkable. Chest, cardiovascular, and neurologic examinations were within normal limits. Hemogram, prothrombin time, and renal function tests were normal, whereas liver function tests were slightly elevated, compatible with the underlying Wilson disease. Serum ceruloplasmin was 10 mcg/dl (normal: 20-55 mcg/dl). Serum and urinary copper was normal. Ultrasound of the abdomen confirmed mild hepatomegaly.
DPA was discontinued and a switch to treatment with zinc salts was begun for Wilson disease control. Skin lesions stopped progressing and no new lesions occurred. Once the disease became stable, individual lesions were treated with cryotherapy sessions (liquid nitrogen) every 3 weeks. The results were remarkable, except for temporary hypopigmentation and persistent central atrophy of the older plaques.
A 21-year-old male patient, affected with Wilson disease from the age of 16 was on long-term treatment with D-penicillamine at daily doses ranging from 1 to 1.5 g. He presented to our Dermatology department with a 2-year history of multiple red-brownish papules over the neck, which were enlarging and unresponsive to several topical treatments. He had been variously diagnosed with tinea corporis infection, lichenoid dermatitis, and granuloma annulare. Upon examination, both sides of the neck (Figure 7) exhibited multiple, non-tender plaques, centered by a hyperkeratotic plug or crust, and arranged in a circinate polycyclical pattern with central scarring and peripheral progression. Several isolated red-yellowish papules were also present. The rest of the physical examination was normal as well as blood chemistry, chest X-ray, cardiovascular, neurologic, and ocular examinations. Serum and urinary copper were normal; serum ceruloplasmin was 6.0 mcg/dl (normal value: 20-55 mcg/dl). Histopathology confirmed the diagnosis of elastosis perforans serpiginosa. He was treated with a series of cryotherapy sessions and local corticosteroids with very slow improvement. Discontinuation of D-penicllamine was followed by zinc salts administration for Wilson disease and after one year of follow-up no new lesions had appeared. Scarring sequelae from former lesions were evident on both sides of the neck.
The D-penicillamine (DPA) pathogenetic process affects the middle and deep dermal elastic fibers (4-10). Two mechanisms of action have been postulated and both are probably relevant to the final elastopathy:
- Copper deficiency secondary to D-penicillamine treatment impairs lysyl oxidase function on elastic fiber cross-linking, a crucial process to stabilize and compact the fibers. This effect requires very high doses and prolonged administration of the drug, as it is characteristically used in Wilson disease. Copper deficiency alone probably it is not sufficient, which is suggested by the observation that EPS has never been documented in Menkes disease, a severe genetic copper deficiency .
- Direct D-penicillamine post-translational inhibition of type I collagen synthesis, which further results in abnormal fiber deposition may also contribute. At the standard therapeutic dose DPA binds to the aldehydes present in collagen and inhibits intermolecular and intramolecular collagen cross-linking . This well-known effect has been exploited for the treatment of circumscribed and systemic scleroderma with benefit . As regards EPS, the formation of complexes with the collagen cross-linked precursors additionally impairs normal maturation of the elastic fibers.
The abnormal dermal elastic fibers accumulate and promote a foreign body reaction. Mehregan AH in 1968 , coined the term “transepithelial elimination” to describe the peculiar histopathology he observed in eleven personal cases of idiopathic EPS, characterized by the formation of epidermal perforating channels through which abnormal dermal elastic material was spontaneously eliminated. The transepidermal elimination seems to be primed by the presence of a specific elastin receptor on the keratinocyte surface. Fujimoto et al  interestingly documented this elastin receptor, strongly expressed in the active peripheral keratotic area, which is not detectable in the central inactive area of EPS. The receptor expression appears to be related to the content of elastic fibers in the dermal material. One may assume that the epidermis, activated by the presence of abnormal elastin, is stimulated to invaginate and delimit narrow channels. The lowest portion of the channels is surrounded by the proliferating epidermis, engulfing the entrance like a pair of pincers  and filled with blue staining necrobiotic material made of epithelial and inflammatory cells mixed with bright eosinophilic fibers . The upper dermis near the channels shows a chronic inflammatory infiltrate, often with several multinucleate giant cells .
Although clinical picture does not differ from that of idiopathic EPS, the histology and electron microscopic alteration of the DPA-induced form are peculiar . In comparison to the idiopathic EPS, there is no elastic fiber hyperplasia in the papillary dermis . With elastic tissue stains, the great alterations are located in the middle dermis, where the elastic fibers show peculiar alterations of morphology: they are thick, coarse and laterally budding. The buds are arranged perpendicular to the principal axis of the fiber, giving an aspect compared to the twigs of a bramble brush  or the teeth of a saw . These very peculiar changes of the elastic fibers have been named “lumpy-bumpy” [11, 21] and are seldom present in non-lesional skin. Atrophy of the skin is consistent and develops early at the center of annular plaques in contrast to idiopathic disease. Iozumi et al  found electron-microscopic evidence of randomly aggregated thin collagen fibers in the scar-like tissue, with no tendency toward normal combined bundle formation, which is consistent with the inhibitory effects of DPA on collagen assemblage and maturation.
On electron microscopy the affected elastic fibers show a normal inner core, with dark microfibrils embedded in electron-lucent elastin, but surrounded by an abnormal wide, homogenous electron-lucent coat . This peripheral material has the same appearance of elastin and protrudes laterally, with sac-like bulging between the adjacent collagen fibers [11, 20].
Microscopic and ultrastructural findings support the hypothesis that the abnormal elastin is produced later in the patient’s life, several years after the drug is started, and surrounds, like a coat, the normal elastic fibers. The coarse and loose elastic fibers resulting from the paucity of cross-linkages are unable to re-expand after contraction on their major axes, producing the lateral budding characteristic of DPA-induced EPS. This dynamic vision of DPA degenerative effects reminds us of another interesting point, which is the age of the patients, usually adolescents and young male adults. These patients still have very active dermal rearrangement and proliferation, which allows clear observation of progressive functional disorders. A possible relationship of sun exposure in the elastic fiber degeneration has not been investigated, but it is interesting that lesions tend to be localized on visible, sun-exposed areas, such as the nape and lateral sides of the neck or the forearms.
DPA-induced EPS is frequently associated with other diseases of the dermal soft tissue, such as cutis laxa [22, 23, 24], pseudoxanthoma elasticum [25-29], and some recently described cases of mucosal elastosis [30, 31], which are considered different expressions of the same degenerative process and may be summarized as one entity: penicillamine-induced degenerative dermatosis . The capacity of penicillamine to induce widespread and various types of cutaneous elastic fiber damage further suggests a potential for affecting the systemic elastic tissue, because similar changes have been demonstrated in arteries and lungs [9, 10, 11]. Immediate discontinuation of the drug is mandatory and patients should be carefully monitored for systemic sequelae, which might require several years to manifest.
To conclude, D-penicillamine may cause significant alterations of the elastic tissue, which are so peculiar that they are easy to distinguish histologically from idiopathic elastosis perforans serpiginosa. A decrease in lysyl oxidase activity and a direct drug interaction with collagen fiber precursors are both involved in this complex and interesting pathophysiology. Misdiagnosis and delayed intervention frequently allows the development of skin atrophy and scarring on very visible areas. Although skin manifestations are relatively innocuous, potential damage to vessels and lungs.
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