Clinical and Laboratory Investigations Dermatology 1992:184:12-18
Department of Dermatology, Yale University School of Medicine. New Haven, Conn.. USA
Key Words Pseudoxanthoma elasticum Penicillamine Elastic fibers
Pseudoxanthoma-elasticum-Like Skin Changes Induced by Penicillamine
Abstract The interference of penicillamine with collagen and elastin cross-linking can lead to wrinkling and anetoderma-like lesions in flexural areas as well as fragility and hemorrhagic blisters in pressure areas. These changes are seen primarily in patients with Wilson’s disease orcystinuria who arc on long-term therapy. This is a report of a patient with cystinuria on long-term, high-dose penicillamine who developed pseudoxanthoma-elasticum-likc lesions. Coalescent yellow papules with a ‘plucked-chicken skin’ appearance were seen in the axillae and on the neck while redundant skin folds were noted in the anterior axillary line and lower buttocks. By light and electron microscopy, involved and uninvolved skin demonstrated ‘lumpy-bumpy’ dermal elastic fibers with no calcium deposition. These histologic changes are similar to those previously described in patients with penicillamine-induced skin lesions.
Introduction Penicillamine (D-ß.ß-dimethylcysteinc) is currently used in the treatment of several disorders including Wil son's disease (hepatolenticular degeneration), cystinuria, severe rheumatoid arthritis, primary biliary cirrhosis and progressive systemic sclerosis. Administration of this drug has resulted in a wide range of mucocutaneous reactions including: urticaria [1], morbilliform eruptions [2], lichen planus [3], dermatomyositis [4], pemphigus erythematosus [5], foliaceus [6] and vulgaris |7|. cicatricial pemphigoid [8], elastosis perforans serpiginosa (EPS) (9] and a dermatopa-
Received: March 25. 1991
Accepted: June 14. 1991
thy characterized by either (1) wrinkling and anetoderma like lesions in flexural areas [ 10] or (2) fragility, bullae, pur pura, milia and wrinkling on extensor and bony surfaces [ 1, 11], Interference of penicillamine with elastin and collagen cross-linking is thought to be the etiology of the latter two reactions (EPS and dermatopathy). These skin changes occur primarily in patients with Wilson’s disease or cystin uria who are on long-term penicillamine therapy [9,11,12]. The following is a report of a case of pseudoxanthoma-elasticum (PXE)-like skin changes in a patient on long-term penicillamine therapy for cystinuria.
Jean Bolognia. M l) Department o f Dermatology. Yale Medical School 533 Cedar Street New Haven. C T 06510 (U SA)
© 1992 Karger ACi. Basel 1018-8665/92/1841 0012 $ 2.75/0
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I.L. Bolognia l. Braverman
Fig. 1. Coalcscent yellow papules in the vault of the axilla.
Case Report
Fig. 2. Redundant skin folds of the lower buttocks (a) and anterior axillary line (b).
and the skin in these areas had the appearance of 'plucked-chicken skin'. The papules also followed the pattern of the skin lines, and this resulted in exaggerated skin creases. Redundant skin folds were observed in both the anterior axillary and inferior gluteal areas (fig. 2a. b). The mucosal surface of the lower lip had fine parallel vertical yellow lines. There was minimal involvement of the inguinal region, and no lesions were found in the popliteal fossae or umbilicus. Solar elastosis on the face and posterior neck was evident. Ocular examination revealed a choroidal nevus in the left eye. but no angioid streaks; peripheral pulses were intact. Complete blood count and
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A 66-year-old man was seen in April 1985 and noted on physical examination to have yellow papules and plaques in the antecubital fos sae and axillae. The lesions were asymptomatic, and the patient was unaware of their presence. No other family members were known to have had either a similar cutaneous eruption or the diagnosis of PXE. 11is mother died at the age of 67 years from a cerebrovascular accident. Otherwise, there was no family history of cardiac or peripheral vascu lar disease, visual impairment or gastrointestinal bleeding. The patient had a history of recurrent renal calculi, beginning in 1943. and he had undergone numerous nephro- or ureterolithotomies from 1943 to 1966. In 1944 and 1962. the stones were analyzed and found to be composed of cystine. A chromatogram of the patient's urine in 1967 showed markedly increased amounts of cystine as well as lysine, ornithine and arginine (the dibasic amino acids) and was consis tent with homozygous cystinuria. His diagnosis of type II cystinuria [13] was based upon: (1) the elevated levels of cystine and lysine in t he urinary excretion patterns of his father and two children (heterozy gotes) and (2) the intermediate level of in vitro transport of cystine and arginine in a jejunal biopsy. Initial treatment of the cystinuria included hydration and alkalinization of the urine. In 1967. penicillamine (500 mg q.i.d.) was begun because of the patient's continued stone forma tion despite conservative therapy. Since that time, he has taken 2 g/day of penicillamine and has formed no further stones. This patient also had multiple medical problems including hyper tension. gout, congestive heart failure and chronic renal insufficiency secondary to chronic pyelonephritis. At the time of presentation, his medications included Inderal 80 mg b.i.d.. digoxin 0.25 mg q.o.d.. hydralazine 100 mg b.i.d.. allopurinol 150m gq.d.. hydrochlorothia zide 50 mg q.d. and penicillamine 500 mg q.i.d. On physical examination, there were pale yellow waxy papules that had coalesced into plaques on the lateral neck, antecubital fossae, axil lae and buttocks (fig. I). Follicular orifices were prominent within many of the papules, especially those on the neck and in the axillae.
SMA-20 were within normal limits except for blood urea nitrogen of 51 mg/dl. creatinine 3.1 mg/dl and glucose 152 mg/dl. A chest X-ray showed only changes of mild congestive heart failure. Urinalysis was remarkable for 2+ proteinuria. Biopsies of involved (antecubital fossa, axilla, buttock) and unin volved (flank) skin were taken. Following routine processing, sections were stained with hematoxylin and cosin. von Kossa (calcium) and Vcrhoeff's iron hematoxylin (elastic fiber) stains. Tissue was also pre pared for transmission electron microscopy by fixation in half-strength Karnofsky’s solution and 1% osmium tetroxide, dehydration and embedding in Spurr resin. Ultrathin sections were stained with uranyl acetate and lead citrate and examined under a Zeiss F.M-9S-2 electron microscope.
Results
14
Bolognia/Braverman
Fig. 3. Saw-toothed elastic fibers in the dermis of involved skin (axilla). Vcrhoeff’s iron hematoxylin stain. X400.
Discussion Cystinuria is an autosomal recessive disorder character ized by an excessive urinary excretion of cystine, ornithine, arginine and lysine. It is the cystine that is poorly soluble at the normal acid pH of the urine, and its increased concen tration results in stone formation. Penicillamine effectively reduces the urinary excretion of cystine by forming a penicillamine-cysteine mixed disulfide (fig.5) that is approxi mately 50 times more soluble than cystine [14]. Penicillamine also interferes with the cross-linking of both elastic and collagen fibers. An initial step in the matu ration of these fibers is the lysyl-oxidase-mediated oxida tion of lysine residues in collagen and elastin and hydroxylysine residues in collagen. They are oxidized to their respective aldehydes - allysinc and hydroxyallysine. These aldehydes then react with one another to form cross-links, and in the case of elastin. lysine plus 3 allysines form either desmosine or isodesmosinc [15] (fig.6). Penicillamine can theoretically interfere with this cross-linking process by cither (1) reacting with these aldehydes and forming a thiazolidine structure [15] (fig.7) or (2) chelating the local stores of copper, the traee metal required for the formation of mature elastin [9. 17]. This interference with the cross-linking of collagen and elastin provides an explanation for the clinical setting and the histologic findings of penicillamine-associated dermatopathy, EPS and PXE-like skin changes. In theory, this drug reacts only with the newly forming collagen and clastic fibers, and as a result these cutaneous changes arc seen only after long-term penicillamine therapy. This was the
Pscudoxanthoma-elasticum-Like Lesions with Penicillamine
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A normal epidermis was seen in hcmatoxylin-eosinstained tissue sections of lesional (axilla, antecubital fossa, buttock) and nonlesional (flank) skin. On low-power examination of lesional skin, an increased eosinophilia was observed in the upper reticular dermis and on higher power, the fibers in these areas had a granular appearance and small perpendicular projections. No abnormalities were noted in the dermis of noninvolved skin. The von Kossa stain for calcium was negative in all of the biopsy specimens. Elastic tissue stains revealed an increase in the number of elastic fibers as well as irregular, serrated fibers in the dermis of both lesional and nonlesional skin. The fibers were jagged and saw-toothed in outline, and they had multiple thorn-like projections (fig.3). These changes were seen in the papillary and reticular dermis and were most striking in the biopsies of the axilla and antecubital fossa; few normal elastic fibers were found in these biopsies. The degree of involvement was less in the dermis of the buttock and flank where approximately 50% of the fibers were abnormal. In electron photomicrographs of lesional skin, many of the dermal elastic fibers had a normal core characterized by fine parallel microfibrils embedded in a moderately dense matrix, but they were studded with multiple buds of differ ent sizes and shapes (fig.4a). These projections were per pendicular to the long axis of the fiber and lacked microfi brils. Other clastic fibers had varying degrees of fragmenta tion. some to the point of total dissolution (fig.4b). The collagen fibers had normal banding patterns, but their width varied in size from 630 to 1,700 A (average = 915 A). In the dermis of nonlesional (flank) skin, both normal and abnormal elastic fibers were observed; the latter were char acterized by multiple buds. Compared to age-matched con trols. the fibroblasts in both lesional and nonlesional skin were normal in appearance.
Fig. 4. Electron photomicrographs of lesional skin (axilla) demonstrating: perpen dicular buds (a) on the dermal elastic fibers that arc amorphous and lack microfibrils (arrow = microfibril in central core) and degeneration of elastic fibers (b). x 14.7IX).
was 3 times greater than in normal controls, but the number of elastin cross-links was only 15% of control [20]. By light microscopy, the irregular shape of the elastic fibers was most apparent in iron-hematoxvlin-stained tissue sections, and in our patient, the fibers had an appearance similar to those described by other authors as ‘moth-eaten’
15
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case in our patient - he received 2 g/day of penicillamine for 19 years. The lesional skin in patients with penicillamineassociated EPS and PXE (including ours) has an increased number of elastic fibers which arc abnormal in appearance and composition [12,18,19]. For example, in 1 patient with PXE-like skin changes, the elastin content of lesional skin
n h 2h
NH2H H nh2 HOOC-Ç— Ç -S -S -Ç — Ç-COOH H H H H
HOOC-Ç— C-S H H H Cysteine
Cystine
NH2 ÇH 3
Fig. 5. Chemical structures of cysteine, cystine, penicillamine
(£>-|3, p-dimethylcysteine) and the penicillamine-cysteine mixed disul fide which is excreted in the urine.
NH2 CH 3
HOOC-C— -C-S H H CH 3
H
nh2
HOOC-C— Ç -S -S -C — C-COOH H
Penicillamine
CH 3
H
H
Penicillamine-cysteine
c@oo©o ÇH.
Fig. 6. Cross-link formation in clastin. Three allysines plus 1 lysine form either dcsmosinc (shown here) or isodesmosine where the lysine-derived side chain opposite the nitrogen (para) is moved to the ortho posi tion. Adapted from Sandberg et al. [16], pub lished with permission from the publisher.
1 Lysine, 3 Allysines
ÇH,
Desmosine
Penicillamine CH, CH, \ 3/ 3 S - C
CH, CH,
\V
H S -C
interference of penicillamine with elastin and collagen cross-linking is the formation of a thiazolidine ring with allysine or hydroxyallysinc [15],
2
—
COOH
[21], ‘saw-toothed’ [19] or ‘thorns of a bramble bush in win ter’ [12], All of these terms have been used to describe the dermal elastic fibers of patients with penicillamine-induced EPS, dermatopathy or PXE-like skin changes [18, 21.22]. The electron-microscopic findings in our case were also similar to those seen in patients with penicillamine-induced EPS. that is multiple buds perpendicular to the long axis of the elastic fiber [12, 19, 21], In 1979. Bardach et al. [21] coined the term ‘lumpy-bumpy’ to describe these unique ultrastructural findings. The elastic fibers in clastofibroma dorsi also have an irregular border and have been described
16
1 I
H ,N —TCH
Bolognia/Braverman
, c h 2-
c h 2- c h 2-
cx
N -C H I COOH
as serrated or globular in outline [23,24], Ultrastructurally, aggregations of granular elastinophilic material surround a central core of normal mature elastic tissue [24], Although the skin changes in our patient resembled PXE clinically, there was no evidence of calcium deposi tion on the dermal elastic fibers in cither the von-Kossastained sections or the electron photomicrographs. It is well established that the deposition of calcium on elastic fibers is a critical factor in the pathogenesis of both the inherited form and the localized acquired cutaneous form of PXE [25, 26]. Our claim that these PXE-like skin changes are
Pseudoxanthoma-elasticum-Like Lesions with Penicillamine
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Fig. 7. A proposed mechanism for the
3
secondary to penicillamine is supported by similar clinical and histologic findings in 4 other patients with Wilson’s dis ease. cystinuria or rheumatoid arthritis who required long term therapy with this drug [17. 18, 27, 28|. The physical findings in these patients included: (1) a ‘plucked-chicken skin’ appearance on the neck and in the axillae with exces sive wrinkling and clastotic papules and (2) redundant skin folds on the lateral trunk. Two patients had a biopsy per formed of lesional skin, and the clastic fibers had the pathognomic saw-toothed appearance [ 18, 28). The yellow discoloration of the skin in diseases such as PXE and solar elastosis has been ascribed to the presence of an increased number of abnormal clastic fibers in the dermis. An explanation is lacking, however, for the distri bution pattern of several disorders that involve elastic tis sue including idiopathic EPS, penicillamine-induced EPS, inherited PXE and penicillamine-induced PXE-like skin changes. These disease processes favor the flexural areas of the body, in particular the neck and the antecubital fossae. Although the turnover time of elastin in the rodent lung and aorta has been estimated in terms of years [29], the pos sibility exists that the turnover rate of clastic tissue in these flexural areas is accelerated, possibly as a result of shearing stresses or stretching [30], Therefore, a disease process that preferentially affects newly synthesized elastic fibers would be most evident in these areas. The identification of PXE-like skin changes in a patient on long-term penicillamine therapy can be of clinical importance. Bardach et al. [21] reported ‘lumpy-bumpy’ elastic fiber changes in the normal skin and lungs of a patient with penicillamine-induced EPS; the abnormal elastic tissue in the lung was associated with a large air cyst.
In a second patient with Wilson's disease on long-term penicillamine, saw-toothed elastic fibers were observed in the skin of the neck and in the submucosa and muscularis propria of the ileum [31] This patient presented with obstruction secondary to ileal stenosis as well as rubbery, elastotic neck folds. A third patient with rheumatoid arthri tis who had taken 750 mg q.d. of penicillamine for 11 years developed PXE-like changes, and on postmortem examin ation, abnormal elastic fibers were noted in the wall of the aorta, the avcolar septa of the lung and the adventitia of viscera ]28], Lastly, in a series of patients with rheumatoid arthritis on low-dose penicillamine, ‘bramble bush’ clastosis was observed in 4 of 6 surgical joint specimens (32], As the number of patients on long-term penicillamine therapy increases, it is likely that the number of reports of PXE-like skin changes will also increase. Meanwhile, the clinical implication of elastic tissue changes in internal organs awaits further observation. It is possible that discon tinuation of this drug will result in a reversal of the elastic fiber abnormalities as has been observed with penicilla mine-induced EPS. We found no obvious evidence of pul monary or gastrointestinal involvement in our patient, and it was decided to continue the penicillamine in light of the morbidity associated with his cystinuria.
Acknowledgments Wc wish to thank Michael Osber for preparing several of the fig ures. Eleanor Savage for her excellent secretarial assistance and Agnes Keh-Ycn for the preparation of the electron photomicrographs.
References 6 Marsden RA. Ryan TJ. Vanhegan Rl. Walshe M. Hill II. Mowat AG: Pemphigus foliaceus induced by penicillamine. Br Med .1 I976:ii: 1423-1424. 7 From E. Frcderikson P: Pemphigus vulgaris following /7-penicillamine. Dermatológica 1976:152:358-362. 8 Shuttlcworth D. Graham-Brown RAC. Hutchinson PE. Jolliffc DS: Cicatricial pem phigoid in //-penicillamine treated patients with rheumatoid arthritis - A report of three eases. Clin Exp Dermatol 1985:10:392-397. 9 Pass F. Goldfischer S. Sternlieb 1. Scheinberg IH: Elastosis perforans serpiginosa during penicillamine therapy for Wilson disease. Arch Dermatol 1973:108:713-715.
10 Johnson WC: Wilson's disease and penicilla mine-induced anetoderma. Arch Dermatol 1977:113:976. 11 Katz R: Penicillamine-induced skin lesions. A possible example of human lathyrism. Arch Dermatol 1967:95:196-198. 12 Hashimoto K. McEvoy B. Belcher R: Ultra structure of penicillamine-induced skin lesions. J Am Acad Dermatol 1981:4:300-315. 13 Rosenberg LE. Downing S. Durant Jl.. Segal S: Cystinuria: Biochemical evidence for three genetically distinct diseases. J Clin Invest 1966: 45:365-371. 14 Bartter FC. Lotz M. Thier S. Rosenberg LE. Potts JT: Cystinuria. Ann Intern Med 1965:62: 796-822.
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1 Stcrnlicb I. Fisher M. Scheinberg IH: Penicil lamine-induced skin lesions. J Rheumatol 1981:8:149-154. 2 Strickland G T : Febrile penicillamine eruption. Arch Neurol 1972:26:474. 3 Powell FC, Rogers RS. Dickson FR: Primary biliary cirrhosis anti lichen planus. J Am Acad Dermatol 1983:9:540-545. 4 Carroll GJ. Will RK. Peter JI5. Garlepp MJ. Dawkins RL: Penicillamine induced polymyo sitis and dermatomvositis. J Rheumatol 1987; 14:995-1001. 5 Amcrian MI.. Ahmed AR: Pemphigus erythe matosus. J Am Acad Dermatol 1984:10: 215-222.
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21 Bardach II. Gcbhart W. Niebaucr G: 'Lumpybumpy' elastic fibers in the skin and lungs of a patient with a penicillamine-induced elastosis perforans serpiginosa. J Cutan Pathol 1979:6: 243-252. 22 Goldstein JB. McNutt NS. Hambrick GW. Ilsu A: Penicillamine dermatopathv with lymphangieetases. Arch Dermatol 1989:125: 92-97. 23 Nagaminc N. Noltara Y. Ito E: Elastofibroma in Okinawa. A clinicopathologic study of 170 cases. Cancer 1982:50:1794-1805. 24 Winkelmann RK. Sam WM Jr: Elastofibroma. Report of a case with special histochcmical and electron-microscopic studies. Cancer 1969:23: 406-415. 25 Martinez-Hernandez A. Iluffer WE: Pseudo xanthoma elasticum: Dermal polyanions and the mineralization of elastic fibers. Lab Invest 1974:31:181-186. 26 Neldncr KH. Martinez-Hernandez A: Local ized acquired cutaneous pseudoxanthoma elas ticum. J Am Acad Dermatol 1979:1:523-530.
27 Bentley-Phillips B: Pseudoxanthoma elasti cum-like skin changes induced by penicilla mine. J R Soe Med 1985:78:787. 28 Burge S. Ryan T: Penicillamine-induced pseudo-pseudoxanthoma elasticum in a patient with rheumatoid arthritis. Clin Exp Dermatol 1988;13:255-258. 29 Rucker RB. l inker D: Structure and metabo lism of arterial elastin. Int Rev Exp Pathol 1977;17:1-47. 30 Cochran RJ. Wilkin JK: An unusual case of calcinosis cutis. J Am Acad Dermatol 1983:8: 103-106. 31 Wassef M. Galian A. Pepin B. Hagucnau M. Vasscl P. Hautefeuille P. Brazy J: Unusual digestive lesions in a patient with Wilson's dis ease treated with long-term penicillamine. N Engl J Med 1985:313:49. 32 Burge S. Dalziel K. Mowat A. Ryan TJ: Elasticfibre damage with low dose penicillamine - A review of 18 patients with rheumatoid arthritis. B rJ Dermatol 1988:119S:50.
Bolognia/Bravcrman
Pscudoxanthoma-clasticum-Like Lesions with Penicillamine
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15 Pinnell SR. Martin G R. Miller EJ: Desmosine biosynthesis: Nature of inhibition by /^-penicil lamine. Science 1968:161:475-476. 16 Sandberg LB. Soskel NT. I.cslie JG : Elastin structure, biosynthesis, and relation to disease states. N Engl J Med 1981:304:566-579. 17 Meyrick Thomas R ll. Kirby .IDT: Elastosis perforans serpiginosa and pseudoxanthoma elasticum-likc skin change due to //-penicilla mine. Clin Exp Dermatol 1985:10:386-391. 18 Meyrick Thomas RH. Light N. Stephens AD. Avery NC. Kirby JDT: Pseudoxanthoma elasticum-like skin changes induced by penicilla mine. J R Soe Med 1984:77:794-798. 19 Kirsch N. I lukill PB: Elastosis perforans serpi ginosa induced by penicillamine. Electron microscopic observations. Arch Dermatol 1977:113:630-635. 20 Light N. Meyrick Thomas R ll. Stephens A. Kirby JDT. Fryer PR. Avery NC: Collagen and elastin changes in //-penicillamine-induced pseudoxanthoma elasticum-like skin. B rJ Der matol 1986:114:381-388.
Department of Dermatology, Yale University School of Medicine. New Haven, Conn.. USA
Key Words Pseudoxanthoma elasticum Penicillamine Elastic fibers
Pseudoxanthoma-elasticum-Like Skin Changes Induced by Penicillamine
Abstract The interference of penicillamine with collagen and elastin cross-linking can lead to wrinkling and anetoderma-like lesions in flexural areas as well as fragility and hemorrhagic blisters in pressure areas. These changes are seen primarily in patients with Wilson’s disease orcystinuria who arc on long-term therapy. This is a report of a patient with cystinuria on long-term, high-dose penicillamine who developed pseudoxanthoma-elasticum-likc lesions. Coalescent yellow papules with a ‘plucked-chicken skin’ appearance were seen in the axillae and on the neck while redundant skin folds were noted in the anterior axillary line and lower buttocks. By light and electron microscopy, involved and uninvolved skin demonstrated ‘lumpy-bumpy’ dermal elastic fibers with no calcium deposition. These histologic changes are similar to those previously described in patients with penicillamine-induced skin lesions.
Introduction Penicillamine (D-ß.ß-dimethylcysteinc) is currently used in the treatment of several disorders including Wil son's disease (hepatolenticular degeneration), cystinuria, severe rheumatoid arthritis, primary biliary cirrhosis and progressive systemic sclerosis. Administration of this drug has resulted in a wide range of mucocutaneous reactions including: urticaria [1], morbilliform eruptions [2], lichen planus [3], dermatomyositis [4], pemphigus erythematosus [5], foliaceus [6] and vulgaris |7|. cicatricial pemphigoid [8], elastosis perforans serpiginosa (EPS) (9] and a dermatopa-
Received: March 25. 1991
Accepted: June 14. 1991
thy characterized by either (1) wrinkling and anetoderma like lesions in flexural areas [ 10] or (2) fragility, bullae, pur pura, milia and wrinkling on extensor and bony surfaces [ 1, 11], Interference of penicillamine with elastin and collagen cross-linking is thought to be the etiology of the latter two reactions (EPS and dermatopathy). These skin changes occur primarily in patients with Wilson’s disease or cystin uria who are on long-term penicillamine therapy [9,11,12]. The following is a report of a case of pseudoxanthoma-elasticum (PXE)-like skin changes in a patient on long-term penicillamine therapy for cystinuria.
Jean Bolognia. M l) Department o f Dermatology. Yale Medical School 533 Cedar Street New Haven. C T 06510 (U SA)
© 1992 Karger ACi. Basel 1018-8665/92/1841 0012 $ 2.75/0
Downloaded by: Kings's College London 137.73.144.138 - 11/2/2017 4:38:30 PM
I.L. Bolognia l. Braverman
Fig. 1. Coalcscent yellow papules in the vault of the axilla.
Case Report
Fig. 2. Redundant skin folds of the lower buttocks (a) and anterior axillary line (b).
and the skin in these areas had the appearance of 'plucked-chicken skin'. The papules also followed the pattern of the skin lines, and this resulted in exaggerated skin creases. Redundant skin folds were observed in both the anterior axillary and inferior gluteal areas (fig. 2a. b). The mucosal surface of the lower lip had fine parallel vertical yellow lines. There was minimal involvement of the inguinal region, and no lesions were found in the popliteal fossae or umbilicus. Solar elastosis on the face and posterior neck was evident. Ocular examination revealed a choroidal nevus in the left eye. but no angioid streaks; peripheral pulses were intact. Complete blood count and
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A 66-year-old man was seen in April 1985 and noted on physical examination to have yellow papules and plaques in the antecubital fos sae and axillae. The lesions were asymptomatic, and the patient was unaware of their presence. No other family members were known to have had either a similar cutaneous eruption or the diagnosis of PXE. 11is mother died at the age of 67 years from a cerebrovascular accident. Otherwise, there was no family history of cardiac or peripheral vascu lar disease, visual impairment or gastrointestinal bleeding. The patient had a history of recurrent renal calculi, beginning in 1943. and he had undergone numerous nephro- or ureterolithotomies from 1943 to 1966. In 1944 and 1962. the stones were analyzed and found to be composed of cystine. A chromatogram of the patient's urine in 1967 showed markedly increased amounts of cystine as well as lysine, ornithine and arginine (the dibasic amino acids) and was consis tent with homozygous cystinuria. His diagnosis of type II cystinuria [13] was based upon: (1) the elevated levels of cystine and lysine in t he urinary excretion patterns of his father and two children (heterozy gotes) and (2) the intermediate level of in vitro transport of cystine and arginine in a jejunal biopsy. Initial treatment of the cystinuria included hydration and alkalinization of the urine. In 1967. penicillamine (500 mg q.i.d.) was begun because of the patient's continued stone forma tion despite conservative therapy. Since that time, he has taken 2 g/day of penicillamine and has formed no further stones. This patient also had multiple medical problems including hyper tension. gout, congestive heart failure and chronic renal insufficiency secondary to chronic pyelonephritis. At the time of presentation, his medications included Inderal 80 mg b.i.d.. digoxin 0.25 mg q.o.d.. hydralazine 100 mg b.i.d.. allopurinol 150m gq.d.. hydrochlorothia zide 50 mg q.d. and penicillamine 500 mg q.i.d. On physical examination, there were pale yellow waxy papules that had coalesced into plaques on the lateral neck, antecubital fossae, axil lae and buttocks (fig. I). Follicular orifices were prominent within many of the papules, especially those on the neck and in the axillae.
SMA-20 were within normal limits except for blood urea nitrogen of 51 mg/dl. creatinine 3.1 mg/dl and glucose 152 mg/dl. A chest X-ray showed only changes of mild congestive heart failure. Urinalysis was remarkable for 2+ proteinuria. Biopsies of involved (antecubital fossa, axilla, buttock) and unin volved (flank) skin were taken. Following routine processing, sections were stained with hematoxylin and cosin. von Kossa (calcium) and Vcrhoeff's iron hematoxylin (elastic fiber) stains. Tissue was also pre pared for transmission electron microscopy by fixation in half-strength Karnofsky’s solution and 1% osmium tetroxide, dehydration and embedding in Spurr resin. Ultrathin sections were stained with uranyl acetate and lead citrate and examined under a Zeiss F.M-9S-2 electron microscope.
Results
14
Bolognia/Braverman
Fig. 3. Saw-toothed elastic fibers in the dermis of involved skin (axilla). Vcrhoeff’s iron hematoxylin stain. X400.
Discussion Cystinuria is an autosomal recessive disorder character ized by an excessive urinary excretion of cystine, ornithine, arginine and lysine. It is the cystine that is poorly soluble at the normal acid pH of the urine, and its increased concen tration results in stone formation. Penicillamine effectively reduces the urinary excretion of cystine by forming a penicillamine-cysteine mixed disulfide (fig.5) that is approxi mately 50 times more soluble than cystine [14]. Penicillamine also interferes with the cross-linking of both elastic and collagen fibers. An initial step in the matu ration of these fibers is the lysyl-oxidase-mediated oxida tion of lysine residues in collagen and elastin and hydroxylysine residues in collagen. They are oxidized to their respective aldehydes - allysinc and hydroxyallysine. These aldehydes then react with one another to form cross-links, and in the case of elastin. lysine plus 3 allysines form either desmosine or isodesmosinc [15] (fig.6). Penicillamine can theoretically interfere with this cross-linking process by cither (1) reacting with these aldehydes and forming a thiazolidine structure [15] (fig.7) or (2) chelating the local stores of copper, the traee metal required for the formation of mature elastin [9. 17]. This interference with the cross-linking of collagen and elastin provides an explanation for the clinical setting and the histologic findings of penicillamine-associated dermatopathy, EPS and PXE-like skin changes. In theory, this drug reacts only with the newly forming collagen and clastic fibers, and as a result these cutaneous changes arc seen only after long-term penicillamine therapy. This was the
Pscudoxanthoma-elasticum-Like Lesions with Penicillamine
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A normal epidermis was seen in hcmatoxylin-eosinstained tissue sections of lesional (axilla, antecubital fossa, buttock) and nonlesional (flank) skin. On low-power examination of lesional skin, an increased eosinophilia was observed in the upper reticular dermis and on higher power, the fibers in these areas had a granular appearance and small perpendicular projections. No abnormalities were noted in the dermis of noninvolved skin. The von Kossa stain for calcium was negative in all of the biopsy specimens. Elastic tissue stains revealed an increase in the number of elastic fibers as well as irregular, serrated fibers in the dermis of both lesional and nonlesional skin. The fibers were jagged and saw-toothed in outline, and they had multiple thorn-like projections (fig.3). These changes were seen in the papillary and reticular dermis and were most striking in the biopsies of the axilla and antecubital fossa; few normal elastic fibers were found in these biopsies. The degree of involvement was less in the dermis of the buttock and flank where approximately 50% of the fibers were abnormal. In electron photomicrographs of lesional skin, many of the dermal elastic fibers had a normal core characterized by fine parallel microfibrils embedded in a moderately dense matrix, but they were studded with multiple buds of differ ent sizes and shapes (fig.4a). These projections were per pendicular to the long axis of the fiber and lacked microfi brils. Other clastic fibers had varying degrees of fragmenta tion. some to the point of total dissolution (fig.4b). The collagen fibers had normal banding patterns, but their width varied in size from 630 to 1,700 A (average = 915 A). In the dermis of nonlesional (flank) skin, both normal and abnormal elastic fibers were observed; the latter were char acterized by multiple buds. Compared to age-matched con trols. the fibroblasts in both lesional and nonlesional skin were normal in appearance.
Fig. 4. Electron photomicrographs of lesional skin (axilla) demonstrating: perpen dicular buds (a) on the dermal elastic fibers that arc amorphous and lack microfibrils (arrow = microfibril in central core) and degeneration of elastic fibers (b). x 14.7IX).
was 3 times greater than in normal controls, but the number of elastin cross-links was only 15% of control [20]. By light microscopy, the irregular shape of the elastic fibers was most apparent in iron-hematoxvlin-stained tissue sections, and in our patient, the fibers had an appearance similar to those described by other authors as ‘moth-eaten’
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case in our patient - he received 2 g/day of penicillamine for 19 years. The lesional skin in patients with penicillamineassociated EPS and PXE (including ours) has an increased number of elastic fibers which arc abnormal in appearance and composition [12,18,19]. For example, in 1 patient with PXE-like skin changes, the elastin content of lesional skin
n h 2h
NH2H H nh2 HOOC-Ç— Ç -S -S -Ç — Ç-COOH H H H H
HOOC-Ç— C-S H H H Cysteine
Cystine
NH2 ÇH 3
Fig. 5. Chemical structures of cysteine, cystine, penicillamine
(£>-|3, p-dimethylcysteine) and the penicillamine-cysteine mixed disul fide which is excreted in the urine.
NH2 CH 3
HOOC-C— -C-S H H CH 3
H
nh2
HOOC-C— Ç -S -S -C — C-COOH H
Penicillamine
CH 3
H
H
Penicillamine-cysteine
c@oo©o ÇH.
Fig. 6. Cross-link formation in clastin. Three allysines plus 1 lysine form either dcsmosinc (shown here) or isodesmosine where the lysine-derived side chain opposite the nitrogen (para) is moved to the ortho posi tion. Adapted from Sandberg et al. [16], pub lished with permission from the publisher.
1 Lysine, 3 Allysines
ÇH,
Desmosine
Penicillamine CH, CH, \ 3/ 3 S - C
CH, CH,
\V
H S -C
interference of penicillamine with elastin and collagen cross-linking is the formation of a thiazolidine ring with allysine or hydroxyallysinc [15],
2
—
COOH
[21], ‘saw-toothed’ [19] or ‘thorns of a bramble bush in win ter’ [12], All of these terms have been used to describe the dermal elastic fibers of patients with penicillamine-induced EPS, dermatopathy or PXE-like skin changes [18, 21.22]. The electron-microscopic findings in our case were also similar to those seen in patients with penicillamine-induced EPS. that is multiple buds perpendicular to the long axis of the elastic fiber [12, 19, 21], In 1979. Bardach et al. [21] coined the term ‘lumpy-bumpy’ to describe these unique ultrastructural findings. The elastic fibers in clastofibroma dorsi also have an irregular border and have been described
16
1 I
H ,N —TCH
Bolognia/Braverman
, c h 2-
c h 2- c h 2-
cx
N -C H I COOH
as serrated or globular in outline [23,24], Ultrastructurally, aggregations of granular elastinophilic material surround a central core of normal mature elastic tissue [24], Although the skin changes in our patient resembled PXE clinically, there was no evidence of calcium deposi tion on the dermal elastic fibers in cither the von-Kossastained sections or the electron photomicrographs. It is well established that the deposition of calcium on elastic fibers is a critical factor in the pathogenesis of both the inherited form and the localized acquired cutaneous form of PXE [25, 26]. Our claim that these PXE-like skin changes are
Pseudoxanthoma-elasticum-Like Lesions with Penicillamine
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Fig. 7. A proposed mechanism for the
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secondary to penicillamine is supported by similar clinical and histologic findings in 4 other patients with Wilson’s dis ease. cystinuria or rheumatoid arthritis who required long term therapy with this drug [17. 18, 27, 28|. The physical findings in these patients included: (1) a ‘plucked-chicken skin’ appearance on the neck and in the axillae with exces sive wrinkling and clastotic papules and (2) redundant skin folds on the lateral trunk. Two patients had a biopsy per formed of lesional skin, and the clastic fibers had the pathognomic saw-toothed appearance [ 18, 28). The yellow discoloration of the skin in diseases such as PXE and solar elastosis has been ascribed to the presence of an increased number of abnormal clastic fibers in the dermis. An explanation is lacking, however, for the distri bution pattern of several disorders that involve elastic tis sue including idiopathic EPS, penicillamine-induced EPS, inherited PXE and penicillamine-induced PXE-like skin changes. These disease processes favor the flexural areas of the body, in particular the neck and the antecubital fossae. Although the turnover time of elastin in the rodent lung and aorta has been estimated in terms of years [29], the pos sibility exists that the turnover rate of clastic tissue in these flexural areas is accelerated, possibly as a result of shearing stresses or stretching [30], Therefore, a disease process that preferentially affects newly synthesized elastic fibers would be most evident in these areas. The identification of PXE-like skin changes in a patient on long-term penicillamine therapy can be of clinical importance. Bardach et al. [21] reported ‘lumpy-bumpy’ elastic fiber changes in the normal skin and lungs of a patient with penicillamine-induced EPS; the abnormal elastic tissue in the lung was associated with a large air cyst.
In a second patient with Wilson's disease on long-term penicillamine, saw-toothed elastic fibers were observed in the skin of the neck and in the submucosa and muscularis propria of the ileum [31] This patient presented with obstruction secondary to ileal stenosis as well as rubbery, elastotic neck folds. A third patient with rheumatoid arthri tis who had taken 750 mg q.d. of penicillamine for 11 years developed PXE-like changes, and on postmortem examin ation, abnormal elastic fibers were noted in the wall of the aorta, the avcolar septa of the lung and the adventitia of viscera ]28], Lastly, in a series of patients with rheumatoid arthritis on low-dose penicillamine, ‘bramble bush’ clastosis was observed in 4 of 6 surgical joint specimens (32], As the number of patients on long-term penicillamine therapy increases, it is likely that the number of reports of PXE-like skin changes will also increase. Meanwhile, the clinical implication of elastic tissue changes in internal organs awaits further observation. It is possible that discon tinuation of this drug will result in a reversal of the elastic fiber abnormalities as has been observed with penicilla mine-induced EPS. We found no obvious evidence of pul monary or gastrointestinal involvement in our patient, and it was decided to continue the penicillamine in light of the morbidity associated with his cystinuria.
Acknowledgments Wc wish to thank Michael Osber for preparing several of the fig ures. Eleanor Savage for her excellent secretarial assistance and Agnes Keh-Ycn for the preparation of the electron photomicrographs.
References 6 Marsden RA. Ryan TJ. Vanhegan Rl. Walshe M. Hill II. Mowat AG: Pemphigus foliaceus induced by penicillamine. Br Med .1 I976:ii: 1423-1424. 7 From E. Frcderikson P: Pemphigus vulgaris following /7-penicillamine. Dermatológica 1976:152:358-362. 8 Shuttlcworth D. Graham-Brown RAC. Hutchinson PE. Jolliffc DS: Cicatricial pem phigoid in //-penicillamine treated patients with rheumatoid arthritis - A report of three eases. Clin Exp Dermatol 1985:10:392-397. 9 Pass F. Goldfischer S. Sternlieb 1. Scheinberg IH: Elastosis perforans serpiginosa during penicillamine therapy for Wilson disease. Arch Dermatol 1973:108:713-715.
10 Johnson WC: Wilson's disease and penicilla mine-induced anetoderma. Arch Dermatol 1977:113:976. 11 Katz R: Penicillamine-induced skin lesions. A possible example of human lathyrism. Arch Dermatol 1967:95:196-198. 12 Hashimoto K. McEvoy B. Belcher R: Ultra structure of penicillamine-induced skin lesions. J Am Acad Dermatol 1981:4:300-315. 13 Rosenberg LE. Downing S. Durant Jl.. Segal S: Cystinuria: Biochemical evidence for three genetically distinct diseases. J Clin Invest 1966: 45:365-371. 14 Bartter FC. Lotz M. Thier S. Rosenberg LE. Potts JT: Cystinuria. Ann Intern Med 1965:62: 796-822.
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1 Stcrnlicb I. Fisher M. Scheinberg IH: Penicil lamine-induced skin lesions. J Rheumatol 1981:8:149-154. 2 Strickland G T : Febrile penicillamine eruption. Arch Neurol 1972:26:474. 3 Powell FC, Rogers RS. Dickson FR: Primary biliary cirrhosis anti lichen planus. J Am Acad Dermatol 1983:9:540-545. 4 Carroll GJ. Will RK. Peter JI5. Garlepp MJ. Dawkins RL: Penicillamine induced polymyo sitis and dermatomvositis. J Rheumatol 1987; 14:995-1001. 5 Amcrian MI.. Ahmed AR: Pemphigus erythe matosus. J Am Acad Dermatol 1984:10: 215-222.
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21 Bardach II. Gcbhart W. Niebaucr G: 'Lumpybumpy' elastic fibers in the skin and lungs of a patient with a penicillamine-induced elastosis perforans serpiginosa. J Cutan Pathol 1979:6: 243-252. 22 Goldstein JB. McNutt NS. Hambrick GW. Ilsu A: Penicillamine dermatopathv with lymphangieetases. Arch Dermatol 1989:125: 92-97. 23 Nagaminc N. Noltara Y. Ito E: Elastofibroma in Okinawa. A clinicopathologic study of 170 cases. Cancer 1982:50:1794-1805. 24 Winkelmann RK. Sam WM Jr: Elastofibroma. Report of a case with special histochcmical and electron-microscopic studies. Cancer 1969:23: 406-415. 25 Martinez-Hernandez A. Iluffer WE: Pseudo xanthoma elasticum: Dermal polyanions and the mineralization of elastic fibers. Lab Invest 1974:31:181-186. 26 Neldncr KH. Martinez-Hernandez A: Local ized acquired cutaneous pseudoxanthoma elas ticum. J Am Acad Dermatol 1979:1:523-530.
27 Bentley-Phillips B: Pseudoxanthoma elasti cum-like skin changes induced by penicilla mine. J R Soe Med 1985:78:787. 28 Burge S. Ryan T: Penicillamine-induced pseudo-pseudoxanthoma elasticum in a patient with rheumatoid arthritis. Clin Exp Dermatol 1988;13:255-258. 29 Rucker RB. l inker D: Structure and metabo lism of arterial elastin. Int Rev Exp Pathol 1977;17:1-47. 30 Cochran RJ. Wilkin JK: An unusual case of calcinosis cutis. J Am Acad Dermatol 1983:8: 103-106. 31 Wassef M. Galian A. Pepin B. Hagucnau M. Vasscl P. Hautefeuille P. Brazy J: Unusual digestive lesions in a patient with Wilson's dis ease treated with long-term penicillamine. N Engl J Med 1985:313:49. 32 Burge S. Dalziel K. Mowat A. Ryan TJ: Elasticfibre damage with low dose penicillamine - A review of 18 patients with rheumatoid arthritis. B rJ Dermatol 1988:119S:50.
Bolognia/Bravcrman
Pscudoxanthoma-clasticum-Like Lesions with Penicillamine
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15 Pinnell SR. Martin G R. Miller EJ: Desmosine biosynthesis: Nature of inhibition by /^-penicil lamine. Science 1968:161:475-476. 16 Sandberg LB. Soskel NT. I.cslie JG : Elastin structure, biosynthesis, and relation to disease states. N Engl J Med 1981:304:566-579. 17 Meyrick Thomas R ll. Kirby .IDT: Elastosis perforans serpiginosa and pseudoxanthoma elasticum-likc skin change due to //-penicilla mine. Clin Exp Dermatol 1985:10:386-391. 18 Meyrick Thomas RH. Light N. Stephens AD. Avery NC. Kirby JDT: Pseudoxanthoma elasticum-like skin changes induced by penicilla mine. J R Soe Med 1984:77:794-798. 19 Kirsch N. I lukill PB: Elastosis perforans serpi ginosa induced by penicillamine. Electron microscopic observations. Arch Dermatol 1977:113:630-635. 20 Light N. Meyrick Thomas R ll. Stephens A. Kirby JDT. Fryer PR. Avery NC: Collagen and elastin changes in //-penicillamine-induced pseudoxanthoma elasticum-like skin. B rJ Der matol 1986:114:381-388.
