Generalized Acquired Cutis Laxa Associated with Multiple Myeloma with Biphenotypic Igg-␭ and Iga-␬ Gammopathy Following Treatment of a Nodal Plasmacytoma

OBSERVATION Generalized Acquired Cutis Laxa Associated With Multiple Myeloma With Biphenotypic IgG-␭ and IgA-␬ Gammopathy Following Treatment of a Nodal Plasmacytoma

H. Douglas New, MD; Jeffrey P. Callen, MD

Background: Cutis laxa is a rare dermatosis that can be demonstrating a persistent monoclonal IgG-␭ M-spike on inherited or acquired. The acquired form is rare and has immunofixation electrophoresis and lytic bone lesions. He been associated with various conditions, including mul- was later found to have biphenotypic IgG-␭ and IgA-␬ multiple myeloma, monoclonal gammopathy of undeter- tiple myeloma. mined significance, and heavy chain deposition disease. Conclusions: Multiple myeloma, plasma cell dyscra- Observations: We describe a 48-year-old man who de- sia, and heavy-chain deposition disease have been very veloped generalized cutis laxa over a 4-year duration. There rarely reported to be associated with acquired cutis laxa were no preceding skin changes except for a history of ery- (ACL). Findings in our patient support the hypothesis thematous plaques with granuloma annulare–like fea- that paraproteinemia is a cause of ACL through immu- tures on his buttocks and lateral hips. He underwent treat- nologic destruction of elastic fibers manifesting as granu- ment of an axillary lymph node plasmacytoma with surgery loma annulare–like plaques. Evaluation for an underly- and radiation 4 years prior to his cutaneous changes and ing gammopathy is essential for the workup of a patient had been clinically monitored with a diagnosis of mono- with new-onset ACL. clonal gammopathy of unknown significance (MGUS). Cu- taneous manifestations prompted a systemic evaluation Arch Dermatol. 2011;147(3):323-328

UTIS LAXA (CL) IS A RARE REPORT OF A CASE dermatosis resulting in loose, wrinkled, redundant skin secondary to de- A 48-year-old man was referred for evalu- fects in dermal elastic tis- ation of “recalcitrant” GA. At the time of re- sue.C When involving the face, patients ferral, we noted a 4-year history of gradu- classically have a “bloodhound-like” or ally developing loose, wrinkled skin of his “hound dog–like” appearance. Extracu- face, chest, upper back, lateral hips, but- taneous manifestations may also occur, in- tocks, and proximal upper extremities. cluding pulmonary emphysema, diver- There were no preceding cutaneous changes ticulae of the gastrointestinal tract or on his face and upper body; however, he de- genitourinary tract, and cardiovascular veloped asymptomatic erythematous defects. Cutis laxa may be inherited or plaques with GA-like features on his but- acquired with acquired cutis laxa (ACL) tocks and hips. Eight years earlier, a nodal plasmacytoma was surgically excised from See also pages 331 and 342 his left axilla. He received local radiation therapy at that time and was clinically moni- having a later onset of disease, and more tored by an oncologist for the working di- generalized involvement and is related to agnosis of monoclonal gammopathy of un- various different etiologies including known significance (MGUS). medications, inflammatory diseases, His medical history was otherwise un- infections, and hematologic disorders.1 remarkable, and his medications in- We describe a 48-year-old man who cluded oral acitretin, 25 mg/d, and daily developed ACL and granuloma annulare oral multivitamins: oral vitamin E, 400 IU; (GA)-like lesions as a paraneoplastic oral vitamin D, 2000 IU; omega-3 fish oil, Author Affiliations: Division of manifestation of early myeloma years 2000 mg; and B-complex vitamin supple- Dermatology, University of after being treated for a lymph node plas- ments. Acitretin was added by the refer- Louisville, Louisville, Kentucky. macytoma. ring dermatologist 1 month prior to his ini-

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©2011 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 Figure 3. Sacral area with nonscaly, somewhat annular, erythematous papules and plaques.

Figure 1. Loose, sagging skin on the face and neck with “bloodhound-like” appearance. Figure 4. A 4-mm punch biopsy specimen from the hip demonstrating paucicellular infiltrate of interstitial histiocytes with intracytoplasmic eosinophilic refractile elastic fiber fragments (hematoxylin-eosin, original magnification ϫ600).

Figure 2. Right lateral hip with loose, wrinkly, redundant folds with faint erythema.

tial presentation to us without improvement of his skin Figure 5. Verhoeff–Van Giesen stain highlights histiocytic cells engulfing disease. His family history was unremarkable. fragmented elastic fibers, as well as diminished elastic fibers in the Physical examination demonstrated a healthy- surrounding dermis (original magnification ϫ600). appearing man who appeared older than his stated age. He had loose, sagging skin on the face and neck along with wrinkled, lax skin on the chest, upper back, proxi- METHODS mal upper extremities, and the lateral aspects of his hips Findings from two 4-mm punch biopsy specimens of the pa- (Figure 1 and Figure 2). Granuloma annulare–like ery- tient’s left hip and upper back revealed a normal epidermis and thematous, nonscaly plaques were noted on his lower dermoepidermal junction with few lymphocytes and histio- back, buttocks, and lateral hips in association with in- cytes around superficial blood vessels and interstitially in the creased wrinkling (Figure 3). upper dermis. A marked decrease in elastic fibers with elasto-

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Sex, Site(s) of Associated Skin Biopsy SPEP, UPEP, Bone Marrow Treatment Source Age, y Cutis Laxa Findings Finding or IFE Evaluation and Outcome Turner et al8 M/29 Face, neck, Urticarial vasculitis with LCV with perivascular IgA myeloma IgA myeloma High-dose pulse axillae, LCV and immune neutrophilic involving kidneys methylprednisolone and shoulders, complex mediated infiltrate with cyclophosphamide; upper glomerulonephritis extravasated urticaria persisted; patient extremities RBCs, fibrin became hemodialysis deposition and dependent and died of his perivascular disease karyorrhexis Marked loss of elastic fibers in zones of LCV Scott et al9 F/44 Face, neck, Started following penicillin Fragmentation and SPEP: IgG Aspirate: 58% Treatment and outcome not axillae, wrists, hypersensitivity reaction granulation of gammopathy immature plasma discussed abdomen Extensive colonic dermal elastic UPEP: IgG with ␬ cells confirming diverticulae, bladder and fibers FLCs and ␬ diagnosis of rectal prolapse, loss of DIF and IIF were attached to heavy myeloma support of eyelids, negative chains palate, and uvula Cho et al10 F/46 Face, neck, Began after penicillin Skin biopsy finding SPEP: monocloncal ␥ Aspirate revealed Prednisone, melphalan, trunk, hypersensitivity reaction consistent with CL spike 58% plasma cells cyclophosphamide; patient extremities with marked facial and DIF: IgG bound to UPEP: IgG and ␬ confirming became bedridden over the neck edema dermal elastic FLCs diagnosis of following 18 mo and died Panacinar emphysema, fibers 24-h urine: 4.6 g myeloma after endotracheal tube was uterine and vaginal protein removed prolapse, rectocele, hiatal hernia, colonic diverticulae Airway obstruction, pulmonary restriction, and hypertension Ting et al11 F/45 Entire body with Followed episodic Absence of elastic SPEP: monoclonal Aspirate showed Treatment and outcome not more severity “puffiness” of eyelids fibers in the upper gammopathy 57% immature discussed on face, neck, Loss of elasticity of dermis and UPEP: ␭ plasma cells axillae, and lungs, bladder, and marked paraproteinuria confirming perineum rectum diminished diagnosis of amount in deep myeloma dermis DIF: negative McCarty M/62 Face, neck, Exercise intolerance and Fragmented dermal SPEP: monoclonal 60% Plasma cells in Melphalan and prednisone et al12 trunk, and fatigue elastic fibers IgG-␬ proteinemia bone marrow initially. Developed extremities Lytic vertebral lesions DIF: negative aspirate spontaneous bilateral confirming humeral fractures requiring myeloma surgery and radiation therapy. Then treatment with doxorubicin, vincristine, and dexamethasone was initiated; serum immunoglobulin levels declined. Skin disease continued to progress Gupta and F/62 Face, neck, Had a 5-y history of IgG Loss of elastic fibers; SPEP: elevated levels Aspirate consistent Prior to onset of CL, patient Helm13 chest, back myeloma prior to no inflammatory of ␥ globulin and with IgG multiple had been prescribed development of CL infiltrate noted ␤2-microglobulin myeloma with vincristine, melphalan, IFE: homogeneous 40% plasma cells doxorubicin, bands to IgG and cyclophosphamide, the ␬ region prednisone, interferon, UPEP: monoclonal granulocyte-colony ␬ FLCs stimulating factor, thalidomide, dexamethasone. At time of presentation, she was taking prednisone, 50 mg every other day, and thalidomide, 100 mg/d which was increased to 400 mg/d; her myeloma “markers” improved, and her cutaneous disease gradually progressed

(continued)

phagocytosis by epitheloid cells and giant cells were observed increased mucin deposition was appreciated. Initially, the biopsy (Figure 4 and Figure 5). Results from periodic acid–Schiff specimen involving his left hip had been diagnosed as GA and and giemsa stains were unremarkable. No evidence of amy- that from his upper back as mid-dermal elastolysis. Further re- loid was seen with crystal violet. No alteration of collagen or view of the specimens concluded that both biopsy specimens

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©2011 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 Table 1. Summary of Acquired Cutis Laxa (ACL) Associated With Plasma Cell Dyscrasias (continued)

Sex, Site(s) of Associated Skin Biopsy SPEP, UPEP, Bone Marrow Treatment Source Age, y Cutis Laxa Findings Finding or IFE Evaluation and Outcome Yoneda M/71 Both thumbs Lumbar back pain, Fingertip biopsy: SPEP: monoclonal Aspirate with Cyclophosphamide; decrease et al14 with lax skin paresthesias of right reduced elastic IgG-␬ immature plasma in serum IgG ␬ and urine leg, night sweats; EKG fibers with UPEP: large cells (no further Bence Jones protein; skin with atrial fibrillation fragmentation amount of Bence details) lesions persisted; rectal Amyloid around Jones ␬ proteins biopsy indicated no Meissner amyloidosis corpuscle Yoneda M/62 Acral sites on Hepatomegaly; osteolytic Fingertip biopsy: Elevated serum IgG Aspirate with Cyclophosphamide and et al14 fingertips and lesions of both femurs; reduction and 16.9 g/L (RR, numerous prednisolone; decrease of soles of feet diffuse osteoporosis; fragmentation of 7.5-18 g/L) immature plasma serum monoclonal IgG ␭ renal insufficiency; elastic fibers SPEP: monoclonal cells (no further and urine Bence Jones hypercalcemia Amyloid IgG ␭ details) protein; cutaneous lesions deposition UPEP: Bence progressed; amyloidosis Jones ␭ proteins involving the liver, kidneys and entire intestine led to death from chronic intestinal pseudo-obstruction and renal failure Appiah F/64 Axillae, medial None discussed Axillary, lip and thigh SPEP and UPEP with Biopsy of bone Treatment and outcome not et al15 thighs, biopsy: nodular prominent marrow: discussed eyelids, labia amyloid deposits homogenous band 25%-30% plasma majora with with decrease and in mid-␥ region cells with ␬ light flesh-colored clumping of elastic IFE: ␬ FLCs chain restrictions; papules with fibers in dermis amyloid deposits loose, in bone marrow wrinkled skin staining for ␬ light of fingertips chains Dicker F/59 Acrolocalized Tongue swelling leading Elliptical biopsy right SPEP: monoclonal Biopsy of bone Cycles of C-VAMP; after 2 et al16 ACL with to airway obstruction; index finger: band marrow: plasma cycles of C-VAMP laxity of tender tense history of carpel tunnel Amyloid UPEP: Bence cell dyscrasia; did skin improved as did the areas of syndrome; deposition in Jones proteins not meet criteria size of her tongue; patient “puffiness” of hypothyroidism dermis; elastic for diagnosis of considering bone marrow fingertips fibers not myeloma transplant at time of resolved assessed owing to publication leaving lax amount of amyloid skin on deposition fingerpads on her thumbs and second and third fingers bilaterally This M/48 Face, neck, Erythematous nonscaly Findings from left hip IFE: monoclonal Bone marrow biopsy Lenalidomide, 25 mg/d orally, article upper trunk, papules and plaques and upper back IgG-␭ M-spike with 10% plasma dexamethasone, 40 mg/wk, axillae, on patient’s lower back biopsy specimens: (stable compared cells oral pamidronate monthly proximal and buttocks; multiple normal epidermis with level 1 year Subsequently, and aspirin, 81 mg. During upper lucent bone lesions in and prior) diagnosed as 5 mo of therapy, patient extremities, skull and ribs; skin dermoepidermal having had stable hematologic lateral hips, lesions developed 4 junction, marked biphenotypic markers, skeletal disease; lower back, years after treatment decrease in elastic IgG-␭ and IgA-␬ skin laxity gradually and buttocks for lymph node fibers with multiple myeloma progressive plasmacytoma of left elastophagocytosis; axilla crystal violet negative for amyloid

Abbreviations: CL, cutis laxa; C-VAMP, cyclophosphamide, vincristine, adriamycin, and methylprednisolone; DIF, direct immunofluorescence; EKG, electrocardiogram; FLC, free light chain; IFE, immunofixation electrophoresis; LCV, leukocytoclastic vasculitis; RBC, red blood cell; RR, reference range; SPEP, serum protein electrophoresis; UPEP, urine protein electrophoresis.

were more suggestive of dermal elastolysis consistent with ACL Immunofixation electrophoresis (IFE) revealed a stable rather than GA. monoclonal IgG-␭ M-spike (0.5 g/dL vs 0.4 g/dL when evalu- Findings from a complete blood cell count, including dif- ated the previous year). One year prior to his presentation, the ferential, hepatic function panel, basic metabolic panel, fast- patient had elevations of serum ␬ free light chain (FLC) level ing lipid profile, thyroid panel, anti-Ro/SSA antibody, anti- (118 mg/L; reference range, 3.3-19.4 mg/L) and serum ␭ FLC La/SSB antibody, antinuclear antibody, anti–double-stranded level (79.3 mg/L; reference range, 5.7-26.3 mg/L). DNA antibody, serum ceruloplasmin, serum copper level, A bone marrow biopsy was performed, revealing 10% plasma serum ␤-2 microglobulin, erythrocyte sedimentation rate, cells. A skeletal survey was also performed, revealing multiple lu- and echocardiogram were negative for disease or were cent bone lesions, less than 5 mm in size, in the patient’s skull along within reference range. Serum levels of IgG, IgA, IgM, albu- with lytic rib lesions. Biphenotypic IgG-␭ and IgA-␬ multiple my- min, total protein, ␣1-globulin, ␣2-globulin, ␥-globulin, and eloma was subsequently diagnosed by the patient’s oncologist. total globulin were also within reference range on serum Treatment with oral lenalidomide, 25 mg/d; dexametha- protein electrophoresis (SPEP). sone, 40 mg/wk; oral pamidronate monthly; and aspirin, 81

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©2011 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 Table 2. Summary of Acquired Cutis Laxa Associated With Immunoglobulin Heavy Chain Deposition

Sex, Clinical Skin Biopsy Investigative Source Age, y Findings Finding Findings Treatment Outcome Tan et al18 M/50 Developed lax skin Skin biopsy: loss of Serum IgG-␭ Prednisolone and Developed on face, neck, elastic fibers in gammopathy with cyclophosphamide emphysema and trunk, and superficial and ␭ FLCs peripheral extremities with a deep dermis IgG glomerular polyneuropathy history of DIF: IgG deposited deposits leading to No mention of gammopathy, around dermal membranoproliferative response of glomerulonephritis; elastic fibers and glomerulonephritis; cutaneous recent 30-lb within walls and hemodialysis changes weight loss lumens of dermal dependent blood vessels No bone marrow involvement Harrington F/38 Lax skin on face, Skin biopsy: marked SPEP: normal Lenalidomide; caused Not discussed et al3 axillae, trunk, and reduction of reversible renal extremities with dermal elastic insufficiency and history of urticaria, fibers with patient then placed renal insufficiency, elastophagocytosis on treatment with monoclonal DIF: IgG dexamethasone immune deposition on and bortezomib deposition of elastic fibers in IgG-heavy chains papillary dermis in heart and kidney Ferna´ndez M/52 Lax skin of face, Skin biopsy: marked IgG-␭ monoclonal Initial treatment with Stabilization of de Larrea neck, axillae and reduction of elastic gammopathy granulocyte CSF; cutaneous disease et al4 groin in setting of fibers patient developed and hemodialysis monoclonal DIF: IgG deposits alveolar dependent at time gammopathy of on the elastic hemorrhage and of publication undetermined fibers in the worsening renal significance who dermis, along the function had renal failure dermoepidermal Treatment with junction, around bortezomib and blood vessels and oral adnexal structures dexamethasone was initiated

Abbreviations: CSF, colony-stimulating factor; DIF, direct immunofluorescence; FLC, free light chain; SPEP, serum protein electrophoresis.

mg/d, was initiated. The patient’s hematologic markers and skel- tion. The pattern of elastic fiber destruction with engulf- etal disease remained stable; however, his cutaneous laxity gradu- ment by phagocytes can be a nonspecific finding but is ally progressed during 5 months on this regimen. characteristic of elastolytic giant cell granuloma, which oc- curs on sun-damaged areas in contrast to our patient. How- COMMENT ever, a papular variant with 2- to 3-mm skin-colored papules occurring on the chest, neck, back, and shoulders of Acquired cutis laxa manifests as localized or general- a 43-year-old woman was recently described in associa- ized laxity and has been associated with inflammatory tion with a IgG-␭ gammopathy.17 dermatoses (ie, urticaria, dermatitis herpetiformis, sar- The patient’s cutaneous changes prompted further sys- coidosis, amyloidosis, systemic lupus erythematosus, ery- temic investigation leading to the diagnosis of early my- thema multiform), medication use (ie, penacillamine, eloma, which could improve his overall survival. It is theo- penicillin, isoniazid), hypersensitivity reaction to insect retically possible that use of immunosuppressive agents bites and related to an underlying hematologic disorder may improve his gammopathy and decrease the progres- (ie, multiple myeloma, lymphoma, immunoglobulin sion of his cutaneous changes; however, the likelihood heavy-chain deposition disease, plasma cell dyscrasia).1-4 is very low given the outcomes of prior reported cases. Acquired cutis laxa has also been reported in patients fol- The exact pathogenesis of ACL is unclear. In the set- lowing cutaneous mastocytosis, Sweet syndrome in pe- ting of myeloma, amyloid light chains are produced by diatric patients (Marshall syndrome), and interstitial plasma cells and are deposited in various organs leading granulomatous dermatitis.5-7 At least 10 patients have been to end-organ failure. Three of the cases14-16 reviewed did described in the literature as having ACL associated with show evidence of amyloid deposition with reduction and multiple myeloma (Table 1).8-16 fragmentation of elastic fibers, and the patient described Our patient’s cutaneous laxity distribution is consis- by Dicker et al16 with localized acrolocalized ACL had so tent with descriptions of prior cases. In contrast to prior much dermal amyloid deposition that elastic fibers could reports, this is the first case, to our knowledge, of ACL due not be evaluated. In addition to amyloid deposition, im- to myeloma associated with the clinical presentation of GA- munoglobulin-heavy chain deposition has also been re- like plaques. It is also interesting to note that the face and ported with ACL (Table 2).3,4,18 Unfortunately, we could upper body had only isolated skin laxity without preced- not assess immunoglobulin deposition owing to lack of tis- ing plaques. Histologic examination of the erythematous sue. This hypothesis could be the basis for the cell- lesions showed marked elastolysis with elastophagocyto- mediated destruction of elastic fibers in the gammopathy- sis by giant cells and lacked evidence of amyloid deposi- associated cases of cutis laxa and the case of papular

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©2011 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 elastolytic giant cell granuloma recently described. How- REFERENCES ever, it is difficult (if not impossible) to determine if the immune deposits are the primary event or a normal re- 1. Hu Q, Reymond JL, Pinel N, Zabot MT, Urban Z. Inflammatory destruction of sponse to repair and “clean up” damaged tissue. elastic fibers in acquired cutis laxa is associated with missense alleles in the elas- In conclusion, ACL is a very rare entity described in tin and fibulin-5 genes. J Invest Dermatol. 2006;126(2):283-290. the literature, and cases related to monoclonal gammopa- 2. Riveros CJ, Gavilań MF, França LF, Sotto MN, Takahashi MD. Acquired localized cutis laxa confined to the face: case report and review of the literature. Int J thy are even scarcer. We believe our case supports the Dermatol. 2004;43(12):931-935. theory that myeloma-associated immunoglobulin depo- 3. 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