Author Affiliations: Division of Dermatology, University of Louisville, Louisville, Kentucky.
Cutis laxa is a rare dermatosis that can be inherited or acquired. The acquired form is rare and has been associated with various conditions, including multiple myeloma, monoclonal gammopathy of undetermined significance, and heavy chain deposition disease.
We describe a 48-year-old man who developed generalized cutis laxa over a 4-year duration. There were no preceding skin changes except for a history of erythematous plaques with granuloma annulare–like features on his buttocks and lateral hips. He underwent treatment of an axillary lymph node plasmacytoma with surgery and radiation 4 years prior to his cutaneous changes and had been clinically monitored with a diagnosis of monoclonal gammopathy of unknown significance (MGUS). Cutaneous manifestations prompted a systemic evaluation demonstrating a persistent monoclonal IgG-λ M-spike on immunofixation electrophoresis and lytic bone lesions. He was later found to have biphenotypic IgG-λ and IgA-κ multiple myeloma.
Multiple myeloma, plasma cell dyscrasia, and heavy-chain deposition disease have been very rarely reported to be associated with acquired cutis laxa (ACL). Findings in our patient support the hypothesis that paraproteinemia is a cause of ACL through immunologic destruction of elastic fibers manifesting as granuloma annulare–like plaques. Evaluation for an underlying gammopathy is essential for the workup of a patient with new-onset ACL.
Cutis laxa (CL) is a rare dermatosis resulting in loose, wrinkled, redundant skin secondary to defects in dermal elastic tissue. When involving the face, patients classically have a “bloodhound-like” or “hound dog–like” appearance. Extracutaneous manifestations may also occur, including pulmonary emphysema, diverticulae of the gastrointestinal tract orgenitourinary tract, and cardiovascular defects. Cutis laxa may be inherited or acquired with acquired cutis laxa (ACL) having a later onset of disease, and more generalized involvement and is related to various different etiologies including medications, inflammatory diseases, infections, and hematologic disorders.1 We describe a 48-year-old man who developed ACL and granuloma annulare (GA)-like lesions as a paraneoplastic manifestation of early myeloma years after being treated for a lymph node plasmacytoma.
A 48-year-old man was referred for evaluation of “recalcitrant” GA. At the time of referral, we noted a 4-year history of gradually developing loose, wrinkled skin of his face, chest, upper back, lateral hips, buttocks, and proximal upper extremities. There were no preceding cutaneous changes on his face and upper body; however, he developed asymptomatic erythematous plaques with GA-like features on his buttocks and hips. Eight years earlier, a nodal plasmacytoma was surgically excised from his left axilla. He received local radiation therapy at that time and was clinically monitored by an oncologist for the working diagnosis of monoclonal gammopathy of unknown significance (MGUS).
His medical history was otherwise unremarkable, and his medications included oral acitretin, 25 mg/d, and daily oral multivitamins: oral vitamin E, 400 IU; oral vitamin D, 2000 IU; omega-3 fish oil, 2000 mg; and B-complex vitamin supplements. Acitretin was added by the referring dermatologist 1 month prior to his initial presentation to us without improvement of his skin disease. His family history was unremarkable.
Physical examination demonstrated a healthy-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, proximal upper extremities, and the lateral aspects of his hips (Figure 1 and Figure 2). Granuloma annulare–like erythematous, nonscaly plaques were noted on his lower back, buttocks, and lateral hips in association with increased wrinkling (Figure 3).
Loose, sagging skin on the face and neck with “bloodhound-like” appearance.
Right lateral hip with loose, wrinkly, redundant folds with faint erythema.
Sacral area with nonscaly, somewhat annular, erythematous papules and plaques.
Findings from two 4-mm punch biopsy specimens of the patient's left hip and upper back revealed a normal epidermis anddermoepidermal junction with few lymphocytes and histiocytes around superficial blood vessels and interstitially in the upper dermis. A marked decrease in elastic fibers with elastophagocytosis by epitheloid cells and giant cells were observed (Figure 4 and Figure 5). Results from periodic acid–Schiff and giemsa stains were unremarkable. No evidence of amyloid was seen with crystal violet. No alteration of collagen or increased mucin deposition was appreciated. Initially, the biopsy specimen involving his left hip had been diagnosed as GA and that from his upper back as mid-dermal elastolysis. Further review of the specimens concluded that both biopsy specimens were more suggestive of dermal elastolysis consistent with ACL rather than GA.
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 ×600).
Verhoeff–Van Giesen stain highlights histiocytic cells engulfing fragmented elastic fibers, as well as diminished elastic fibers in the surrounding dermis (original magnification ×600).
Findings from a complete blood cell count, including differential, hepatic function panel, basic metabolic panel, fasting lipid profile, thyroid panel, anti-Ro/SSA antibody, anti-La/SSB antibody, antinuclear antibody, anti–double-stranded DNA antibody, serum ceruloplasmin, serum copper level, serum β-2 microglobulin, erythrocyte sedimentation rate, and echocardiogram were negative for disease or were within reference range. Serum levels of IgG, IgA, IgM, albumin, total protein, α1-globulin, α2-globulin, γ-globulin, and total globulin were also within reference range on serum protein electrophoresis (SPEP).
Immunofixation electrophoresis (IFE) revealed a stable monoclonal IgG-λ M-spike (0.5 g/dL vs 0.4 g/dL when evaluated the previous year). One year prior to his presentation, the patient had elevations of serum κ free light chain (FLC) level (118 mg/L; reference range, 3.3-19.4 mg/L) and serum λ FLC level (79.3 mg/L; reference range, 5.7-26.3 mg/L).
A bone marrow biopsy was performed, revealing 10% plasma cells. A skeletal survey was also performed, revealing multiple lucent bone lesions, less than 5 mm in size, in the patient's skull along with lytic rib lesions. Biphenotypic IgG-λ and IgA-κ multiple myeloma was subsequently diagnosed by the patient's oncologist.
Treatment with oral lenalidomide, 25 mg/d; dexamethasone, 40 mg/wk; oral pamidronate monthly; and aspirin, 81 mg/d, was initiated. The patient's hematologic markers and skeletal disease remained stable; however, his cutaneous laxity gradually progressed during 5 months on this regimen.
Acquired cutis laxa manifests as localized or generalized laxity and has been associated with inflammatory dermatoses (ie, urticaria, dermatitis herpetiformis, sarcoidosis, amyloidosis, systemic lupus erythematosus, erythema multiform), medication use (ie, penacillamine, penicillin, isoniazid), hypersensitivity reaction to insect bites and related to an underlying hematologic disorder (ie, multiple myeloma, lymphoma, immunoglobulin heavy-chain deposition disease, plasma cell dyscrasia).1- 4 Acquired cutis laxa has also been reported in patients following cutaneous mastocytosis, Sweet syndrome in pediatric patients (Marshall syndrome), and interstitial granulomatous dermatitis.5- 7 At least 10 patients have been described in the literature as having ACL associated with multiple myeloma (Table 1).8- 16
Our patient's cutaneous laxity distribution is consistent with descriptions of prior cases. In contrast to prior reports, this is the first case, to our knowledge, of ACL due to myeloma associated with the clinical presentation of GA-like plaques. It is also interesting to note that the face and upper body had only isolated skin laxity without preceding plaques. Histologic examination of the erythematous lesions showed marked elastolysis with elastophagocytosis by giant cells and lacked evidence of amyloid deposition. The pattern of elastic fiber destruction with engulfment by phagocytes can be a nonspecific finding but is characteristic of elastolytic giant cell granuloma, which occurs on sun-damaged areas in contrast to our patient. However, a papular variant with 2- to 3-mm skin-colored papules occurring on the chest, neck, back, and shoulders of a 43-year-old woman was recently described in association with a IgG-λ gammopathy.17
The patient's cutaneous changes prompted further systemic investigation leading to the diagnosis of early myeloma, which could improve his overall survival. It is theoretically possible that use of immunosuppressive agents may improve his gammopathy and decrease the progression of his cutaneous changes; however, the likelihood is very low given the outcomes of prior reported cases.
The exact pathogenesis of ACL is unclear. In the setting of myeloma, amyloid light chains are produced by plasma cells and are deposited in various organs leading to end-organ failure. Three of the cases14- 16 reviewed did show evidence of amyloid deposition with reduction and fragmentation of elastic fibers, and the patient described by Dicker et al16 with localized acrolocalized ACL had so much dermal amyloid deposition that elastic fibers could not be evaluated. In addition to amyloid deposition, immunoglobulin-heavy chain deposition has also been reported with ACL (Table 2).3,4,18 Unfortunately, we could not assess immunoglobulin deposition owing to lack of tissue. This hypothesis could be the basis for the cell-mediated destruction of elastic fibers in the gammopathy-associated cases of cutis laxa and the case of papularelastolytic giant cell granuloma recently described. However, it is difficult (if not impossible) to determine if the immune deposits are the primary event or a normal response to repair and “clean up” damaged tissue.
In conclusion, ACL is a very rare entity described in the literature, and cases related to monoclonal gammopathy are even scarcer. We believe our case supports the theory that myeloma-associated immunoglobulin deposition on elastic fibers triggers a cell-mediated immune response leading to their destruction phagocytosis. In our patient, this resulted in decreased skin laxity and the development of plaques with a clinical presentation strikingly resembling GA. Clinicians should be aware of this association and evaluate for the presence of a gammopathy with immunofixation electrophoresis when a patient presents with ACL and/or GA-like plaques with histologic characteristics resembling the so-called elastolytic giant cell granuloma.
Correspondence: Jeffrey P. Callen, MD, Division of Dermatology, University of Louisville, 310 E Broadway, Floor 2A, Louisville, KY 40202 (firstname.lastname@example.org).
Accepted for Publication: July 14, 2010.
Author Contributions: Both authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: New and Callen. Acquisition of data: New and Callen. Analysis and interpretation of data: New and Callen. Drafting of the manuscript: New and Callen. Critical revision of the manuscript for important intellectual content: Callen. Administrative, technical, and material support: Callen. Study supervision: Callen.
Financial Disclosure: Dr Callen has received honorarium from Amgen, Abbott, Genentech, Centocor, Electrical Optical Sciences, Celgene, and Medicis. He serves on a safety monitoring committee for Celgene.
Disclaimer: Dr Callen is Associate Editor of the Archivesof Dermatology, but he was not involved in any of the decisions regarding review of the paper or its acceptance.
Additional Contributions: Janine Malone, MD, assisted with the dermatopathologic photographs and captions.
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The Rational Clinical Examination: Evidence-Based Clinical Diagnosis
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