Case Report | Open Access
Sophia Z. Shalhout, Myrna R. Nahas, Reed E. Drews, David M. Miller, "Generalized Acquired Cutis Laxa Associated with Monoclonal Gammopathy of Dermatological Significance", Case Reports in Dermatological Medicine, vol. 2020, Article ID 7480607, 10 pages, 2020. https://doi.org/10.1155/2020/7480607
Generalized Acquired Cutis Laxa Associated with Monoclonal Gammopathy of Dermatological Significance
Background. Cutis laxa is a rare dermatosis that is inherited or acquired and clinically features loose, wrinkled, and redundant skin with decreased elasticity. This heterogeneous connective tissue disorder may be localized or generalized, with or without internal manifestations. Generalized cutis laxa often has a cephalocaudal progression and is attributed to inflammatory cutaneous eruptions, medications, and infections. Cutis laxa is also associated with several other conditions including rheumatoid arthritis, systemic lupus erythematosus, and plasma-cell dyscrasias. Case Presentation. We report an unusual case of a 35-year-old male with progression of generalized acquired cutis laxa and vasculitis that occurred over a period of one year. No cutaneous inflammatory eruption preceded or accompanied his decreased skin elasticity, and a biopsy of the skin showed elastolysis. His cutaneous manifestation led to systemic evaluation and an eventual diagnosis of smoldering multiple myeloma accompanied by aortitis and anemia. His myeloma and vasculitis were successfully treated with cyclophosphamide, bortezomib, and dexamethasone and high-dose prednisone, respectively, with no improvement to his cutis laxa. Conclusions. The presence of monoclonal gammopathy is strongly associated with several dermatological entities such as acquired cutis laxa. We propose a new term for the dermatological manifestations caused by paraproteinemia: monoclonal gammopathy of dermatological significance, or MGODS, and stress the evaluation of an underlying gammopathy in the setting of certain dermatologic conditions, including scleromyxedema and amyloidosis. We present a case of a newly acquired cutis laxa secondary to plasma-cell dyscrasias that exemplifies MGODS, alongside a brief literature review, and underscore the clinical relevance of monoclonal gammopathies of dermatological significance.
Cutis laxa (CL), or elastolysis, is a rare heterogeneous dermatosis with several etiologies. CL is typically inherited as a dominant, recessive, or X-linked recessive condition. Clinically, CL is characterized by loosely hanging, pendulous skin folds, resulting in the appearance of premature aging. Histologically, degeneration of the dermal elastic fibers is observed. Internal organ involvement is often seen in patients with CL and can affect the pulmonary, gastrointestinal, urogenital, and cardiovascular systems. Prognosis of CL may vary and largely depends on the implicated gene mutation as well as the extent of systemic involvement. It may range from a fatal outcome in certain cases of inherited CL to a normal life expectancy in the less severe forms. CL is a progressive disorder with insidious onset that worsens with age. In rare cases, CL may be acquired de novo or associated with preceding cutaneous inflammatory eruptions with adult-onset of disease. CL is also associated with infections, drug hypersensitivity reactions, and plasma-cell dyscrasias. We report a rare case of generalized acquired CL and aortitis, without preceding inflammatory lesions or eruptions, most likely secondary to multiple myeloma. The presence of monoclonal gammopathy is strongly associated with several dermatological entities and cutaneous manifestations. We suggest these should be referred to as monoclonal gammopathy of dermatological significance, or MGODS, and stress the evaluation of an underlying gammopathy in the setting of several well-established dermatological features. We present a case of MGODS and provide a brief literature review of other cases of acquired cutis laxa associated with monoclonal gammopathy.
2. Case Presentation
A 35-year-old male noticed the progression of loosening and thinning of his skin over the period of one year. These areas had been asymptomatic with no preceding inflammatory dermatosis. The patient’s past medical history included hypertension and long-standing anemia of uncertain etiology.
On physical exam, profound laxity of the periocular skin, neck, axillary, and back was appreciated (Figures 1 and 2). The clinical presentation was suggestive of an acquired cutis laxa. A biopsy of involved skin demonstrated sparse superficial perivascular lymphocytic inflammation with rare giant cells. An elastic stain showed a decrease in the elastic fibers in the reticular dermis compared to a biopsy of uninvolved skin; no significant changes in the dermal collagen were appreciated on Masson’s Trichome staining. Findings consistent with granulomatous slack skin were absent. In aggregate, the clinical and pathological presentation were consistent with an acquired cutis laxa (ACL).
Serology work-up for autoimmune connective tissue disease was negative for rheumatoid factors, antineutrophil cytoplasm antibodies, and anti-nuclear antibodies. Chromosomal microarray analysis performed on DNA extracted from a peripheral blood specimen returned normal findings. Anemia work-up demonstrated normal iron stores, normal renal function, and decreased reticulocyte count. He was found to have an elevated C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), and an IgG-kappa paraprotein of 1.36 g/dL. The patient was initially diagnosed with monoclonal gammopathy of undetermined significance (MGUS) and anemia of inflammation. Due to suspicion of a connection between his MGUS and cutis laxa, further evaluation revealed an abnormal kappa/lambda free-light chain ratio of 5.86. A PET-CT (Positron emission tomography-computed tomography) did not reveal evidence of skeletal lytic lesions or extraosseous findings of plasmacytoma. However, mild fluorodeoxyglucose avidity of the vascular walls of the aorta and branching vessels was seen, and in the setting of elevated CRP and ESR, was consistent with aortitis and mild vasculitis (Figure 3). Subsequent bone marrow biopsy demonstrated 20% plasma cells in the bone marrow core and 13% of aspirate.
In the setting of end-organ dysfunction presumed to be secondary to a plasma-cell dyscrasia (cutis laxa and vasculitis), the patient was started on CyBorD (cyclophosphamide, bortezomib, dexamethasone). His second cycle was delayed due to a left inguinal herniorrhaphy with unremarkable wound healing. CyBorD was tolerated well by the patient. Upon completion of his sixth cycle of CyBorD, a PET-CT revealed continued aortitis, a hiatal hernia, umbilical hernia, and small bowel-containing right inguinal hernia. The level of monoclonal IgG-kappa protein continued to decline (280 mg/dL), but C-reactive protein levels remained elevated. He was given high-dose oral prednisone, 60 mg/d, to treat his vasculitis which resulted in near normal C-reactive protein levels. His cutis laxa did not improve in response to corticosteroids and immunosuppressive therapy. However, at one-year posttreatment, his cutis laxa did not clinically appear to have progressed.
3. Discussion and Conclusions
ACL is extremely rare and can be generalized or localized. Several conditions warrant discussion in the differential diagnosis of the skin manifestations in this patient, including anetoderma, and mid-dermal elastolysis. Anetoderma usually involves the trunk and extremities and consists of well-circumscribed atrophic or depressed patches or saccular outpouchings of wrinkled skin. The histological finding of anetoderma is loss of elastic fibers in the papillary and reticular dermis. Mid-dermal elastolysis is clinically characterized by well-circumscribed fine wrinkles or perifollicular papular protrusions usually involving the trunk and upper extremities. Mid-dermal elastolysis is histologically characterized by focal loss of elastic fibers in the mid-dermis.
ACL has been associated with inflammatory dermatoses, including urticaria, systemic lupus erythematosus, dermatitis herpetiformis, and amyloidosis. Cases of ACL due to medication exposure and arthropod bite reactions have been reported [1, 2]. Our patient is most consistent with reports of ACL associated with underlying hematological disorders including multiple myeloma, plasma-cell dyscrasia, and heavy chain deposition disease [3, 4]. The clinical features, treatment, and outcomes of previous cases reported in the literature of ACL associated with plasma-cell dyscrasias and monoclonal gammopathies are summarized in Table 1. There are reports of at least 23 cases, with ∼20% reporting acral localization of cutis laxa, ∼30% reporting a diagnosis of multiple myeloma associated with amyloidosis, and ∼50% describing a preceding cutaneous process. Very few reports describe stabilization of cutis laxa following systemic therapy administered to treat the underlying monoclonal gammopathy. Unlike other connective tissue disorders, ACL has not been associated with vascular fragility, and surgery is not contraindicated since ACL is not thought to affect wound healing. Early management with plastic surgical procedures such as rhytidectomy can be beneficial to mitigate symptoms. However, serial reconstructive procedures are usually required since CL often progresses with time.
Systemic elastolysis has been reported in adult-onset ACL. The most significant internal organs often involved are associated with pulmonary, cardiovascular (i.e., heart failure, ectasia of the aorta, and aortic aneurysms), gastrointestinal (i.e., diverticula and hernias), and urogenital (i.e., hernias, uterine prolapse, and cystocele) systems [25–27]. It is unclear if the aortitis, large vessel vasculitis, and numerous hernias experienced by this patient were related to the paraprotein and elastolysis [4, 8]. Although the exact pathophysiology is unknown, myeloma-associated immunoglobulin deposition is thought to result in a cell-mediated immune response and promotes phagocytic destruction of elastic fiber [4, 28]. In our patient, we suspect that the paraprotein contributed to decreased skin laxity as well as involvement of the vasculature and gastrointestinal system. There is one case report of congenital cutis laxa associated with aortitis in a 17-month-old child . However, to our knowledge, there are no reports of ACL and aortitis secondary to multiple myeloma.
We propose a new term for the dermatological manifestations caused by paraproteinemia: monoclonal gammopathy of dermatological significance or MGODS. This term encapsulates a variety of diagnoses that present with paraproteins and may have significant cutaneous involvement such as nodular and light chain amyloid, cryoglobulinemia, necrobiotic xanthogranuloma, scleromyxedema, papular mucinosis, and POEMS syndrome . Table 2 provides a nonexhaustive list of well-established conditions associated with monoclonal gammopathy and a summary of pertinent cutaneous findings.
MGODS may present in the setting of an otherwise monoclonal gammopathy of undetermined significance (MGUS). Indeed, in our case, the patient was initially diagnosed with MGUS, but the recognition of the likely ACL representing an MGODS prompted further evaluation, including a bone marrow biopsy, resulting in the diagnosis of smoldering myeloma. Given that skin manifestations are not part of diagnostic criteria for progression beyond MGUS, our case report and the term MGODS highlights the utility of recognizing cutaneous manifestations of monoclonal gammopathies as it may guide evaluation and, in some cases, management. End-organ dysfunction is often the impetus to initiate treatment for plasma-cell dyscrasias, with skeletal, renal, and hematological abnormalities being the most common organs triggering induction of therapy. In certain contexts, however, gammopathies of dermatological significance may necessitate initiation of therapy. The types of skin dysfunction that warrant the induction of systemic treatment are far from agreed upon and often require multidisciplinary consultation.
|ACL:||Acquired cutis laxa|
|CyBorD:||Cyclophosphamide, bortezomib, and dexamethasone|
|ESR:||Erythrocyte sedimentation rate|
|LHCDD:||Light and heavy chain deposition disease|
|MGODS:||Monoclonal gammopathy of dermatological significance|
|MGUS:||Monoclonal gammopathy of undetermined significance|
|POEMS:||Polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes|
|PET-CT:||Positron emission tomography-computed tomography.|
Written informed consent was obtained from the patient for publication of this case report and any accompanying images.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
RED, MRN, and DMM managed the patient. SZS wrote the manuscript and provided revisions. All the authors read, critically revised, and approved the final version of the manuscript.
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