Skip to main content

Advertisement

We're creating a new version of this page. See preview

  • Case report
  • Open Access
  • Open Peer Review

Scleredema associated with immunoglobulin A-κ smoldering myeloma: a case report and review of the literature

  • 1,
  • 1Email author,
  • 1,
  • 1,
  • 1,
  • 1,
  • 1,
  • 1 and
  • 1
Journal of Medical Case Reports201913:145

https://doi.org/10.1186/s13256-019-2072-1

  • Received: 23 October 2018
  • Accepted: 4 April 2019
  • Published:
Open Peer Review reports

Abstract

Background

Scleredema is a rare sclerodermoid skin condition characterized by diffuse symmetrical thickening of the upper part of the body. Its association with monoclonal gammopathy and myeloma was recently described; very few cases have been reported to date.

Case presentation

A 66-year-old Sri Lankan woman who had been followed in a dermatology unit for 34 years with diffuse systemic sclerosis presented with an acute exacerbation of the skin disease. Absence of Raynaud’s phenomenon; sclerodactyly; characteristic lung, gastrointestinal, and cardiac involvement of systemic sclerosis; and repeatedly negative antinuclear antibodies test results led to reevaluation for the possibility of scleredema. Skin biopsies from four body sites showed normal epidermis and thickened reticular dermis with swollen collagen bundles separated from one another by clear spaces, resulting in fenestration. The skin appendages were not atrophied or bound down. Alcian blue staining showed interstitial mucin deposition. Serum protein electrophoresis demonstrated an abnormal monoclonal band in the β-region with a paraprotein level of 8.9 g/dl. Immunofixation showed an abnormal band in the γ-region consisting of immunoglobulin A and κ. Bone marrow biopsy revealed abnormal monoclonal plasma cells (15%) with multinuclearity. There was no evidence of end organ damage, and whole-body magnetic resonance imaging did not reveal any evidence of bone involvement. The patient’s diagnosis was revised as scleredema type 2 associated with IgA-κ, and she was referred to a hemato-oncologist for chemotherapy, which led to significant improvement in the skin condition.

Conclusions

Scleredema is a rare disorder that has an enigmatic, rare association with monoclonal gammopathy. Dermatologists should be aware of this rare but important association.

Keywords

  • Scleredema
  • Smoldering myeloma
  • Monoclonal gammopathy

Introduction

Scleredema is rare sclerodermoid skin disease characterized by symmetrical diffuse woody induration of the upper part of the body owing to thickened dermis and excessive dermal mucin deposition. Though the commonest association of it is diabetes mellitus (type 3) [1], scleredema has been reported to occur with a history of an antecedent infection (type 1) and many other systemic diseases. Of them, monoclonal gammopathy was a recently described unusual association (type 2) with unknown significance. A high degree of suspicion is needed to differentiate scleredema from scleroderma when scleredema has a chronic course with generalized involvement. Owing to the rarity of the disease and subtle differences in the skin manifestation, histopathological assessment with mucin staining is invaluable in doubtful instances.

We report a case of a patient with long-standing widespread scleredema associated with immunoglobulin A-κ smoldering myeloma, which was misdiagnosed as scleroderma for many years. Only a few case reports are available in the literature on scleredema associated with myeloma; to the best of our knowledge, this is the first patient to be reported with scleredema who was diagnosed with smoldering myeloma of IgA-κ. This case report highlights the importance of awareness of scleredema because it is rare and can be misdiagnosed and, if diagnosed, it can be treated. We also include a detailed literature review.

Case presentation

A 66-year-old Sri Lankan woman who had been followed in a dermatology unit for 34 years for diffuse systemic sclerosis presented to our institution with an acute exacerbation of the skin disease. She was treated with corticosteroids and cyclophosphamide pulses and subsequently with mycophenolate mofetil for the skin condition. She did not have any other past medical or family history of systemic diseases, chronic infections, malignancies, or genetic diseases. She was a housewife, was unemployed, and was not exposed to any indoor or outdoor toxins, chemicals, or radiation. She was a nonsmoker and nonalcoholic.

On examination, she had widespread thickening of the skin predominantly involving the trunk and proximal extremities (Fig. 1). She did not have sclerodactyly, but she had deformities in keeping with osteoarthritis (Fig. 2). She denied cold-induced episodic acral bluish discoloration suggestive of Raynaud’s phenomenon. She was not febrile, and the result of her general examination was normal without pallor, cyanosis, clubbing, lymphadenopathy, or bilateral ankle edema. Her respiratory and cardiovascular examination results were normal with a heart rate of 82 beats per minute and a blood pressure of 130/80 mmHg. The result of her neurological examination was normal with normal funduscopy without any cranial neuropathy or peripheral neuropathy. Repeated echocardiography did not reveal any evidence of pulmonary hypertension. Upper gastroduodenoscopy did not show reflux disease. Radiographically, there was no evidence of interstitial lung disease. The patient’s autoimmune antibody profile (antinuclear antibody, anti-double-stranded DNA, perinuclear antineutrophil cytoplasmic antibodies, cytoplasmic antineutrophil cytoplasmic antibodies, anti-Smith antibody, anti RO and anti-LA, antitopoisomerase antibody, anticentromere antibody, and complements) was persistently negative, and her full blood count, urine full report, and renal and liver function were normal (Table 1). Absence of Raynaud’s phenomenon; sclerodactyly; characteristic lung, gastrointestinal, and cardiac involvement of systemic sclerosis; and repeatedly negative antinuclear antibody test results lead us to reevaluate the patient for the possibility of scleredema.
Fig. 1
Fig. 1

Widespread thickening of the skin predominantly involving the trunk and proximal extremities

Fig. 2
Fig. 2

The patient did not have sclerodactyly but had deformities in keeping with osteoarthritis

Table 1

Full blood count, liver function test, and serum electrolyte results

Investigation

Value

Normal range

Comment

WBC

9.32 ×  103/μl

4–10

Normal

Lymphocytes

2.17 × 103/μl

0.8–4

Normal

Serum creatinine

0.9 mg/dl

60–120

Normal

Serum potassium

3.4 mmol/L

3.5–5.1

Normal

AST

27 U/L

10–35

Normal

Albumin

38 g/L

35–45

 

Alkaline phosphatase

104 U/L

100–360

Normal

Ionized calcium

1.21 mmol/ L

1.0–1.3

Normal

Amylase

68 U/ L

22–80

Normal

Neutrophils

6.09 × 103/μl

2–7

Normal

Platelets

277 × 103/μl

150–450

Normal

Serum sodium

138 mmol/L

135–148

Normal

   

Normal

ALT

20 U/L

10–40

Normal

INR

1.26

 

Normal

Serum magnesium

1.7 mg/dl

1.7–2.7

Normal

Troponin I

< 0.1 ng/ml

< 0.5

Normal

Abbreviations: ALT Alanine aminotransferase, AST Aspartate aminotransferase, INR International normalized ratio, WBC White blood cells

Skin biopsies from four body sites showed normal epidermis and thickened reticular dermis with swollen collagen bundles separated from one another by clear spaces, resulting in fenestration. The skin appendages were not atrophied or bound down. Alcian blue staining showed interstitial mucin deposition suggestive of scleredema. Serum protein electrophoresis demonstrated an abnormal monoclonal band in the gamma region with a paraprotein level of 8.9 g/dl. Immunofixation showed an abnormal band in the gamma region consisting of IgA and κ. Bone marrow biopsy revealed abnormal monoclonal plasma cells (15%) with multinuclearity. There was no evidence of end organ damage with normal calcium, renal function, and full blood count, and whole-body magnetic resonance imaging did not reveal any evidence of bone involvement (Fig. 3). The patient’s diagnosis was revised as scleredema type 2 associated with IgA-κ smoldering myeloma. She was commenced on intravenous immunoglobulin (IVIG) monthly (1 g/kg for 2 days per month), and a hemato-oncologist started intravenous bortezomib cycles (1.7 g on day 1, day 8, day 22, and day 29). Currently, she was receiving 6 months of IVIG and four cycles of intravenous bortezomib, and significant improvement of the skin was observed.
Fig. 3
Fig. 3

Normal whole-body magnetic resonance imaging

Discussion

In this report, we present a case of a patient with widespread thickening of the skin predominantly involving the trunk and proximal extremities for more than 30 years who was misdiagnosed with systemic sclerosis. Absence of Raynaud’s phenomenon; sclerodactyly; characteristic lung, gastrointestinal, and cardiac involvement of systemic sclerosis; and repeatedly negative antinuclear antibody test results led to reevaluation of the diagnosis. Later she was diagnosed with scleredema with smoldering myeloma, and she responded well to treatment.

In keeping with the literature, even though scleredema with monoclonal gammopathy is reported, multiple myeloma (MM)-associated scleredema is rare. In 1974, Korting et al. reported one patient with MM; in 1984, Venencie et al. reported one patient with smoldering myeloma; and in 1987, Ohta et al. reported one patient with MM [24]. After that, several case reports were reported (Table 2). Seven were male patients, six were female, and the majority were above the age of 50. Interestingly, one patient was in his 20s [5]. Only two patients were reported with smoldering myeloma (one with IgG-κ and the other with IgG-λ) and scleredema [2, 6] in the literature, and all the others had MM (five with IgG-κ, four with IgA-κ, one with IgG-λ, and one with IgA-λ; two had IgG and the light chain was not mentioned). This shows that the number of patients with IgG and IgA were observed in almost equal numbers and that the majority of patients had κ-light chains compared with λ-light chains (10 patients with κ, 3 patients with lambda). Even in scleredema associated with monoclonal gammopathy without MM, IgG-κ predominates (10 of 23 cases in one review) [7]. Our patient is the first to be reported with scleredema who was diagnosed with smoldering myeloma of IgA-κ.
Table 2

Literature review of patients with myeloma and scleredema

Year

Age (years)

Sex

Clinical features

Myeloma

Bone marrow plasma cells

Myeloma investigations

Treatment

Prognosis

Reference

1974

37

M

2 years of disease

MM (IgG-κ)

 

Urine Bence-Jones-positive

Chemotherapy

Good response

[3]

1984

69

M

 

Smoldering myeloma (IgG-κ)

    

[2]

1987

64

M

Rapid onset of skin involvement of face and chest; 7 years of little change; rapid progression to involvement of the shoulders, arms, back, abdomen, and thighs over 2 years

MM (IgG-κ); IgG concentration of 4500 mg/dl

 

Urine immunoelectrophoresis IgG-κ monoclonal proteinuria, anemia; skeletal survey normal

Prednisolone 80 mg/day and melphalan 14 mg/day, given for 4 days and repeated monthly

From the sixth cycle, clear clinical evidence of softening of the skin and improved joint mobility

[4]

1988

72

F

Symmetrical woody induration of face, neck, chest, shoulders, upper back, chest, abdomen, thigh over 2 years

MM (IgG-κ); IgG concentration of 2900 mg/dl

 

Osteolytic lesions, Bence-Jones-negative

Melphalan

Recovery in 1.5 years

[14]

1988

76

F

Stiffening of the skin of upper trunk, arms, neck, face over 24 h with woody induration

MM (IgA-κ); IgA 814 mg/dl

20%

Urine κ-light chains, multiple lytic lesions on skull x-ray

IV cyclophosphamide 750 mg over 3 days, prednisolone 30 mg daily for 3 days; six pulses; each pulse over interval of 3 weeks

Complete recovery of scleredema and remission of MM

[15]

1988

62

F

Thickening of skin over 23 years with induration over face, neck, thorax, arms with loss of movements of the underlying joints

MM (IgG-λ); IgG 2500 mg/dl

40%

anemia, urine Bence-Jones λ-light chains, cardiomyopathy

Pulse chemotherapy

Death with sepsis

[9]

1992

46

M

Stiffening of face, neck, back, shoulders, chest, arms, hands, fingers with woody induration

Smoldering myeloma (IgG-λ)

28%

   

[6]

1995

74

M

Marked induration of the skin of neck, shoulders, upper chest, back, and upper arms over 15 years

MM; IgA-κ; IgA, 2530 mg/dl

67%

Anemia, Bence-Jones protein (κ-light chain), osteolytic lesions

Chemotherapy with intravenous vincristine, cyclophosphamide, oral melphalan, prednisone 90 mg; six cycles at 3-weekly intervals

After the sixth chemotherapy cycle, myeloma was in remission; marked improvement of the skin

[7]

1997

56

F

Scleredema over the last 6 years with acanthosis nigricans

MM; IgA-κ

  

Melphalan and prednisolone

Recovery

[10]

2000

63

F

thickening of the skin on the face, neck, shoulders, arms, and upper torso while receiving treatment for MM

MM; IgG-κ; IgG 9600 mg/dl

80%

Urine IgG-κ light chain protein, anemia, lytic lesions in the skull

Melphalan 10 mg/day, cyclophosphamide 200 mg/day, prednisolone 60 mg/day given for 5 days, vincristine 2 mg given on the first day; six courses with a 3-week gap

Softening of the skin observed from sixth treatment cycle

[8]

2001

70

F

over 12 months of period, she had developed a progressive induration and stiffness of the skin of her face, neck, shoulders, and upper aspect of her arms

MM; IgA-λ; IgA, 1830 mg/dl

38%

Urine Bence-Jones protein

Oral melphalan, oral prednisone; six pulses, each pulse at an interval of 1 month

Clinical evidence of softening of the involved skin observed

[16]

2008

28

M

Eight years of progressive diffuse cutaneous thickening of face, trunk, arms, and thighs

MM; IgA-κ

55%

Anemia, myelofibrosis

Thalidomide, dexamethasone

Improvement in the texture of the skin

[5]

2013

60

M

Symmetric, nonpitting swelling of the face, neck, trunk, and upper extremities

MM; IgG-κ

10%

Multiple osteolytic lesions

IV cyclophosphamide, bortezomib, dexamethasone; six cycles and autologous stem cell transplant

Skin induration gradually decreased during treatment with complete recovery

[12]

2015

62 (two patients)

 

Generalized symptomatic scleredema

IgG MM

  

IV cyclophosphamide, bortezomib, dexamethasone, and IVIG

Significant improvement

[13]

Abbreviations: IgG Immunoglobulin G, IV Intravenous, IVIG Intravenous immunoglobulin, MM Multiple myeloma, M male, F female

The diffuse woody induration described in almost all the cases in the literature involved the face, neck, back, shoulders, chest, and upper arm. Similar to our patient, all the patients had skin manifestations for a long time before the diagnosis of myeloma, except in one case where the skin changes appeared while the patient was receiving treatment for myeloma [8]. As in our patient, none of the patients in the literature had Raynaud’s phenomenon; sclerodactyly; or characteristic lung, gastrointestinal, or cardiac involvement of systemic sclerosis, which is important to differentiate from systemic sclerosis. One case report described a patient with MM and scleredema who developed cardiomyopathy. Deposition of acid mucopolysaccharide in the heart is proposed as the mechanism for this scleredema cardiomyopathy [9]. Acanthosis nigricans [10] and myelofibrosis [5] are also described in patients with scleredema and MM.

The possible pathology of monoclonal gammopathy and scleredema is still not clear. Kovary et al. suggested that paraproteins may function as antibodies directed against connective tissues, but monoclonal immunoglobulins were not detected in the skin by direct immunofluorescence microscopy [11]. This is in contrast to scleromyxedema (lichen myxedematosus), from which scleredema can be distinguished clinically and histologically [11]. Ohta et al. showed that serum from patients with scleredema stimulates collagen production in normal skin fibroblast cultures, collagen production in autologous cell cultures, and sulfate incorporation into fibroblasts [4]. They suggested that circulating serum factors in these patients, possibly related to the paraproteins, may stimulate the synthesis of extracellular macromolecules by dermal fibroblasts, leading to dermal fibrosis. On the basis of these studies, we can postulate that immunological factors may play a role in the pathogenesis of scleredema.

Interestingly, all the patients in the literature showed improvement of the skin condition with therapy. Different chemotherapy regimens, including melphalan, cyclophosphamide, vincristine, and thalidomide combined with steroids, were used in these cases (Table 1). A bortezomib-based regimen has also shown a convincing response [12, 13]. In the two case reports with scleredema associated with smoldering myeloma, we were unable to find any specific therapy given for the skin condition. However, IVIG has shown significant skin condition improvement in two patients with scleredema [13]. Grudeva-Popova and Dobrev suggested that noninvasive skin elasticity measurements can be used to assess improvement after treatment [8].

Conclusions

We highlight that scleredema should be considered in the differential diagnosis of patients with diffuse skin thickening without characteristic features of systemic sclerosis. In these patients, it is also important to investigate for monoclonal gammopathy and myeloma. Even if the initial screening result is negative, serum protein electrophoresis should be performed at regular intervals because paraproteinemia may appear later and, when present, may progress to myeloma. This case report and others in the literature show that this condition is treatable with significant improvement of the skin condition.

Abbreviations

ALT: 

Alanine aminotransferase

AST: 

Aspartate aminotransferase

IgG: 

Immunoglobulin G

INR: 

International normalized ratio

IV: 

Intravenous

IVIG: 

Intravenous immunoglobulin

MM: 

Multiple myeloma

WBC: 

White blood cells

Declarations

Acknowledgements

None to declare.

Funding

No source of funding.

Availability of data and materials

The datasets supporting the conclusions of this article are included within the article.

Authors’ contributions

BSDPK and HMMTBH did the literature survey and prepared the main manuscript. BSDPK, GHDCJ, BSD, DPL, TB, and CNG were involved in the diagnosis and management of the patient. SCS and SRC assisted in the histopathological diagnosis. SRC and CNG did the proofreading and correction of the manuscript. All authors read and approved the final manuscript.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
National Hospital of Sri Lanka, Colombo, Sri Lanka

References

  1. Rongioletti F, Kaiser F, Cinotti E, Metze D, Battistella M, Calzavara-Pinton PG, Damevska K, Girolomoni G, Andre J, Perrot JL, et al. Scleredema: a multicentre study of characteristics, comorbidities, course and therapy in 44 patients. J Eur Acad Dermatol Venereol. 2015;29(12):2399–404.View ArticleGoogle Scholar
  2. Venencie PY, Powell FC, Su WP. Scleredema and monoclonal gammopathy: report of two cases. Acta Derm Venereol. 1984;64(6):554–6.PubMedGoogle Scholar
  3. Korting GW, Gilfrich HJ, Meyer zum Büschenfelde KH. Scleredema adultorum and multiple myeloma [in German]. Arch Dermatol Forsch. 1974;248(4):379–85.View ArticleGoogle Scholar
  4. Ohta A, Uitto J, Oikarinen AI, Palatsi R, Mitrane M, Bancila EA, Seibold JR, Kim HC. Paraproteinemia in patients with scleredema: clinical findings and serum effects on skin fibroblasts in vitro. J Am Acad Dermatol. 1987;16(1 Pt 1):96–107.View ArticleGoogle Scholar
  5. Rao S, Kar R, Pati HP, Saxena R. Scleredema-associated IgA myeloma with myelofibrosis in a young adult: a case report. Turk J Haematol. 2008;25(4):195–7.PubMedGoogle Scholar
  6. Schmidt KT, Gattuso P, Messmore H, Shrit MA, Massa M, Welykyj S. Scleredema and smoldering myeloma. J Am Acad Dermatol. 1992;26(2 Pt 2):319–21.View ArticleGoogle Scholar
  7. Pujol JA, Bueno M, Fuertes MA, Gimenez H, Carapeto FJ. Improvement of scleredema associated with IgA multiple myeloma after chemotherapy. Clin Exp Dermatol. 1995;20(2):149–52.View ArticleGoogle Scholar
  8. Grudeva-Popova J, Dobrev H. Biomechanical measurement of skin distensibility in scleredema of Buschke associated with multiple myeloma. Clin Exp Dermatol. 2000;25(3):247–9.View ArticleGoogle Scholar
  9. Rimon D, Lurie M, Storch S, Halon D, Eisenkraft S, Laor A, Cohen L. Cardiomyopathy and multiple myeloma: complications of scleredema adultorum. Arch Intern Med. 1988;148(3):551–3.View ArticleGoogle Scholar
  10. Valente L, Velho GC, Farinha F, Bernardo A, Ribeiro P, Massa A. Scleredema, acanthosis nigricans and IgA/Κ multiple myeloma [in French]. Ann Dermatol Venereol. 1997;124(8):537–9.PubMedGoogle Scholar
  11. Kovary PM, Vakilzadeh F, Macher E, Zaun H, Merk H, Goerz G. Monoclonal gammopathy in scleredema: observations in three cases. Arch Dermatol. 1981;117(9):536–9.View ArticleGoogle Scholar
  12. Szturz P, Adam Z, Vasku V, Feit J, Krejci M, Pour L, Hajek R, Mayer J. Complete remission of multiple myeloma associated scleredema after bortezomib-based treatment. Leuk Lymphoma. 2013;54(6):1324–6.View ArticleGoogle Scholar
  13. Krejci M, Adam Z, Pour L, Michalkova E, Sandecka V, Szturz P, Kral Z, Mayer J. Scleredema associated with multiple myeloma or MGUS: treatment report of four cases [abstract]. Clin Lymphoma Myeloma Leukemia. 2015;15(Suppl 3):e207.View ArticleGoogle Scholar
  14. Hodak E, Tamir R, David M, Hart M, Sandbank M, Pick A. Scleredema adultorum associated with IgG-κ multiple myeloma – a case report and review of the literature. Clin Exp Dermatol. 1988;13(4):271–4.View ArticleGoogle Scholar
  15. Salisbury JA, Shallcross H, Leigh IM. Scleredema of Buschke associated with multiple myeloma. Clin Exp Dermatol. 1988;13(4):269–70.View ArticleGoogle Scholar
  16. Santos-Juanes J, Osuna CG, Iglesias JR, De Quiros JF, del Rio JS. Treatment with chemotherapy of scleredema associated with IgA myeloma. Int J Dermatol. 2001;40(11):720–1.View ArticleGoogle Scholar

Copyright

© The Author(s). 2019

Advertisement