Papular mucinosis associated with scleroderma

ARTICLE

Papular mucinosis (scleromyxedema/lichen myxedematosus) is a rare disease characterized by a symmetric distribution of erythematous to yellowish papules and/or papules, most commonly involving the face, neck and arms [1] accompanied by diffuse skin thickening in some cases. In the diffuse sclerotic variant, some authors exclusively reserve the term "scleromyxedema" in light of its clinical resemblance to systemic scleroderma [2].

Some cases of papular mucinosis are associated with systemic diseases such as paraproteinaemia [3, 4], systemic lupus erythematosus [5-7], non-Hodgkin's lymphoma [8], hypothyroidism [9] and myopathy [1]. The association of scleroderma with papular mucinosis has been rarely reported [10, 11]. Scleroderma fibroblasts synthesize more collagen than those from normal subjects [12]. The cause of this excessive production of collagen in scleroderma is unknown; both intrinsic overactivity and excessive stimulation of fibroblasts may occur [13]. Mucin deposits are also found in the dermis of scleroderma patients [14]. In this report, we describe a rare and interesting case of papular mucinosis associated with scleroderma.

Case report

A 49-year-old Japanese woman developed Raynaud's phenomenon in December of 1989. When she visited our hospital in September of 1994, slight swelling and mild sclerodactyly in her fingers, induration of the lingula, and facial edema were observed. However, her condition at that time did not satisfy the criteria for scleroderma proposed by Barnett and Conventry [15] and LeRoy et al. [16]. Since a diagnosis of endogenous depression had been made by a psychiatrist, she had been treated with etizolam (1 mg/day), amitriptyline hydrochloride (20 mg/day) and sulpiride (200 mg/day). She had never been exposed to environmental factors such as tryptophan, organic solvents and aliphatic hydrocabons. Since May 1996, the Raynaud's phenomenon had exacerbated and the fingers showed a sausage-like appearance (Fig. 1). Multiple, elevated, asymptomatic, skin-colored papules on the dorsal regions of hands were also observed. The number of these papules gradually increased. Blood cell counts, laboratory data on liver and renal function were all within normal limits. Serum protein immunoelectrophoresis demonstrated a mild polyclonal IgG hypergammaglobulinemia (1,940 mg/dl, normal range = 650-1,600 mg/dl), while the levels of IgA and M were within normal ranges. The titer of antinuclear antibody was 1:1,280 in a speckled pattern, whereas anti-RNP antibody, anticentromere antibody, anti-Scl-70 antibody, anti-SS-A antibody, anti-SS-B antibody and anti-Sm antibody were all negative. No abnormality was found on chest X-ray and ECG. Capillaroscopical findings of the cuticle-proximal nailfolds showed the dilatation and partial absence of the capillary loops of proximal nailfolds [17]. A barium swallow test revealed a dilatation of the upper and middle parts of the esophagus. Anti-thyroid and anti-microsomal antibodies were weakly positive with titers of 1:80 and 1:20, respectively; the levels of T₃, T₄ and TSH were within normal ranges.

Histological findings for the papules on the dorsal regions of her right hand showed a perivascular lymphocytic infiltrate within the superficial dermis, accompanied by sclerosis and a striking deposition of mucin in the mid and lower dermis (Fig. 2). The abundant deposited substance was positive for alcian blue (pH 2.5) stain (Fig. 3), but negative for alcian blue (pH 2.5) stain following digestion by hyaluronidase, alcian blue stain (pH 1.0) and PAS stain. The substance showed a diffuse metachromatic staining pattern with toluidine blue stain at pH 4.0 and 7.0 but not at pH 2.0. These findings suggested that the mucinotic material contained hyaluronic acid. On the other hand, the skin from the dorsal aspect of her left forearm showed slightly thickened collagen fibers with mild mucinosis in the dermis. A diagnosis of papular mucinosis associated with scleroderma type I was made, the latter according to the criteria of Barnett and Coventry [15]. The patient also satisfied the criteria for the limited cutaneous systemic sclerosis type according to the classification scheme of LeRoy et al. [16].

She received treatment with prostaglandin E₁ derivatives, 10 µg, intravenously every day for 2 months. The papules have diminished in size and her sclerodactyly has become less prominent, suggesting the effectiveness of prostaglandin E₁ derivatives in this case.

Discussion

Cutaneous mucinosis is a heterogenous group of disorders characterized by an accumulation of mucin in the dermis (Table I). The pathogenesis may be related to various disorders, such as metabolic or collagen-vascular disease and paraproteinemia [18]. A lichenoid eruption with discrete papules is localized or generalized in papular mucinosis/lichen myxedematosus [2]. On the other hand, the confluent papular and sclerotic form is observed in scleromyxedema, where diffuse thickening of the skin underlies the papules. An unusual form of cutaneous mucinosis, acral persistent papular mucinosis, has been reported [19-21]. It is characterized by multiple, discrete papules located symmetrically on the back of the hands, wrists and distal forearms; focal mucin deposits in the upper dermis are seen [21]. It is unclear as to whether acral persistent papular mucinosis is a distinct entity or a variant of the papular form of lichen myxoedematosus/scleromyxedema, i.e. papular mucinosis [20]. This current case showed similar clinical findings to this type of cutaneous mucinosis. Its uniqueness lies in an association with limited cutaneous scleroderma. Scleromyxedema, which is the generalized lichenoid papular variant of papular mucinosis [22], is characterized by papules with diffuse thickening of the skin similar to scleroderma. Because sclerodactyly and Raynaud's phenomenon were clearly observed in this case, the diagnosis of papular mucinosis with scleroderma was made.

It is well known that collagen fibers are impaired and collagen synthesis is enhanced in scleroderma fibroblasts [23, 24], and the mRNA levels of procollagen increase in scleroderma fibroblasts compared with normal fibroblasts [25-27]. Furthermore, scleroderma fibroblasts have a disturbed interaction with collagen fibers [28]. However, the aetiology of scleroderma has not been completely defined. Mucin deposits are found in the dermis, mainly in the deep reticular dermis and interlobular septa in patients with scleroderma and morphea [14, 29, 30]. The mucin deposits localize to areas of sclerosis [29] and may be among the earliest histological findings in scleroderma [30]. It may be reasonably speculated that in some instances papular mucinosis may represent a special form of scleroderma associated with prominent if not dominant mucin production. In the patient with papular mucinosis associated with systemic lupus erythematosus, enhanced glycosaminoglycan production is observed in both normal and the patient's fibroblasts when incubated with the patient's serum [7].

Since the serum from patients with papular mucinosis stimulates DNA synthesis and proliferation of fibroblasts [31], some unknown serum factors may be involved in the pathogenesis of the mucinosis and sclerosis seen in this disorder.

REFERENCES

1. Helfrich DJ, Walker ER, Martinez AJ, Medsger TA Jr. Scleromyxedema myopathy: case report and review of the literature. Arthritis Rheum 1988; 31: 1437-9.

2. Black MM. Mucinoses. In: Champion RH, Burton JL, Ebling FJG, eds. Textbook of Dermatology 5th edition. London: Blackwell Scientific Publications, 1992: 2325-6.

3. Lai A, Fat RF, Suurmond D, Radl J, van Furth R. Scleromyxoedema (lichen myxedematosus) associated with a paraprotein, IgG1 of type kappa. Br J Dermatol 1973; 88: 107-16.

4. Wright RC, Franco RS, Denton D, Blaney DJ. Scleromyxedema. Arch Dermatol 1976; 112: 63-6.

5. Rongioletti F, Rebora A. Papular and nodular mucinosis associated with systemic lupus erythematosus. Br J Dermatol 1986; 115: 631-6.

6. Egawa H, Abe-Matsuura Y, Tada J, Arata J. Nodular cutaneous lupus mucinosis associated with atrophic blanche-like lesions in a patient with systemic lupus erythematosus. J Dermatol 1991; 21: 674-9.

7. Pandya AG, Sontheimer RD, Cockerell CJ, Takashima A, Piepkorn M. Papulonodular mucinosis associated with systemic lupus erythematosus: possible mechanisms of increased glycosaminoglycan accumulation. J Am Acad Dermatol 1995; 32: 199-205.

8. Giménez Garcia R, Gil Garcia S, Suarez Vilela D, Moro Sanchez MJ. Scleromyxedema associated with non-Hodgkin lymphoma. Int J Dermatol 1989; 28: 670-1.

9. Archibald GC, Calvert HT. Hypothyroidism and lichen myxoedematosus. Arch Dermatol 1977; 113: 884-5.

10. Kantor GR, Bergfeld WF, Katzin WE, Reynolds OD, Biscardi AP, Lobur DM, Box TA, Schreiber MJ Jr, Ratliff NB. Scleromyxedema associated with scleroderma renal disease and acute psychosis. J Am Acad Dermatol 1986; 14: 879-88.

11. Harris RB, Perry HO, Kyle RA, Winkelmann RK. Treatment of scleromyxedema with melphalan. Arch Dermatol 1979; 115: 295-9.

12. Buckingham RB, Prince PK, Rodnan GP, Taylor F. Increased collagen accumulation in dermal fibroblast cultures from patients with progressive systemic sclerosis (scleroderma). J Lab Clin Med 1978; 92: 5-21.

13. Rowell NR, Goodfield MJD. Systemic sclerosis. In: Champion RH, Burton JL, Ebling FJG, eds. Textbook of Dermatology 5th edition. London: Blackwell Scientific Publications, 1992: 2241-6.

14. Rongioletti F, Gambini C, Micalizzi C, Pastorino A, Rebora A. Mucin deposits in morphea and systemic scleroderma. Dermatology 1994; 189: 157-8.

15. Barnett AJ, Coventry DA. Scleroderma: clinical features, course of illness and responses to treatment in 61 cases. Med J Aust 1969; 1: 992-1001.

16. LeRoy EC, Black C, Fleishmajer R, Jablonska S, Krieg TA Jr, Rowell N, Wollheim F. Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J Rheumatol 1988; 15: 202-5.

17. Maeda M, Matsubara K, Kachi H, Mori S, Kitajima Y. Histopathological and capillaroscopical features of the cuticles and bleeding clots in ring or middle fingers of systemic scleroderma patients. J Dermatol Sci 1995; 10: 35-41.

18. Dinneen AM, Dicken CH. Scleromyxedema. J Am Acad Dermatol 1995; 33: 37-43.

19. Rongioletti F, Rebora A. Acral persistent papular mucinosis: a new entity. Arch Dermatol 1986; 122: 1237-9.

20. Flowers SL, Cooper PH, Landes HB. Acral persistent papular mucinosis. J Am Acad Dermatol 1989; 21: 293-7.

21. Borradori L, Aractingi S, Blanc F, Verola O, Dubertret L. Acral persistent papular mucinosis and IgA monoclonal gammopathy: report of a case. Dermatology 1992; 185: 134-6.

22. Truhan AP, Roenigk HH Jr. The cutaneous mucinosis. J Am Acad Dermatol 1986; 14: 1-18.

23. LeRoy EC. Increased collagen synthesis by scleroderma skin fibroblasts in vitro. J Clin Invest 1974; 54: 880-9.

24. Uitto J, Bauer EA, Eizen AZ. Increased biosynthesis of triple-helical type I procollagen associated with unaltered expression of collagenase by skin fibroblasts in culture. J Clin Invest 1979; 64: 921-30.

25. Kahari VM, Heino J, Larjava H, Vuorio E. Alteration in scleroderma fibroblasts surface glycoproteins associated with increased collagen synthesis. Acta Derm Venereol (Stockh) 1987; 67: 199-205.

26. Ohta A, Uitto J. Procollagen gene expression by scleroderma fibroblasts in culture: inhibition of collagen production and reduction of pro-alpha 1(I) collagen messenger RNA steady-state levels by retinoids. Arthritis Rheum 1987; 30: 401-11.

27. Ignotz RA, Endo T, Massague J. Regulation of fibronectin and type I collagen mRNA levels by transforming growth factor-ß. J Biol Chem 1987; 262: 6443-6.

28. Ivarsson M, McWhirter A, Black CM, Rubin K. Impaired regulation of collagen pro-alpha 1(I) mRNA and change in pattern of collagen-binding integrins on scleroderma fibroblasts. J Invest Dermatol 1993; 101: 216-21.

29. Fleischmajer R, Perlish JS. Glycosaminoglycans in scleroderma and scleredema. J Invest Dermatol 1972; 58: 129-32.

30. Uitto J, Helin G, Aelin P, Lorenzen I. Connective tissue in scleroderma, a biochemical study on the correlation of fractionated glycosaminoglycans and collagen in human skin. Acta Derm Venereol (Stockh) 1971; 51: 401-6.

31. Harper RA, Rispler J. Lichen myxedematosus serum stimulates human skin fibroblast proliferation. Science 1978; 199: 545-7.