Scleromyxedema with Corneal Deposits HARRY M. GOLDIN, MD,* ALAN J. AXELROD, MD,t DARRYL M. BRONSON, MD,* ELISE TORCZYNSKI, MD,t CARLOS M. ARROYAVE, MD, PhD,t SIDNEY BARSKY, MD*

Abstract: Scleromyxedema (Arndt-Gottron syndrome) is a rare cutaneous dis­ease in which hyaluronic acid is deposited in the dermis. The authors describe a patient with scleromyxedema and corneal deposits. A corneal biopsy demon­strated hyaluronic acid deposition in the corneal stroma and amyloid P compo­nent in Bowman's membrane. This is the first report of scleromyxedema in­volving the cornea. It is also the first report of amyloid P component deposition in the cornea occurring independent of corneal amyloid deposits. [Key words: acid mucopolysaccharide, amyloid P component, corneal deposits, hyaluronic acid, lichen myxedematosus, papular mucinosis, scleromyxedema.] Ophthal­mology 94:1334-1338, 1987

Scleromyxedema (Arndt-Gottron syndrome) is a var­ient of lichen myxedematosus (papular mucinosis) and represents a rare cutaneous fibromucinous disorder of unknown etiology. I It is associated with a unique para­protein and is characterized by infiltration of the skin with hyaluronic acid, producing thickening of the skin with overlying fine papules. Scleromyxedema is a pro­gressive disease which most commonly involves the face, neck, upper trunk, forearms, and hands. Infiltra­tion of the face may exaggerate facial folds and produce a saddened appearance or it may impair the opening of the mouth. Infiltration of the skin of the extremities may interfere with joint mobility and result in flexion con­tractures.2,3

Scleromyxedema and/or lichen myxedematosus have been associated with many disorders including multiple myeloma,4 dermatomyositis,5,6 esophageal aperistalsis,7 acute organic brain syndrome,8 pachydermoperios­tosis,9 atherosclerosis, 10 psoriasis, 1

I and necrotizing pan­niculitis.12

Autopsy studies have failed to demonstrate significant internal organ involvement in patients with scleromyx-

From the Department of Medicine: Division of Dermatology, the Depart­ment of Surgery,t Division of Ophthalmology, and the Department of Immunology,t Cook County Hospital, Chicago.

Presented in part at the Annual Meeting of the American Academy of Dermatology, Las Vegas, Nevada, December 7, 1985.

Reprint requests to Harry M. Goldin, MD, Division of Dermatology, Cook County Hospital, 720 S Wolcott, Rm 104, Chicago, IL 60612.

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edema and/or lichen myxedematosus. However, mucin deposition has been found in the lungs, kidneys, adrenal glands, and pancreas of some patients. 3,13

Corneal opacities have not been reported previously in association with scleromyxedema or lichen myxede­matosus. The following report is the first such presenta­tion of scleromyxedema involving the cornea.

CASE REPORT

A 25-year-old black man presented with a 2-month history of pruritus, erythema, and scaling over his trunk, face, and ears (Fig 1). The patient was otherwise healthy and was taking no medications. He denied dysphagia, dyspnea, Raynaud's phe­nomenon, or weight loss.

Results of physical examination showed the skin of the face, ears, neck, back, and chest to be diffusely thickened, firm, and slightly erythematous with accentuation of the skin folds. Fine lichenoid papules were present over the affected areas. Hyper­pigmented and lichenified patches were also present over the arms, chest, and back. There was no lymphadenopathy. The remainder of the physical examination was normal.

Results of electrolytes, glucose, blood urea nitrogen, cal­cium, magnesium, phosphorus, liver function tests, complete blood count, platelets, erythrocyte sedimentation rate, antinu­clear antibody, rapid plasma reagin test, and urinalysis were normal or negative. The serum thyroxine level was 5.4 ~g/dl (normal, 4-11 ~g/dl) and the T3 resin uptake was 29.5% (nor­mal, 24-36%).

Quantitative immunoglubulin levels were: IgG, 1960 mg/dl (normal, 759-1228 mg/dl); IgA, 196 mg/dl (normal, 104-228 mg/dl); and IgM, 89 mg/dl (normal, 64-174 mg/d) . A small

GOLDIN et al • SCLEROMYXEDEMA WITH CORNEAL DEPOSITS

Fig 1. Clinical appearance of the patient. Notice the markedly thick­ened skin, exaggerated skin folds, and overlying papules.

spike in the post-gamma region was seen on serum protein electrophoresis and was identied as an IgG lambda mono­clonal protein by immunoelectrophoresis. No Bence Jones protein was detected in the urine.

Results of roentgenographic examination of the chest and a skeletal bone survey were normal. Results of a bone marrow examination showed normal cellularity with 2 to 3% plasma cells. The electrocardiogram was normal. An echocardiogram showed left ventricular hypertrophy.

A biopsy of skin from the forearm showed hyperkeratosis and slight irregular hyperplasia of the epidermis. The dermis showed a markedly increased number of fibroblasts which were occasionally aggregated into fascicles (Fig 2). The colloi­dal iron stain demonstrated large amounts of mucin in the upper dermis. Mucin was not observed after digestion with hyaluronidase. Verhoeff-van Gieson's stain demonstrated normal elastic fibers in the dermis. IgG, IgA, IgM, lambda, kappa, Clq, C3, C4, fibrinogen , and amyloid P component were not demonstrated in the deJ;1l1is with either direct immu­nofluorescence or immunoperol'idase studies, although an in­creased network of fibronectin was observed in the dermis. A diagnosis of scleromyxedema was made.

During the next several months, the patient complained of severe pruritus which was poorly controlled with various oral antihistamines and topical triamcinolone 0.1 % ointment. He had progressive thickening' of his skin which resulted in a leo­nine facies, impairment of the function of his hands, and diffi­:ulty in opening his mouth. The patient declined treatment with prednisone or chlorambucil.

Because of complaints of blurred vision, the patient was seen by an ophthalmologist. The uncorrected visual acuity was 20/20 + 1 in the right eye and 20/20 +2 in the left. The skin of the upper and lower eyelids was thick and hard, but there was no impairment of lid closure. There were no lid margin or conjunctival abnormalities. Results of the slit-lamp examina­tion disclosed symmetrical deposits in both corneas consisting of linear, point~d. refractile crystals in the anterior to mid­stroma, rounder, fluffier opacities in the mid-stroma, and dif­fuse, larger aggregates in the posterior stroma (Fig 3). The opacities became more confluent the more posteriorly they were located in the cornea, so that in the pre-Descemet's area, there were no completely clear spaces between the deposits. At any given stromal depth, the deposits were distributed evenly across the cornea, extending to the limbus in all meridians. The stroma was not thickened. The corneal epithelium was smooth and there were no areas of uptake from topical fluores­cein. Keratometry failed to show any epithelial irregularities. Neither cornea was vascularized nor inflamed. The anterior chambers were deep and without flare or cells. The lenses were clear and there were no vitreous or fundus abnormalities.

The available family members, including the patient's sister,

Fig 2. Histologic appearance of the skin showing thickened collagen and an increased number of fibroblasts in the upper half of the dermis (hematoxylin-eosin; original magnification, X63).

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OPHTHALMOLOGY • OCTOBER 1987 • VOLUME 94 • NUMBER 10

Fig 3. A, slit-beam cross-section showing refractile crystals in the anterior corneal stroma with larger, fluffier opacities posteriorly. B, broad-beam illumination showing mUltiple white opacities of varying sizes and shapes. The deposits are distributed evenly throughout the central and peripheral cornea.

niece, and daughter, had normal slit-lamp examination re­sults.

A 1 X 2-mm corneal specimen of one half corneal thickness was obtained from the right eye by free hand excision midway between the center of the cornea and the limbus. The corneal biopsy specimen was divided into two sections. One section was placed in 1 % glutaraldehyde and the other section was frozen in liquid nitrogen. After the preparation of sections for immunofluorescence and immunoperoxidase staining, the re­mainder of the frozen specimen was placed in formaldehyde and processed for light microscopy.

Light microscopic sections demonstrated diffuse staining of the corneal stroma with alcian blue and colloidal iron (Fig 4, top). Staining was not observed after predigestion with testicu­lar hyaluronidase (Fig 4, center), demonstrating that the mucin was hyaluronic acid. Periodic acid-Schiff's reagent stained both the corneal stromal collagen and the deposit's intense magenta. Staining with hematoxylin-eosin, Congo red, and Prussian blue failed to demonstrate deposits.

IgG, lamba, kappa, C3, and albumin were not observed in the cornea with either direct immunofluorescence or immuno­peroxidase procedures. Both direct immunofluorescence and immunoperoxidase studies for amyloid P component demon­strated diffuse and discrete aggregates in the region of Bow­man's membrane ofthe patient's cornea (Fig 5), but not in two normal control corneas.

Electron microscopic sections of the cornea did not demon­strate deposits in the epithelium, basement membrane, or Bowman's membrane. Occasional artifactual vacuoles were seen in the most anterior corneal lamellae, sometimes asso­ciated with keratocytes. Ring-like deposits were not present.

Results of a follow-up slit-lamp examination 1 year later showed somewhat larger and more numerous deposits. How­ever, the visual acuity was unchanged.

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COMMENT

Results of histologic examinations of skin from pa­tients with scleromyxedema show deposits of acid mu­copolysaccharides in the papillary and upper reticular dermis.1O Hyaluronic acid is the major mucopolysac­charide present, but chondroitin-4-sulfate and chon­droitin-6-sulfate have also been demonstrated. Hyal­uronic acid is hygroscopic and when hydrated, swells to produce the cutaneous induration and thickening. 14

Large stellate fibroblasts are a prominent histologic fea­ture and are irregularly distributed in the mucinous ma­teria1.3

The paraprotein associated with lichen myxedema­tosus and its variant scleromyxedema was first observed in 1964 by McCarthy and associateslS as an abnormal globulin which migrated in the post-gamma region on serum protein electrophoresis. It has been present in most cases of lichen myxedematosus as an IgG lambda benign monoclonal gammopathy, but IgG kappal6 and IgA 17 paraproteins have also been reported. It differs from normal IgG by its marked basicity, 18 smaller size, 19

and absence of significant antigenic portions of the Fd fragment. 19

Results of direct immunofluorescence studies in pa­tients with lichen myxedematosus and scleromyxedema have been variable. IgG has been demonstrated in a nonspecific pattern in the upper dermis l9 and in associa­tion with mucin. IS In other studies, the immunoglobulin has been present in a pericellular pattern associated with

GOLDIN et al • SCLEROMYXEDEMA WITH CORNEAL DEPOSITS

Fig 4. Top, section of cornea showing linear and granular (arrow) deposits of acid mucopolysaccharides along collagen bundles (colloidal iron stain; original magnification, X160). Center, section of cornea pretreated with testicular hyaluronidase showing the absence of hyal­uronic acid (colloidal iron stain; ori~nal magnification, X 160). Fig 5. Bottom, anti-amyloid P component immunofluorescence study of cornea showing diffuse and discete aggregates in the region of Bow­man's membrane (arrowheads).

complement,20 between collagen bundles,21 and at the dermal-epidermal junciion.21 Finally, many other stud­ies, including the current case, have failed to demon­strate immunoglobulins in the dermis. 1 1,22,23

Corneal mucopolysaccharide deposition has been de­scribed in patients with the systemic mucopolysacchari­doses, corneal fleck dystrophy, and macular corneal dystrophy. Corneal fibroblasts are capable of producing a variety of mucopolysaccharides including keratan sul­fate, chondroitin, chondroitin sulfates, and hyaluronic acid.24

Corneal fibroblasts may be responding to a stimulus similar to the one causing the cutaneous fibroblasts to proliferate and produce hyaluronic acid. Yaron and as­sociates25 have demonstrated a factor in the serum of patients with scleromyxedema which initiates fibroblast proliferation and hyaluronic acid production. Harper and Risplerl6 have shown this stimulus to be indepen­dent of the IgG fraction.

Amyloid P-component is a pentagonally shaped gly­coprotein associated with amyloid fibrils of both sys­temic and localized amyloidosis.26 Amyloid P compo­nent is also found in normal serum (serum amyloid P component), normal glomerular basement membrane, and in association with elastic fibersY In normal human skin, amyloid P component is found associated with the elastic tissue fibers of the papillary and reticular dermis27 and in the basement membrane of normal sweat gland ducts.28 Abnormal amyloid P component staining patterns have been demonstrated in the skin from patients with abnormal elastic tissue.29 Amyloid P component was not demonstrated in the skin of our patient with scleromyxedema despite the presence of normal elastic fibers in the dermis.

Amyloid P component has been demonstrated in the corneal amyloid deposits from patients with corneallat­tice dystrophy30 and primary familial amyloidosis of the cornea.31 However, in the absence of amyloid deposits, amyloid P component has not been demonstrated pre­viously in corneal tissue. The significance of the amyloid P component in Bowman's membrane is not clear. It is also unclear as to what relationship exists between the amyloid P component in Bowman's membrane and the hyaluronic acid deposits in our patient's corneal stroma.

A patient with scleromyxedema and corneal deposits has been presented. A corneal biopsy demonstrated hy­aluronic acid deposition in the corneal stroma and amyloid P component in Bowman's membrane. This is the first report of scleromyxedema involving the cornea, and of amyloid P component in the cornea independent of corneal amyloid deposits.

ADDENDUM

After this article was accepted for publication, a patient with scleromyxedema and corneal deposits was reported (Pusateri TJ, Margo CE, Groden LR: Corneal manifestations of sclero­myxedema. Ophthalmology 94:510-13, 1987). The deposits were in the superficial cornea (subepithelial), involved the en­tire cornea of both eyes, and consisted of irregularly shaped whorls of grayish-white material arranged in a swirling pattern. The corneal deposits stained for IgG and lambda chains, but not for acid mucopolysaccharide.

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OPHTHALMOLOGY • OCTOBER 1987 • VOLUME 94 • NUMBER 10

ACKNOWLEDGMENT

The authors thank Robert Stark, MD, (deceased) for his assistance in evaluating the patient.

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