Deposition disorders

Deposition disorders comprise a diverse group of conditions or diseases in which there is accumulation, deposition, or production of substances in the skin. Typically, these substances are products of abnormal metabolism or degenerative phenomena occurring locally or systemically. The major cutaneous deposits may be subdivided into the hyalinoses, mucinoses, and mineral salts.

Touart DM, Sau P: Cutaneous deposition diseases. Part I, J Am Acad Dermatol 39:149–171, 1998.

With light microscopy, amyloid appears as amorphous, hyaline-like, eosinophilic deposits. Amyloid demonstrates green birefringence with the alkaline Congo red stain, reddish metachromasia with crystal violet, and yellow-green fluorescence with thioflavin-T stain (Fig. 16-1). These stains are not absolutely specific for amyloid, as false-positive results may occur with the other hyaline-like deposition disorders.

Amyloidosis may be classified according to clinical presentation and type of amyloid fibril protein deposition (Table 16-1). The amyloid in the macular and lichenoid variants is derived from degenerated tonofilaments of keratinocytes. Nodular amyloidosis is formed from light-chain–derived AL protein produced locally by plasma cells. It cannot be distinguished from primary systemic amyloidosis, and therefore, systemic disease should be excluded in all patients with nodular amyloidosis. There are also rare forms of hereditary systemic amyloidoses that have less frequent skin manifestations.

Cutaneous lesions are seen in about 30% of cases of primary or myeloma-related systemic amyloidosis. The most common skin lesions are petechiae or ecchymoses due to amyloid deposition within blood vessel walls with subsequent fragility and dermal hemorrhage. These are often seen at sites predisposed to trauma, such as the hands or intertriginous areas. Pinching the skin gives characteristic purpuric lesions known as “pinch purpura.” Purpura around the eyes may occur spontaneously but is also seen following proctoscopy or vomiting (“postproctoscopic purpura”) (Fig. 16-2). Waxy papules, nodules, or plaques may be present. Less common manifestations include sclerodermoid plaques, bullae, alopecia, and nail dystrophy.

Mucous membrane involvement with macroglossia occurs in 20% of cases. Hepatomegaly is found in about 50% of cases. Cardiac involvement may manifest as a restrictive cardiomyopathy or constrictive pericarditis. Peripheral nerve involvement results in paresthesias, peripheral neuropathy, and median nerve entrapment (carpal tunnel syndrome). Proteinuria is found in 80% to 90% of patients at some time during their course. Renal failure usually develops late in the disease course but may be a cause of death.

Table 16-1. Classification of Amyloidosis

CLINICAL DISORDER	AMYLOID PROTEIN PRECURSOR	AMYLOID PROTEIN
Primary systemic amyloidosis	Immunoglobulin light chain	AL
Myeloma-associated amyloidosis	Immunoglobulin light chain	AL
Secondary systemic amyloidosis	Serum amyloid A lipoprotein	AA
Primary localized cutaneous amyloidosis
Macular amyloidosis	Keratinocyte tonofilaments	−
Lichen amyloidosis	Keratinocyte tonofilaments	−
Nodular amyloidosis	Immunoglobulin light chain (produced locally by plasma cells)	AL

Prokaeva T, Spencer B, Kaut M, et al: Soft tissue, joint, and bone manifestations of AL amyloidosis: clinical presentation, molecular features, and survival, Arthritis Rheum 56:3858–3868, 2007.

Silverstein SR: Primary, systemic amyloidosis and the dermatologist: where classic skin lesions may provide the clue for early diagnosis, Dermatol Online J 11:5, 2005.

Lichen amyloidosis is the most common form of localized cutaneous amyloidosis. Lesions are pruritic, flesh-colored to brown papules, often with overlying scale (Fig. 16-3A). Papules may coalesce into verrucous plaques. The shins are the most common site of involvement. In macular amyloidosis, pruritic macular hyperpigmentation occurs most commonly in the interscapular area. The chest or extremities are less commonly involved. The lesions have a characteristic reticulate or rippled appearance. Both of these variants of primary localized cutaneous amyloidosis occur more frequently in patients from the Middle East, Asia, and Central and South America. The etiology of both lichen and macular amyloidosis is unclear but thought to be related to chronic scratching or frictional exposure. An autosomal dominant family history may be found in up to 10% of patients with lichen amyloidosis. Lichen amyloidosis is occasionally associated with multiple endocrine neoplasia type 2A.

Tanaka A, Arita K, Lai-Cheong JE, et al: New insight into mechanisms of pruritus from molecular studies on familial primary localized cutaneous amyloidosis, Br J Dermatol 161:1217–1224, 2009.

Nodular amyloidosis typically presents as solitary or multiple waxy nodules (Fig. 16-3B). Common sites of involvement include the face, scalp, lower extremities, and genitalia. It may be associated with the subsequent development of systemic amyloidosis up to 15% of cases. Rarely, it is found in association with Sjögren’s syndrome.

Kalajian AH, Waldman M, Knable AL: Nodular primary localized cutaneous amyloidosis after trauma: a case report and discussion of the rate of progression to systemic amyloidosis, J Am Acad Dermatol 57(Suppl 2):S26–S29, 2007.

Yoneyama K, Tochigi N, Oikawa A, et al: Primary localized cutaneous nodular amyloidosis in a patient with Sjögren’s syndrome: a review of the literature, J Dermatol 32:120–123, 2005.

Organs commonly involved in secondary systemic amyloidosis include the liver, spleen, and kidneys, resulting in hepatosplenomegaly and nephrotic syndrome, respectively. Although skin lesions are generally lacking, biopsy of subcutaneous abdominal fat may demonstrate amyloid deposition.

Hazenberg BP, Bijzet J, Limburg PC, et al: Diagnostic performance of amyloid A protein quantification in fat tissue of patients with clinical AA amyloidosis, Amyloid 14:133–140, 2007.

Lachmann HJ, Goodman HJ, Gilbertson JA, et al: Natural history and outcome in systemic AA amyloidosis, N Engl J Med 356:2361–2371, 2007.

Lipoid proteinosis, also known as hyalinosis cutis et mucosae and Urbach-Wiethe disease, is a rare autosomal recessive genodermatosis in which skin and mucous membranes are infiltrated with a hyaline scleroprotein. The presenting symptom, hoarseness, develops in infancy due to involvement of the vocal cords with hyaline deposits. Bullae, pustules, and crusts, followed by acneiform scars, are seen on the face and extremities. Waxy papules develop along the eyelids, producing a characteristic “string of beads” appearance. Later, verrucous plaques occur on the elbows and knees. Lipoid proteinosis is caused by loss-of-function mutations in the extracellular matrix protein 1 gene (ECM1).

Bahhady R, Abbas O, Ghosn S, et al: Erosions and scars over the face, trunk, and extremities, Pediatr Dermatol 26:91–92, 2009.

Colloid milium is a cutaneous eruption characterized by flesh-colored to yellow-brown translucent papules that may coalesce into plaques. The eruption is most commonly found in adults in areas of chronic sun exposure, but a rare juvenile form is also recognized. Amorphous fissured eosinophilic material in the papillary dermis is seen on histopathology. Excessive sun exposure is a likely etiologic factor in adult colloid milium.

Pourrabbani S, Marra DE, Iwasaki J, et al: Colloid milium: a review and update, J Drugs Dermatol 6:293–296, 2007.

Erythropoietic protoporphyria, also termed protoporphyria, has the largest eosinophilic deposits in cutaneous lesions. This autosomal dominant disorder of porphyrin metabolism is caused by a deficiency of the enzyme ferrochelatase (heme synthetase). Symptoms begin in early childhood and include photosensitivity, pruritus, burning, erythema, and edema. Chronic changes include a waxy, “cobblestone” thickening of the skin and shallow scars or pits. Increased protoporphyrin may be identified in the feces and blood, although urinary porphyrins are usually normal.

Lecha M, Puy H, Deybach JC: Erythropoietic protoporphyria, Orphanet J Rare Dis 4:19, 2009.

The mucinoses are a heterogeneous group of disorders characterized by dermal mucin deposition. This mucin is largely hyaluronic acid, an acid mucopolysaccharide, with smaller amounts of chondroitin sulfate and heparin. Disorders resulting in diffuse mucin deposition include generalized myxedema, pretibial myxedema, lichen myxedematosus, scleredema, reticular erythematous mucinosis, and the mucopolysaccharidoses (storage diseases). Mucin deposition may also be focal or localized, as with follicular mucinosis (alopecia mucinosa), cutaneous focal mucinosis, and digital mucous cyst.

Jackson EM, English JC 3rd: Diffuse cutaneous mucinoses, Dermatol Clin 20:493–501, 2002.

Patients with pretibial myxedema develop nodules or diffuse plaques usually on the anterior lower legs, although involvement of other sites has been rarely reported (Fig. 16-4A). The lesions result from large amounts of dermal mucin deposition. Pretibial myxedema is seen in 1% to 4% of patients with Graves’ disease and, less commonly, in patients with autoimmune thyroiditis.

Fatourechi V: Pretibial myxedema: pathophysiology and treatment options, Am J Clin Dermatol 6(5):295–309, 2005.

Scleromyxedema is nearly always associated with serum paraproteinemia, usually IgG with lambda light chains. Rare cases with kappa light chains have been reported. Waldenström’s macroglobulinemia or multiple myeloma may be rarely associated.

Rongioletti F, Rebora A: Updated classification of papular mucinosis, lichen myxedematosus, and scleromyxedema, J Am Acad Dermatol 44:273–281, 2001.

Scleredema presents as a firm, woody induration of the skin typically involving the upper trunk, posterior neck, and shoulders. Histologically, it is characterized by an accumulation of dermal mucin and increased sclerosis of dermal collagen. Scleredema may be seen in several different clinical settings, including postinfection, in association with diabetes mellitus, and in the setting of paraproteinemia.

Boin F, Hummers LK: Scleroderma-like fibrosing disorders, Rheum Dis Clin North Am 34:199–220, 2008.

A digital mucous cyst is a common solitary, asymptomatic, semitranslucent, dome-shaped nodule that typically presents in adults and elderly patients on the dorsal finger near the proximal nail fold or distal interphalangeal joint (Fig. 16-4B). It may distort the nail matrix, resulting in a groove in the nail plate. Clear, gelatinous mucoid material can be expressed from the cyst. The pathogenesis is controversial; however, it is often attributed to degenerative changes in the distal interphalangeal joints.

Lin YC, Wu YH, Scher RK: Nail changes and association of osteoarthritis in digital myxoid cyst, Dermatol Surg 34:364–369, 2008.

Uric acid crystals in gout are most commonly deposited in the synovium, soft tissues, and skin. The most common site is the synovium of joints, producing acute gouty arthritis. The metatarsophalangeal joint of the great toe is classically involved. Uric acid deposition in the skin and soft tissues results in gouty tophi, which are seen in 20% to 50% of patients. Common sites of involvement include the helix of the ear, elbows, and digits (Fig. 16-5A). These gouty tophi may ulcerate and discharge monosodium urate crystals that appear as a thick chalky material. Under light microscopy, these crystals are needle-shaped and birefringent (Fig. 16-5B).

Thissen CA, Frank J, Lucker GP: Tophi as first clinical sign of gout, Int J Dermatol 47(Suppl 1):49–51, 2008.

Acute attacks of gout may be treated with a variety of agents, including colchicine, nonsteroidal antiinflammatory agents, or systemic corticosteroids. Long-term therapy may include colchicine, allopurinol, probenecid, or urine alkalinization (to increase uric acid solubility).

Eggebeen AT: Gout: an update, Am Fam Physician 76:801–808, 2007.

Calciphylaxis is a type of metastatic calcification in which there is calcification of the walls of small- and medium-sized blood vessels in the dermis and subcutis resulting in infarction of the overlying skin. Clinically, patients develop livedo reticularis–like mottling, painful hard plaques, and necrotic ulcers. It is usually seen in the setting of chronic renal failure and secondary hyperparathyroidism (Fig. 16-6). Calciphylaxis, however, has uncommonly been reported with normal levels of calcium and phosphate and in the absence of renal disease.

Daudén E, Oñate MJ: Calciphylaxis, Dermatol Clin 26:557–568, 2008.

Osteoma cutis is the deposition of bone within cutaneous tissues. Primary osteoma cutis involves normal skin and can be associated with several syndromes including Albright hereditary osteodystrophy, fibrodysplasia ossificans progressiva, and congenital platelike osteomatosis. Secondary osteoma cutis or metaplastic ossification occurs in association with or secondary to trauma, inflammatory skin conditions, or neoplasia. Miliary osteoma cutis of the face presents as multiple, small, firm papules on the face, typically in women afflicted with acne, although it may also arise on normal skin.

Touart DM, Sau P: Cutaneous deposition diseases. Part II, J Am Acad Dermatol 39:527–544, 1998.