Pathogenesis

Mucinosis has an unknown pathogenesis. In general, circulating cytokines, such as tumor necrosis factor-alpha, transforming growth factor beta, and interleukin-1, increase fibroblast reproduction and glycosaminoglycan production. Fibroblasts can produce more DNA when exposed to serum from patients with scleromyxedema in vitro [3].

Classification

There are two types of cutaneous mucinosis: primary, where mucin deposition is the major histological feature that leads to clinically unique lesions, and secondary, where mucin constitutes a secondary finding. There are two types of primary mucinoses: degenerative-inflammatory and hamartomatous-neoplastic. Degenerative-inflammatory forms are further divided into dermal and follicular forms [4].

Classification of Primary Mucinoses

Classification of Secondary Mucinoses (Associated with Histological Deposition of Mucin)

Granuloma Annulare (GA)

An annular pattern of multiple papules characterizes this benign granulomatous skin disorder [5]. Ranges from skin color to red in most cases. Several variants of GA occur, including localized (subdivided into generalized annular plaques and disseminated papular) that affect children, perforating, and subcutaneous [5,6]. The incidence and prevalence of GA have not been assessed in large cohort studies [7]. As of yet, the etiology and pathogenesis of GA are unknown. Histologically, a delayed-type hypersensitivity reaction is most likely [8]. According to studies, interferon-gamma-producing T helper 1 lymphocytes promote inflammation and tissue destruction by activating macrophages [6].

Although generalized GA may occur as an isolated cutaneous-limited disorder, numerous potential systemic conditions have been described in association, including diabetes mellitus, cancer, thyroid disease, rheumatoid arthritis, lipid abnormalities, HIV, hepatitis B, hepatitis C, BCG vaccination, and COVID-19. GA was recently reported following the COVID-19 vaccine, and it may also be triggered by insect bites, trauma, and herpes zoster [9].

In order to get an accurate diagnosis of GA, a skin biopsy is recommended for clinicopathological correlation. Among the differential diagnoses for GA are nummular eczema, psoriasis, sarcoidosis, necrobiosis lipoidica, tinea, lupus, eruptive xanthomas, leprosy, verruca vulgaris, and granulomatous mycosis fungoides [10,11]. Based on the clinical background, subcutaneous lesions should be distinguished from panniculitis, sarcoidosis, rheumatoid nodules, and infection.

In order to diagnose GA, histopathology presents distinctive features including dermal palisading granulomas with collagen degeneration in the center, mucin, and lymphohistiocytic infiltration [12]. There are four different patterns of histiocytes in GA: interstitial, palisading granulomas, nodule formation similar to sarcoidosis, and a combination of these [11]. In contrast to generalized GA, localized GA usually exhibits more prominent collagen necrosis [12]. A perforating GA differs from other variants in that collagen is expelled through the epidermis [13].

Generally, granuloma annulare does not require treatment because the patches disappear on their own within several months [10]. Sometimes, however, they persist for a long time [11]. An individual lesion may benefit from treatment, but the treatment is not curative [12]. An effective treatment includes topical corticosteroid ointment under occlusion, intralesional steroid injections, cryotherapy or laser ablation, imiquimod cream, and topical calcineurin inhibitors (tacrolimus and pimecrolimus) [13]. In widespread granulomas annulare, systemic steroids, isotretinoin, methotrexate, potassium iodide, dapsone, hydroxychloroquine, pentoxifylline, and phototherapy may be considered [12].

Lichen Myxedematosus (Lichen Myxedematosus)

This is also known as papular mucinosis, a rare skin disorder characterized by mucin deposits in the skin [14]. Lichen myxedematosus has localized and generalized forms [1]. Localized scleromyxedema is more favorable than generalized scleromyxedema, which can involve other organs and sometimes be fatal [3].

Lichen myxedematosus and scleromyxedema are often used interchangeably, but scleromyxedema refers to the generalized form [4].

Lichen myxedematosus has no known cause [14]. Monoclonal gammopathy, in which blood levels of an immunoglobulin called paraprotein are abnormally high, is almost always associated with scleromyxedema [15]. IgG-lambda light chain molecules are usually involved [4]. There may be a small increase in plasma cells in the bone marrow [3]. Other cases of scleromyxedema have been linked to cancers of the bone marrow, such as myeloma, lymphoma, and leukemia [1]. There have been several cases of localized lichen myxedematosus associated with HIV infection, hepatitis C infection, toxic oil exposure, and contaminated L-tryptophan [16].

Adults between the ages of 30 and 50 are often affected by scleromyxedema [1]. Both men and women are affected equally [4]. Scleromyxedema is characterized by skin-colored papules on the face, trunk, and extremities [14]. The mucous membranes and scalp are not affected [15]. The papules are 2–3 mm in diameter, waxy, and closely arranged [4]. Their color may change to red-brown over time. The brow may develop deep furrows as the condition progresses [1]. Skin stiffening, fingers (sclerodactyly), and reduced mobility of the mouth can occur, similarly to systemic sclerosis scleroderma, without telangiectasia or calcinosis [15].

Small, firm, waxy papules are confined to a few sites in the localized forms of lichen myxedematosus [15]. The distribution and course of each localized form subtype differ [14]. There is no hardening of the skin, and the disease is usually stable. In the blood, there are no abnormal levels of protein [16].

The main diagnostic test for suspected lichen myxedematosus is a skin biopsy, which shows characteristic pathological signs. Among other tests, serum and urine protein electrophoresis for paraproteins, thyroid function, and auto-antibodies, including antinuclear factor, may also be performed [3].

It is possible to refer the patient to a hematologist and undergo a bone marrow biopsy if paraprotein is present. In patients with widespread skin involvement, a general physician may assess the involvement of internal organs [14].

There are difficulties and disappointments associated with treating scleromyxedema. Treatments have included isotretinoin, corticosteroids, methotrexate, UVA1 phototherapy, PUVA, intravenous immunoglobulin, plasmapheresis, electron beam radiation, and dermabrasion [17].

Treatments that interfere with the development of precursor cells of the bone marrow have been tried, but they are usually reserved for patients with severe and rapidly progressive diseases [17]. The most common of these therapies are: cyclophosphamide, melphalan, and chlorambucil. As a result of its ability to modulate the immune system, thalidomide has emerged as a potential treatment in recent years. Skin induration (hardening) may be reduced with topical corticosteroid creams and oral isotretinoin [18].

Pretibial Myxedema

This is a form of diffuse mucinosis characterized by the accumulation of glycosaminoglycans in the dermis and subcutis [19]. Glycosaminoglycans, also known as mucopolysaccharides, are complex carbohydrates that maintain tissue hydration and lubrication [3]. A major glycosaminoglycan in pretibial myxedema is hyaluronic acid, which is created by fibroblasts [19].

Pretibial myxedema is also known as localized myxedema, thyroid dermopathy, and infiltrative dermopathy [4]. Lower leg swelling and lumpiness are most commonly seen on the shins (pretibial areas) [20].

Up to 13% of people with severe eye disease suffer from tibial myxedema, which affects 0.5–4.3% of patients with Graves’ disease. Also seen in patients with Hashimoto thyroiditis, primary hypothyroidism (underactive thyroid), and euthyroidism (normal thyroid function) [3]. TSH-R antibodies are present in high concentrations in the serum. The most common age group for this condition is between 40 and 60 years of age. It more commonly affects females, with a female-to-male ratio of 3.5:1 [21].

Scleredema

An unknown cause of cutaneous mucinosis. There is a difference between scleredema and scleroderma, in which the skin is fibrotic (morphea and systemic sclerosis).

There is an adult population affected by scleredema [22]. Many people with scleredema have underlying systemic diseases. Diabetes mellitus, hyperparathyroidism, Sjögren’s syndrome, rheumatoid arthritis, multiple myeloma, malignant insulinoma, and HIV infection are among them [23].

During a skin biopsy, mucin deposits are found between collagen bundles in the dermis, confirming the diagnosis [23]. Since scleredema is rare, there is no established treatment. PUVA, cyclophosphamide, oral corticosteroids, ciclosporin, UVA1 phototherapy, and electron beam radiation have all shown some benefits [22–24].

Alopecia Mucinosis (follicular mucinosis)

Under a microscope, follicular mucinosis is the appearance of mucin around the hair follicles [25]. Bald patches of skin with prominent hair follicles are characteristic of the condition [1]. In the dermis, mucin looks like stringy, clear, or whitish goo largely composed of hyaluronic acid. A number of other types of mucinosis are described and classified: a primary and acute condition that occurs in children and adolescents (Pinkus type), a primary and chronic condition that affects people over 40 years old, a secondary condition associated with benign or malignant skin conditions, and a rare condition called urticaria-like follicular mucinosis [26].

In the case of alopecia mucinosis, there is no known cause, but it is believed that mucinous material deposits and accumulates in hair follicles and sebaceous glands, resulting in an inflammatory condition that subsequently destroys hair follicle function [27].

Most commonly, alopecia mucinosis affects the face, neck, and scalp, but it can affect any part of the body [25]. It appears as grouped follicular papules within reddened, dry patches or plaques. The diameter of patches or plaques is usually 2–5 cm, but they can be larger [3]. There may be one lesion at the onset, or multiple lesions may develop over time. The early stages of hair loss are non-scarring and reversible, but in more advanced stages, the hair follicles are destroyed, resulting in scarring [27].

On biopsy, alopecia mucinosa is diagnosed by its clinical appearance and histopathological findings: accumulation of mucin in sebaceous glands and pilosebaceous follicles, keratinous debris within cystic cavities, inflammation, and degeneration of follicular structures [28].

Currently, there is no proven treatment for mucinous alopecia [27]. Primary and acute alopecia mucinosis in children usually resolves spontaneously [26]. In other forms of the disease, spontaneous resolution is rare, making it difficult to assess the effect of treatment [25]. In addition to topical, intralesional, and systemic corticosteroids, oral antibiotics such as minocycline, dapsone, indomethacin, interferons, topical and systemic, photochemotherapy (PUVA), topical nitrogen mustard, radiation, UVA1 phototherapy, and topical bexarotene 1% gel have been tried with limited success [28,29]. If the underlying skin disease is cutaneous T-cell lymphoma, secondary alopecia mucinosis should be treated appropriately [29].

The aim of the present study is to examine the different skin diseases containing mucin in the skin over a ten-year period, trying to find the frequency of these diseases.

Statement of Human and Animal Rights

All the procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the 2008 revision of the Declaration of Helsinki of 1975.

Statement of Informed Consent

Informed consent for participation in this study was obtained from all patients.

Copyright by Khalifa E. Sharquie, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.