Mucinosis cutaneous (overview) L98.5

Group of etiologically and clinically heterogeneous diseases with focal or diffuse accumulation of glycosaminoglycans(mucins), a mucus-like substance already physiologically present in the skin. The pathogenesis of mucinoses is usually unclear.

A Primary cutaneous mucinoses

A1 Primary dysthyroid mucinoses

• Generalized myxedema (hypothyroidism)
• Localized myxedema (hyperthyroidism)
  • Pretibial myxedema

  • Atypical localized my xedema (extremities, trunk, face, eyelids)

A2 Primary eutyhreote diffuse cutaneous mucinoses

• A2.1.Lichen myxoedematosus group
• Generalized (usually paraproteinemic) lichen myxoedematosus (a.k.a. scleromyxoedema)
• Localized lichen myxoedematosus group
  • Acral persistent papular mucinosis
  • Nodular lichen myxoedematosus
  • Cutaneous mucinosis of childhood
  • Mucinosis cutaneous juvenile self-healing
  • Mucinosis multiple cutaneous focal/with associated ecases
  • Lichen myxoedematosus in HIV/HCV patients
  • Atpyic forms of lichen myxoedematosus (scleromyxedema without paraproteinemia, scleromyxedema in renal disease; periocular lichen myxoedematosus/Qureshi F et al 2015).
• A2.2 Other primary euthyroid cutaneous mucinoses.
  • Scleroedema adultorum Buschke
    • Type I- postinfectious, mainly after streptococcal infections (mostly self-limited, childhood + younger women).
    • Type II- patients with monoclonal gammopathy (middle-aged men)
    • Type III patients with diabetes mellitus/metabolic syndrome (middle-aged men)
  • Reticular erythematous mucinosis (REM syndrome) and plaque-like form of cutaneous mucinosis (Perry)
  • Toxic cutaneous mucinosis

A3 Primary euthyroid, neoplastic/naevoid/degenerative (localized) cutaneous mucinoses.

• Myxoma cutaneous (angiomyxoma/possibly partial symptoms of syndromic entities - e.g. Carney complex)
• nevus mucinosus
• Digital mucoid cyst (mucoid dorsal cyst)
• see also mucinosis, oral focal as counterpart to cutaneous focal mucinosis

A4 Primary euthyroid follicular cutaneous mucinosis

• Mucinosis follicularis (see also Alpecia mucinosa).
• Mucinous follicular nevus
• Mucinous eccrine nevus (variant of eccrine hamartoma)
• Urticular follicular mucinosis (entity is controversial)

B Secondary cutaneous mucinosis (increased cutaneous mucin deposition in various primary "non-mucinous" diseases, especially in collagenoses+various tumors (modified after Rongioletti and Rebora 2001a):

B1: Secondary cutaneous mucinosis (associated phenomenon with various tumors)

• mycosis fungoides
• Basal cell carcinoma
• Warts
• Keratoacanthomas
• Squamous cell carcinoma of the skin
• Mesenchymal/neural tumors

• Hereditary progressive mucinous histiocytosis

B2 Secondary cutaneous mucinosis (associated with autoimmune diseases + various other pathologies)

• Lupus erythematosus (cutaneous lupus mucinosus)
• Dermatomyositis
• Systemic scleroderma
• Köhlmeier-Degos disease (syndrome)
• Granuloma anulare
• Pachydermoperiostosis
• Hypertrophic scars
• Actinic elastosis
• Acanthosis nigrans
• Cancellous dermatitis
• Neuropathia mucinosa cutanea

The extracellular matrix of the dermis consists of collagenous and elastic fibers and an interfibrillar ground substance. This is composed of various glycoproteins, water and salt. The main component of this basic substance are the proteoglycans (also known as mucins), which are bound to glycosaminoglycans via their protein content with a filamentous, central core (core protein). The proteoglycan molecules consist mainly of hyaluronic acid, dermatan sulfate, chondroitin-4-sulfate and chondroitin-6-sulfate. The dermis obtains its particular consistency through hydrostatic interactions of these components. When glycosaminoglycan metabolism is disturbed, quantitative and/or qualitative shifts in the extracellular matrix of the dermis can occur, often noticeable by changes in the consistency of the dermis.

An overproduction of glycosaminoglycans can be triggered, for example, by thyroid diseases, by immunological disorders or by viral infections (HIV, Hepatis C).

It is remarkable that in cultured fibroblasts collagen and glycosaminoglycan production can be increased by recombinant interleukin-6 (Duncan MR et al. 1991).

The complex classification of cutaneous mucinoses listed here, follows several principles at the same time. First, it is basically divided into

• A) Primary (idiopathic) cutaneous mucinoses

and

• B) Secondary cutaneous mucinoses

are subdivided. "Primary cutaneous mucinoses", are defined as those diseases in which pathological primary dermal mucin production is proven to be the causative, pathogenetic principle. Furthermore, primary cutaneous mucinoses are classified with respect to thyroid functions in:

• Euthyroid primary cutaneous mucinoses

and

• dysthyroid primary cutaneous mucinoses

differentiated.

Thegroup of dysthyroid primary cutaneous mucinoses is well manageable with 3 clinical representatives, essentially comprises the myxedema group, whereby dermatologically the mostly hyperthyroid, localized myxedema (mostly pretibially localized, therefore "pretibial myxedema", more rarely localized on the face, shoulders, abdomen) play the largest clinical role.

The group of euthyroid primary (distinct) cutaneous mucinoses , on the other hand, is extensive, clinically heterogeneous. The representatives of the extensive lichen myxedematosus group stand out as inflammatory diseases. The most prominent representative of this group is scleromyxoedema, which is listed in the new classifications as "generalized paraproteinemic lichen myxoedematosus". This renaming is intended to highlight the pathogenetic relationship to several other localized members of the localized lichen myxoedematosus group. "Scleromyxedema Arndt-Gottron of the historical nomenclature," is the rare, often fatal, systemic variant of lichen myxoedematosus with characteristic skin-colored lichenoid papules, areal thickening and induration of the skin with storage of mucins, and markedly increased fibrosis of the dermis. Facial involvement results in peculiar limitation of facial expression. Systemic considerations include cardiovascular involvement, as well as myopathies and neurologic symptoms. Monoclonal paraproteinemia (MGUS) is frequently present (>90%), usually of the IgG1 lambda type, less commonly of the IgG kappa type. The etiologic relationships between mucinosis and paraproteinemia have not yet been established.

The group of non-generalized, focal or attenuated (discrete lichen myxoedematosus) lichen myxoedematosus variants isarbitrarily composed, once according to localization (acral persistent papular mucinosis) according to clinical and morphological criteria (nodular lichen myxoedematosus, self-healing cutaneous mucinosis, discrete lichen myxoedematosus) or according to etiologies(HIV-associated (HCV-associated lichen myxoedematosus, "toxic oil syndrome", scleromyxedema in renal disease).In fact, the similarities are essentially found in the concordant histological findings. In other words, the individual variants cannot be differentiated on the basis of the fine tissue, so that the final diagnosis can only be made on the basis of histology, clinical findings and the course of the disease.

Other euthyroid primary diffuse cutaneous mucinoses: Another clinically important clinical picture, which also belongs to the group of euthyroid primary cutaneous mucinoses with diffusely interstitially distributed mucin deposits, but not to the lichen myxedematosus group, is scleroedema adultorum, which is often also diabetogenically triggered. Compared to the representatives of lichen myxoedematosus, clinically the papular component is completely absent. The skin is uniformly thickened, somewhat purple shimmering, with a "peau d`orange" surface. Histologically, there are distinct differences from lichen myxoedematosus in that fibroblast proliferation is absent. The thickened, window-like dispersed collagen fibers are more reminiscent of late-stage scleroderma. Scleroedema adultorum Buschke occurs in 3 variants:

• Type I mainly after streptococcal infections (often self-limiting in younger women and children)
• Type II in patients with monoclonal gammopathy (middle-aged men)
• Type III in association with diabetes mellitus in middle-aged men.

Of clinical note, the "self-healing juvenile cutaneous mucinosis" described by pediatricians, which is listed in the lichen myxoedematosus group, takes a clinical course quite similar to that of type I Buschke's scleroedema. This disease also begins febrile, accompanied by arthralgias and arthritides, muscle pain, and generalized weakness. Conspicuous are areal periorbital edema reminiscent of juvenile dermatomyositis.

The REM syndrome (reticular erythematousmucinosis) described by Gerd-Klaus Steigleder in 1974, and its 14 years older sister, the "plaque-like form of cutaneous mucinosis" described by the American dermatologist Harald Otto Perry, also belong to the group of euthyroid primary, diffuse, cutaneous mucinoses (note: probably they are one and the same entity). Both clinical pictures are a "black box" regarding their etiopathogenesis. An increased photosensitivity, a viral induction but also immunological triggers are discussed. An associated lupus erythematosus has to be clarified as well as an HIV/HCV infection. Chloroquine and hydroxychloroquine are used therapeutically for idiopathic forms.

Primary euthyroid follicular cutaneous mucinoses: Primary euthyroid follicular cutaneous mucinoses are a category all their own. Here, the follicular epithelia and not the fibroblasts are causative for mucin formation. Again, the statement that the clinical diagnosis is based solely on a histologic phenomenon that can occur as an epiphenomenon in a number of inflammatory diseases is valid. On the one hand, in children and young adults, this histopathologic feature may conceal harmless, usually localized, follicular inflammatory disease patterns. In combination with clinically conspicuous hair loss, the clinical picture is called alopecia mucinosa. A different clinical emphasis is given to disseminated mucinosis follicularis, which may occur as a manifestation of folliculotropic cutaneous T-cell lymphoma (see folliculotropic mycosis fungoides below).

Secondary cutaneous mucinoses. In the so-called secondary cutaneous mucinoses, one cannot speak of autochthonous "mucinous disease patterns". It is a heterogeneous collection of skin diseases in which secondary mucinous deposits occur. The commonality of this group thus refers to a histological phenomenon without specific clinical relevance.

Detection of mucins by Hale reaction or Alzian blue staining. If mucinosis is suspected, the specimen should be fixed in absolute alcohol with 1% formalin.

Clinical picture; histological evidence of mucin deposits in the skin.

See below the clinical pictures listed in the tables.

Classification of mucinoses

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2. Biondo G et al (2019) Clinical, dermoscopic, and histologic aspects of two cases of cutaneous focal mucinosis. An Bras Dermatol 94:334-336.
3. Brown-Falco O et al (1967) E.M.O. syndrome. Exophthalmos, myxodema circumscriptum praetibiale and osteoarthrophatia hypertrophicans (EMO syndrome). Munch Med Wochenschr 79:1523-1529
4. Buschke A (1900) Proceedings of the Berlin dermatological society. Arch Dermatol Syph 53:383-386.
5. Buschke A (1902) On scleredema. Berl Klin Wochenschr 39:955-957
6. Carder KR et al (2003) Self-healing juvenile cutaneous mucinosis. Pediatr Dermatol 20: 35-39.
7. Colomb D et al (1973) Mucinosis d'evolution regressive sans paraproteins chez une jeune fille. Lyon Med 230:474-475
8. Diamond MP (1959) The syndrome of oxophthalmos, hypertrophic osteoarthropathy and localized myxedema: a review of the literature and report of a case. Ann Intern Med 50:206-213
9. Duncan MR et al (1991) Stimulation of collagen and glycosaminoglycan production in cultured human adult dermal fibroblasts by recombinant human interleukin 6. J Invest Dermatol 97: 686-692.
10. Geagea C et al (2019) Self-healing juvenile cutaneous mucinosis: A case report in the Middle East. Am J Case Rep 20:65-69.
11. Gottron HA (1954) Scleromyxedema. A peculiar manifestation of myxthesauroderma. Arch Dermatol Syph (Berlin) 199:71-91.
12. Guarda NH et al (2023) Case for diagnosis. Multiple infiltrated plaques in a patient with human immunodeficiency virus and hepatitis C co-infection: lichen myxedematosus. An Bras Dermatol 98:398-400.
13. Hunter C (1917) A rare disease in two brothers. Proc R Soc Med 10:104-116.
14. Jablonska S et al (1959) Mucinosis follicularis. Dermatologist 10:27-33
15. Jackson EM et al (2002) Diffuse cutaneous mucinoses. Dermatol Clin 20: 493-501
16. Kim KJ (2002) A case of pretibial mucinosis without thyroid disease. J Dermatol 29: 383-385.
17. Kreibich C (1926) Mucin in skin diseases. Arch Dermatol Syph 1150:243-248.
18. Montgomery H, Underwood LJ (1953) Lichen myxoedematosus; differentiation from cutaneous myxedemas or mucoid states. J Invest Dermatol 20:213-236
19. Muscardin LM et al (2003) Acneiform follicular mucinosis of the head and neck region. Eur J Dermatol 13: 199-202.

20. Ogita A et al (2012) Nodular-type lichen myxedematosus: a case report. Case Rep Dermatol 2:195-200.

21. Ord WM (1878) On myxedema, a term proposed to be applied to an essential condition in the "cretinoid" affection occasionally observed in middle-aged women. Med Chir Trans 61:57
22. Podda M et al (2001) Cutaneous mucinosis of infancy: is it a real entity or the paediatric form of lichen myxoedematosus (papular mucinosis)? Br J Dermatol 144: 590-593
23. Qureshi F et al (2015) Periocular scleromyxedema. Ophthalmic Plast Reconstr Surg 31:e119-120.
24. Rongioletti F et al (1986) Acral persistent papular mucinosis: a new entity. Arch Dermatol 122:1237-1239.
25. Rongioletti F et al (2001) Updated classification of papular mucinosis, lichen myxedematosus, and scleromyxedema. J Am Acad Dermatol 44: 273-281
26. Steigleder GK et al (1974) REM syndrome: reticular erythematous mucinosis (round-cell erythematosis), a new entity? Br J Dermatol 91:191-199
27. Trotter WR et al. 1942) Localized pretibial myxoedema in association with toxic goitre. Q J Med 11:229-240
28. Sonntag M et al (2003) Papulonodular mucinosis associated with subacute cutaneous lupus erythematosus. Dermatology 206: 326-329
29. Tan E et al (2003) Cutaneous mucinosis in dermatomyositis associated with a malignant tumor. J Am Acad Dermatol 48: S41-42.
30. Van Zander J et al (2002) Papular and nodular mucinosis as a presenting sign of progressive systemic sclerosis. J Am Acad Dermatol 46: 304-306
31. Wang N et al (2017) A case report of atypical nodular cutaneous lupus mucinosis. Medicine (Baltimore) 96:e8391.
32. Weindorf N et al (1988) Plaque cutaneous mucinosis with telangiectasias. Dermatologist 39: 589-592