Myxedema is one of several cutaneous changes in hypothyroidism.^{4.15.16. and 17.} The changes are most pronounced around the eyes, nose, and cheeks, often giving a characteristic facies, and also on the distal extremities. The skin is cold, dry, and pale with widespread xerosis, especially on the extensor surfaces. ¹⁸ A diffuse, non-scarring alopecia may be present. ¹⁹ Cutis verticis gyrata is a rare presentation. ²⁰

Palmoplantar keratoderma is a poorly recognized presentation of myxedema. ²¹ Glycosaminoglycans are deposited in other organs of the body as well as the skin and it has been suggested that there is impaired degradation, rather than increased synthesis, of these substances.^{5. and 22.} Muscle weakness is sometimes present. ²³

Generalized and pretibial myxedema have been grouped together as ‘dysthyroidotic mucinoses’ in the excellent review of the cutaneous mucinoses by Rongioletti and Rebora. ²⁴

Pretibial myxedema (thyroid dermopathy) is found in 1–4% of patients with Graves’ disease, particularly those with exophthalmos, but it may not develop until after the correction of the hyperthyroidism. ²⁵ Rarely, it may precede the diagnosis of hyperthyroidism. ²⁶ It may also occur in patients with non-thyrotoxic Graves’ disease²⁷ and occasionally in association with Hashimoto’s thyroiditis. ²⁸ It has been associated with an ectopic, hyperplastic nodule arising in a thyroglossal duct residue. ²⁹ Pretibial myxedema has been reported in euthyroid patients with stasis dermatitis, ³⁰ and in patients with morbid obesity who have lower leg lymphedema. ³¹

It presents as sharply circumscribed nodular lesions, diffuse non-pitting edema, or elephantiasis-like thickening of the skin.^{18.32. and 33.} There may be overlap of these lesions or progression from nodular to more diffuse plaques. ²⁵ The anterior aspect of the lower legs, sometimes with spread to the dorsum of the feet, is the most usual site of involvement, although, rarely, the upper trunk, upper extremities, and even the face, neck or ears have been involved.^{34.35. and 36.} Edema of the eyelids, not associated with the deposition of mucin, may occur in hyperthyroidism. ³⁷ Localization to scar tissue, skin grafts, and the toes has been reported.^{38.39.40.41.42. and 43.} Acropachy (digital clubbing and diaphysial proliferation) is rare, with an incidence of less than 1%. ⁴⁴ Because sites other than the pretibial region can be affected, the term thyroid dermopathy is more appropriate. ¹⁸ Slow resolution of the lesions often occurs after many years. Hyperhidrosis and/or hypertrichosis, limited to areas of thyroid dermopathy, have been reported.^{18. and 45.}

The precise pathogenesis of pretibial myxedema is unknown. The theory that pretibial myxedema results from the stimulation of fibroblasts by LATS (long-acting thyroid stimulator) is no longer tenable, although one or multiple other substances or autoantibodies are presumably involved.^{34. and 46.} A circulating factor that stimulates increased synthesis of glycosaminoglycans by normal skin fibroblasts is present in increased amounts in patients with pretibial myxedema.^{47. and 48.} Furthermore, fibroblasts from pretibial skin cultured in the presence of serum from patients with pretibial myxedema produce increased amounts of hyaluronic acid. ⁴⁹ The response of refractory cases of pretibial myxedema to octreotide (a somatostatin analogue with insulin-like growth factor 1 (IGF-1) antagonist properties) suggests that expression of IGF-1 receptor on fibroblasts may be up-regulated in this condition, leading to increased secretion of hyaluronic acid. ⁵⁰ Other explanations for this effect are possible. There is no primary lymphatic abnormality. ²⁵ Hydrostatic forces appear to play a role in the localization of the pretibial mucinosis. ⁵¹

Papular mucinosis (lichen myxedematosus) is a rare cutaneous mucinosis in which multiple, asymptomatic, pale or waxy papules, 2–3 mm in diameter, develop on the hands, forearms, face, neck, and upper trunk. ⁵⁶ A discrete papular variant also occurs. ⁵⁷ It has been reported, rarely, in patients with hepatitis C⁵⁸ and with HIV infection^{11.59.60.61.62. and 63.} and also in the L-tryptophan-induced eosinophilia–myalgia syndrome, ⁶⁴ in generalized morphea, ⁶⁵ subclinical hypothyroidism, ⁶⁶ and in patients with morbid obesity. ⁶⁷ Self-healing cases have been reported, ⁶⁸ indicating the overlap between this entity and self-healing cutaneous mucinosis (see below). Papular mucinosis with systemic involvement has also been reported. ⁶⁹

Scleromyxedema is a variant in which lichenoid papules and plaques are accompanied by skin thickening involving almost the entire body.^{70.71.72. and 73.} The face, neck, hands, and forearms are sites of predilection. Involvement of the glabella region may give rise to bovine or leonine facies.^{70. and 74.} The Koebner phenomenon due to a scratch test has been reported. ⁷⁵ Adults in the third to fifth decades, and older, are most commonly affected. A paraproteinemia, particularly of IgG lambda type, is almost invariably present in scleromyxedema and sometimes in papular mucinosis.^{4.76. and 77.} Other classes of immunoglobulins are sometimes present; ⁷⁸ a few patients have a normal immunoglobulin profile. ⁷⁹ Multiple myeloma and Waldenström’s macroglobulinemia are rare associations.^{80. and 81.} Bizarre neurological symptoms, ⁸² underlying carcinoma,^{56.83. and 84.} chronic hepatitis C, ⁸⁵ pachydermoperiostosis, ⁵⁶ dermatomyositis, ⁸⁶ scleroderma,^{81. and 87.} atherosclerosis, ⁸⁸ esophageal aperistalsis, ⁸⁹ and multiple keratoacanthomas⁷⁸ have all been reported in association with scleromyxedema. ⁸¹

Scleromyxedema is usually progressive, but spontaneous resolution has been reported. ⁹⁰ Mucin has been noted in other organs in a few autopsy cases, but it has been specifically excluded in others.^{56.91.92. and 93.} Rarely, hypothyroidism has been present.^{94. and 95.}

In 2001, Rongioletti and Rebora provided an updated classification of papular mucinosis/lichen myxedematosus/scleromyxedema. ⁹⁶ The generalized and sclerodermoid form is best known as scleromyxedema. The localized form has several subtypes. ⁹⁷ They include acral persistent papular mucinosis, self-healing papular mucinosis (juvenile and adult variants), papular mucinosis of infancy, and nodular lichen myxedematosus as variants, despite the absence of fibrosis in some of these conditions.

It has been postulated that a serum factor stimulates fibroblast proliferation and increased production of glycosaminoglycans.^{87. and 98.} Whether this factor is identical to the monoclonal immunoglobulin is controversial.^{81. and 99.} In one study, cultured skin fibroblasts from a patient with scleromyxedema produced an IgG immunoglobulin. ¹⁰⁰

An unusual scleromyxedema-like disease has been reported in renal dialysis patients and in other circumstances. The terms ‘nephrogenic fibrosing dermopathy’ and ‘nephrogenic systemic fibrosis’ have been applied to this condition. It is considered, in detail, below.

Response to high- and low-dose intravenous immunoglobulin, interferon alfa, prednisone, retinoids, high-dose pulsed methylprednisolone, thalidomide, melphalan, electron-beam therapy, extracorporeal photopheresis, and autologous stem cell transplantation has been reported.^{101.102.103.104.105.106.107.108.109.110.111.112.113.114.115.116. and 117.} The localized type has been treated with tacrolimus ointment. ⁹⁷

Acral persistent papular mucinosis, which affects mainly women, is characterized by discrete, flesh-colored papules 2–5 mm in diameter on the back of the hands and, less commonly, on the forearms^{124.125.126.127.128.129.130. and 131.} and calves. ¹³² Approximately 30 cases have been reported. ¹³³ The lesions increase in number with the years. There is usually no associated disease. ¹³⁴ It is best regarded as a variant of papular mucinosis (lichen myxedematosus).^{96. and 135.}

A patient with a self-healing plaque on the dorsum of one hand has been reported as self-healing localized cutaneous mucinosis. ¹³⁶ This case does not fit neatly into any of the current classifications of the mucinoses.

The lesions in acral persistent papular mucinosis are asymptomatic. No treatment is effective. ¹³⁷

There have been several reports of infants presenting with multiple, small, papular lesions on the upper extremities or trunk.^{2.138.139.140. and 141.} The distribution of the lesions and their early onset raise the possibility that the lesions reported are connective tissue nevi of proteoglycan type (nevus mucinosus).^{142. and 143.} There has been abundant mucin in the papillary dermis, no significant increase in fibroblasts, and a few chronic inflammatory cells in a perivascular distribution. In one case, however, there was both fibrosis and fibroblast proliferation, leading the authors to suggest that cutaneous mucinosis of infancy could be a pediatric form of papular mucinosis (lichen myxedematosus). ¹⁴⁴ This is the currently accepted view.

There have been several reports of a cutaneous mucinosis characterized by the rapid onset in childhood of infiltrated plaques on the head and torso and deep nodules on the face and periarticular region, with spontaneous resolution in weeks or months.^{145.146.147.148.149. and 150.} Other reports have described a familial variant, ¹⁵¹ and rare cases in adults.^{152. and 153.} The existence of self-healing cases of papular mucinosis (lichen myxedematosus) ⁶⁸ illustrates the arbitrary nature of the current classification of some mucinoses and lends support to the notion of Rongioletti and Rebora in 2001 that many of these entities are clinical variants of papular mucinosis (lichen myxedematosus).^{96. and 154.} Notwithstanding this view, this mucinosis is thought to represent a reactive or reparative response to some antigenic stimulation, such as inflammation or a viral infection. ¹⁵⁵ It has developed in a child with a nephroblastoma who was undergoing chemotherapy. ¹⁴⁹

This condition, previously called nephrogenic fibrosing dermopathy, is a scleromyxedema-like disease of the skin and other organs that occurs in a subset of patients with renal insufficiency.^{158.159.160. and 161.} Renal dialysis is not a prerequisite for its development. ¹⁶² It may follow severe acute-kidney injury. ¹⁶³ Cowper has done much of the work in describing the features of this entity.^{160.164.165. and 166.}

It evolves over a period of days to weeks with thickening and hardening of the skin, muscle weakness, and generalized pain. Diaphragmatic involvement is a serious complication that can lead to death.^{167.168. and 169.} The skin lesions are indurated papules and plaques, involving predominantly the trunk and extremities.^{170. and 171.} Facial papules are rare. ¹⁷² A patient with lesions limited to the breast, mimicking inflammatory breast carcinoma, has been reported. ¹⁷³ In another case there was a localized plaque on the forearm along a vein that was traumatized during the infusion of erythropoietin. ¹⁷⁴ This substance has been suggested as a possible cofactor in producing this disease. ¹⁷⁵ Pediatric cases are rare. ¹⁷⁶

The sudden appearance of this condition in 1997 and its association with renal insufficiency led to an extensive search for the etiological agent. In 2006, gadolinium-based contrast agents used in magnetic resonance imaging (MRI) were implicated as the causative agent, in patients who had renal disease and were often acidotic. ¹⁷⁷ Gadolinium had been used a few weeks prior to the onset of the disease in each case.^{178.179.180.181.182. and 183.} Gadolinium has since been identified in the tissues of affected patients.^{160.184.185.186. and 187.} It has recently been suggested that the gadolinium product involved is gadodiamide. ¹⁸⁸ Gadodiamide is retained in apatite-like deposits. It may be mobilized over time from these bone stores. ¹⁸⁹ The fibrosis caused by this agent may result from the up-regulation of transglutaminases in the affected tissue. ¹⁹⁰ Transforming growth factor beta (TGF-β) also plays a role in producing the fibrosis. ¹⁹¹

Parenthetically, the author has never seen a case, possibly because the dose of gadolinium used in Brisbane is lower than in the United States. Nephrogenic systemic fibrosis has recently been reported in a gadolinium-naive renal transplant recipient. ¹⁹²

Improvement in cutaneous lesions has been reported with UVA1 phototherapy, ¹⁹³ high-dose intravenous immunoglobulin, ¹⁹⁴ and extracorporeal photopheresis.^{188. and 195.} Retinoids have been used with PUVA therapy, giving significant clinical improvement. ¹⁹⁶

Hopefully this disease is destined to become another historical footnote, like the eosinophilia–myalgia syndrome and others. ¹⁹⁷

Reticular erythematous mucinosis (REM) was first described by Steigleder and colleagues in 1974. ²¹⁹ It presents with erythematous maculopapules and infiltrated plaques, often with a reticulated or net-like pattern, in the midline of the back or chest, sometimes spreading to the upper abdomen.^{220.221.222.223. and 224.} Rarely, the face and arms²²⁵ are involved and one case is said to have involved the gums. ²²⁶ There is a predilection for young to middle-aged females. Sunlight and hormonal influences may cause exacerbations and induce mild pruritus.^{4.224. and 227.} The lesions may subside after many years. Progression to cutaneous lupus erythematosus sometimes occurs, one of the reasons why Ackerman regards this condition as a variant of lupus erythematosus. Two cases of mycosis fungoides that clinically mimicked REM have been reported. ²²⁸

One study has shown that fibroblasts from lesional skin exhibit an abnormal response to exogenous interleukin-1β, ²²⁹ but a more recent study has shown that the accumulation of hyaluronan in REM may be related to populations of factor XIIIa⁺/HAS2⁺ dermal dendrocytes rather than to dermal fibroblasts. ²³⁰ HAS2 is one of three genetically distinct isoforms of hyaluronan synthase (HAS), the enzyme thought to be responsible for the synthesis of hyaluronan, a major component of the dermal matrix. ²³⁰

Topical tacrolimus and UVA1 radiation have been found to be a safe alternative to systemic antimalarials in the treatment of this condition.^{229. and 230.}

Scleredema (scleredema adultorum of Buschke) is characterized by the development of non-pitting induration of the skin with a predilection for symmetrical involvement of the posterior neck, the shoulders, the upper trunk, and the face.^{241. and 242.} Localization to the thighs and periorbital region have been reported.^{243. and 244.} In cases of more widespread involvement, the upper part of the body is always involved much more than the lower part, and the feet are spared. The condition occurs at all ages, although nearly 50% of cases develop in children and adolescents. ²⁴⁵ There is a predilection for females.

There are several different clinical settings.^{246. and 247.} In one group the onset is sudden and follows days to weeks after an acute febrile illness caused by streptococci or viruses. A case occurring in association with HIV infection has been reported. ¹¹ It has followed scabies infestation complicated by secondary bacterial infection with streptococci. ²⁴⁸ Spontaneous resolution occurs in approximately one-third of the post-infectious group after 6–18 months. This group is now seen less frequently than previously. Another clinical group has an insidious onset, without any predisposing illness, and a protracted course. The third group is associated with insulin-dependent, maturity onset diabetes, which is difficult to control.249.^{250.251. and 252.} Vascular complications of diabetes are common. ²⁵³ It can also be associated with type 2 diabetes.^{254. and 255.} A fourth group is associated with a monoclonal gammopathy.^{256.257.258.259.260.261.262.263.264.265. and 266.} Extracorporeal photopheresis and chemotherapy have been used to treat such cases.^{267. and 268.} Other associations are mechanical stress, ²⁶⁹ carcinoma of the gallbladder, ²⁷⁰ and rheumatoid arthritis. ²⁷¹ Scleredema is insidious in onset and prolonged in its course.

Systemic manifestations such as ECG changes, serosal effusions, and involvement of skeletal, ocular and tongue musculature may develop. Cutaneous abscesses or cellulitis may precede or follow the onset of the condition.^{272. and 273.} Rarely, there is erythema at sites of skin thickening. ²⁷⁴ Two cases with overlap features between scleredema and stiff-skin syndrome have been reported. ²⁷⁵

Scleredema is characterized by the accumulation of glycosaminoglycans, particularly hyaluronan, in the dermis with concurrent dermal sclerosis. The etiology is unknown, although fibroblasts from the fibrotic skin of patients with scleredema show enhanced collagen production and elevated type I procollagen messenger RNA levels in the cultured fibroblasts. ²⁵⁸ This suggests that fibroblasts from involved skin have a biosynthetically activated phenotype. ²⁷⁶

Scleredema has been successfully treated with UVA1 phototherapy. ²⁷⁷

Focal mucinosis usually presents as a solitary, asymptomatic, flesh-colored papule or nodule on the face, trunk, or proximal and mid extremities of adults.^{283.284.285. and 286.} The nodules average 1 cm in diameter. There has been a report of multiple nodules localized to a ‘palm-wide area’ of the right leg²⁸⁷ and also a report of multiple lesions in a patient with hypothyroidism, which responded to thyroxine. ⁹⁴ Digital lesions with the histology of focal mucinosis have been described in scleroderma (see p. 310). It has been reported in association with other cutaneous mucinoses. ²⁸⁸ Oral focal mucinosis is a related condition. ²⁸⁹ The case reported as ‘reactive pseudotumoral papular mucinosis’ is best regarded as a variant of focal mucinosis. ²⁹⁰

It is thought that increased amounts of hyaluronan are produced by fibroblasts at the expense of the connective tissue elements. ²⁹¹

Digital mucous cysts occur as solitary, dome-shaped, shiny, tense cystic nodules on the dorsum of the fingers, usually involving the base of the nail. ²⁹³ Subungual cases, distal to the nailfold, also occur. ²⁹⁴ Multiple cysts on a single finger have been reported; they were of the ganglionic subtype (see below). ²⁹⁵ The toes are uncommonly involved. The cysts are found in the middle-aged or elderly and there is a slight female preponderance. A second type, overlying the distal interphalangeal joint, is related to a ganglion as injection studies have demonstrated a connection with the underlying joint cavity. ²⁹⁶ It has been suggested that all digital mucous cysts connect with this joint. ²⁹⁷ Ganglions at other sites are beyond the scope of this book.^{298. and 299.} A superficial angiomyxoma arising on the finger has been reported; it mimicked a digital mucous cyst. ³⁰⁰

A skin flap that includes the undersurface of the cyst and the tissues between the cyst and the distal interphalangeal joint, but avoiding removal of the skin itself, has been used successfully in their treatment. ²⁹⁷ Infrared coagulation has also been used. ³⁰¹

Mucoceles (mucous cysts) result from the rupture of a duct of a minor salivary gland with extravasation of mucus into the submucosal tissues, most commonly of the lower lip. ³⁰⁴ They may also develop in the buccal mucosa or tongue. Multiple superficial mucoceles on the lips and oral mucosa have been reported in association with graft-versus-host disease. ³⁰⁵ A case reported on the anterior neck was related to the presence of ectopic minor salivary glands. ³⁰⁶ Mucoceles are found mostly in young adults.

Mucoceles are translucent, whitish or bluish nodules with a firm cystic consistency and vary in size up to 1 cm in diameter. They occasionally rupture spontaneously or after minor trauma.

A superficial variant of mucocele, which results in vesicular lesions that may be mistaken for mucous membrane pemphigoid, has been reported. ³⁰⁷ They may be single or multiple and they arise on non-inflamed mucosa.

Cutaneous myxomas have been reported in approximately 50% of the patients with the complex of cardiac myxomas, spotty pigmentation (lentigines and blue nevi), and endocrine overactivity.^{308.309.310.311.312. and 313.} This combination of lesions is known as Carney’s complex (OMIM 160980), an autosomal dominant condition which has been mapped via linkage analysis to chromosome 2p16 and 17q2. ³¹⁴ A mutation in the PRKAR1α gene on the chromosome 17q22–q24 locus has been identified in patients with Carney’s complex, particularly those with atrial myxomas. This gene, which is a tumor-suppressor gene, encodes the R1-α regulatory subunit of cyclic adenosine monophosphate-dependent protein kinase A (PKA). ³¹⁵ The gene located on 2p16 has not yet been identified.

The cutaneous myxomas may be the earliest manifestation of the syndrome. ³¹⁶ They are typically found on the eyelids, nipples and buttocks, and in the external ear canals; they are frequently misdiagnosed as fibroepithelial lesions. ³¹⁷ Spotty pigmented lesions (lentigines and blue nevi) are typically found on the face, specifically along the lips and around the eyes.^{317. and 318.} Similar cases have been reported as the NAME or LAMB syndrome (see Ch. 32, p. 710).

Solitary and disseminated myxomas unassociated with any systemic abnormalities may also occur.^{319.320.321.322. and 323.} They are benign neoplasms, but they are included here because of their prominent stromal mucin. ³²⁴ They are probably the same entity as solitary superficial angiomyxoma (see Ch. 34, p. 844).

In one reported case, a patient with multiple periorbital myxomas progressed to a scleromyxedema-like dermatosis. ³²⁵

Nevus mucinosus (mucinous nevus) is a variant of connective tissue nevus in which there is a deposition of acid mucopolysaccharides (proteoglycans) in the dermis.^{142. and 328.} The existence of such an entity has been postulated for some time in the light of the nevoid lesions of the other connective tissue elements – collagen and elastic tissue. Cases previously reported as cutaneous mucinosis of infancy (see above) may represent examples of nevus mucinosus.

The lesions are small papules, in a grouped, zosteriform or linear arrangement, on the extremities or trunk.^{329.330. and 331.} They are present at birth or appear in childhood or early adult life. ³³² A familial case has been reported. ³³³

Progressive mucinous histiocytosis (OMIM 142630), a rare, autosomal dominant histiocytosis of childhood, is characterized by multiple small papules composed of epithelioid and spindle-shaped histiocytes set in abundant stromal mucin. Sporadic cases have been reported. ³³⁵ This entity is discussed in more detail with the histiocytoses (see p. 956).

Mucin deposition may be present in a wide variety of connective tissue diseases and in some tumors. These conditions include dermatomyositis, lupus erythematosus (see below), scleroderma, ³³⁶ linear morphea, ³³⁷ the toxic oil syndrome, hypertrophic scars, connective tissue nevi, granuloma annulare, malignant atrophic papulosis (Degos’ disease), erythema annulare centrifugum, postinflammatory hyperpigmentation, ³³⁸ Still’s disease, ³³⁹ mycosis fungoides, ³⁴⁰ and Jessner’s lymphocytic infiltrate.^{4. and 5.} Localized mucinosis may follow erysipelas, ³⁴¹ or be associated with lower leg edema and morbid obesity. ³¹ Mucin is sometimes present in large amounts around the secretory coils of the eccrine glands of the lower leg when sweat excretion is blocked. ⁵ Tumors containing mucin include neurofibromas, neurilemmomas, nerve sheath myxomas, chondroid syringomas, and some basal cell carcinomas. A diffuse dermal mucinosis can be found occasionally in biopsies of lesional skin from patients with discoid and systemic lupus erythematosus (SLE).^{342. and 343.} Rarely, patients with SLE and systemic sclerosis can present with papulonodules or plaques due to a diffuse mucinous deposition in the skin (Fig. 13.14).^{336.343.344.345.346.347.348.349.350. and 351.} In these individuals, the deposition occurs in areas free from specific lesions of lupus erythematosus and it produces clinically distinct manifestations. A factor (or factors) in the patient’s serum appear(s) to stimulate fibroblasts to produce increased amounts of glycosaminoglycan. ³⁴⁷ Multiple plaques of mucinosis have been reported as the sole manifestation of dermatomyositis in a patient with a nasopharyngeal carcinoma. ³⁵² A solitary plaque on the face has been reported in a patient with secondary extramedullary cutaneous plasmacytoma. ³⁵³

The case reported as ‘plaque-like erythema with milia’ occurred in a renal transplant recipient on cyclosporine (ciclosporin), which was implicated in the pathogenesis. There were extensive mucin deposits in the dermis. ³⁵⁴

Finally, patients with mitral valve prolapse in which myxomatous degeneration of mitral valve leaflets occurs, have been found to have increased cutaneous deposits of proteoglycan (mucin) in the skin. ³⁵⁵

Follicular mucinosis (alopecia mucinosa) is an uncommon inflammatory dermatosis with a predilection for adults in the third and fourth decades of life. ³⁵⁹ A congenital case has been reported. ³⁶⁰ Three clinical types have traditionally been recognized:^{361. and 362.} a benign transient form with one or several plaques or grouped follicular papules, usually limited to the face or scalp and with accompanying alopecia;^{363.364.365.366.367. and 368.} a more widely distributed form with follicular papules, plaques, and nodules on the extremities, face, and trunk and a course often exceeding 2 years; ³⁶⁹ and a third group, accounting for 15–30% of cases, with widespread lesions and associated with malignant lymphoma of the skin or mycosis fungoides.^{370.371.372.373. and 374.} Rarely, patients with leukemia cutis, ³⁷⁵ leukemia without skin lesions, ³⁷⁶ Hodgkin’s disease, ³⁷⁷ familial reticuloendotheliosis, ³⁷⁸ Sézary syndrome,^{379. and 380.} squamous cell carcinoma of the tongue, ³⁸¹ and angiolymphoid hyperplasia^{382. and 383.} have also had this presentation. This third group was regarded by Hempstead and Ackerman³ as belonging to the group of secondary follicular mucinoses because of the lack, at that time, of convincing examples of follicular mucinosis (alopecia mucinosa) progressing to mycosis fungoides or cutaneous lymphoma.^{384. and 385.} However, cases of follicular mucinosis progressing to mycosis fungoides have since been well documented.^{386. and 387.} A study of T-cell clonality in follicular mucinosis has shown a monoclonal T-cell population in all patients with associated cutaneous T-cell lymphoma and also in 9 of 16 patients with the primary form of the disease. ³⁸⁸ In another series of 4 cases, presenting as an acneiform eruption of the face in early adulthood, 2 cases have demonstrated a clonal rearrangement of the T-cell receptor within the cutaneous infiltrate. ³⁸⁹ A more recent study from Graz, Austria, has also cast doubt on the validity of the continued separation of the so-called ‘primary form’ of follicular mucinosis from the lymphoma-associated group. Not only was there some clinical overlap between the two groups, but histopathological examination did not allow differentiation of the two groups.^{390. and 391.} Furthermore, a monoclonal rearrangement of the TCR gene was demonstrated by PCR analysis in 4 of 10 cases from the primary group and 7 of 17 cases from the lymphoma-associated group. ³⁹⁰ These authors postulate that even the primary form of follicular mucinosis may be a form of localized cutaneous T-cell lymphoma.^{390. and 392.} These cases raise the question – when does follicular mucinosis become mycosis fungoides?^{393. and 394.} Ackerman and colleagues have also proposed that alopecia mucinosa is mycosis fungoides.^{395. and 396.} Contrary views still exist. ³⁹⁷ LeBoit has challenged the view that there are only two choices – inflammatory disease or mycosis fungoides – for the pathogenesis of follicular mucinosis (alopecia mucinosa). He has raised the possibility that its lesions are ‘an expression of a self-limited proliferation of lymphocytes, e.g. a benign neoplasm of them’. ³⁹⁸ He also points out that lymphocytic infiltrates are the only ones in which clonality has been used to infer malignancy. ³⁹⁸ Guitart and Magro have included idiopathic follicular mucinosis in their classification of cutaneous T-cell lymphoid dyscrasias, a unifying term for idiopathic chronic dermatoses with persistent T-cell clones. ³⁹⁹ This is another ‘third choice’, and the one favored by the author of this book.

The protean clinical presentations attributed to follicular mucinosis, such as eczematous, ⁴⁰⁰ annular, pityriasis rosea-like, ⁴⁰¹ and folliculitis, are in many cases examples of specific dermatoses in which secondary follicular mucinosis is present.

Although it has been postulated that follicular keratinocytes are the source of the mucopolysaccharides,^{3. and 402.} this has not been confirmed in another study, which proposed a role for cell-mediated immune mechanisms in the etiology. ³⁸⁵ A more recent study has found active secretion of hyaluronate by follicular keratinocytes in follicular mucinosis, but CD44 expression (a cell-surface receptor of hyaluronate) was not increased. ⁴⁰³

Primary follicular mucinosis has been successfully treated with photodynamic therapy. ⁴⁰⁴

Follicular mucinosis may be found as an incidental phenomenon in rare cases of lichen simplex chronicus, hypertrophic lichen planus, discoid lupus erythematosus, acne vulgaris, pseudolymphoma, nevocellular nevi, ⁴¹² and arthropod bite reactions. ³ Cases associated with the ingestion of various drugs, such as calcium channel blockers, beta-blockers, antihistamines, antidepressants, and imatinib, have been reported. ⁴¹³ The superficial follicular spongiosis seen in some cases of atopic dermatitis, Grover’s disease, and actinic prurigo, ⁴¹⁴ as well as in infundibulofolliculitis, may contain small amounts of mucin. ⁴¹⁵

There is one report of an adolescent male who developed two plaques on the face characterized by prominent perifollicular mucin. The lesions were regarded as being of nevoid origin. ⁴¹⁶ Perifollicular mucinosis has also been reported in a patient with HIV infection and an atypical pityriasis rubra pilaris-like eruption. ⁴¹⁷