Pretibial Myxedema (Thyroid Dermopathy)

Are You Confident of the Diagnosis?

What you should be alert for in the history

The diagnosis of pretibial myxedema (also referred to as thyroid dermopathy [TD]) can only be made in confidence with a history of autoimmune thyroid disease, especially Graves disease. In the absence of such history, or laboratory confirmation of thyroid autoimmunity [TA], one should consider other disorders in the differential diagnosis.

Depending on the rapidity of onset and the degree of involvement, patients may be either asymptomatic or notice swelling of their legs that may be of cosmetic concern only or noticeably symptomatic. Patients may note that their shoes feel tight. Occasionally they may appreciate that the skin is moist (due to hyperhidrosis) or is developing excess hair (hypertrichosis) in the areas of involvement. In extensive cases, patients may have a foot drop due to nerve compression. Inquire whether the patient has other cutaneous manifestations related to hyperthyroidism, notably any history of hair loss, heat intolerance, redness of the palms, or pruritus (especially if associated with urticaria).

As virtually all patients with TD have a component of Graves ophthalmopathy, ask about dry eyes, photophobia, tearing, a pressure sensation behind the eyes or diplopia. If patients have associated thyroid acropachy, the fingers and toes may feel tight and appear swollen. Does the wedding band still fit?

Characteristic findings on physical examination

On physical examination, there are several variants of TD that may demonstrate overlapping features. The majority of cases are diffuse, presenting as a nonpitting edema with an orange-brown hue (Figure 1). In chronic cases hyperpigmentation and hyperkeratosis may be noted. Infiltration often leads to a peau d’orange (orange peel) appearance. Plaques may be observed individually or on a background of diffuse involvement. The nodular variant has more of a tumoral appearance, with occasional lesions appearing fungating or polypoid (Figure 2).

Figure 1.

Classical diffuse type of pretibial myxedema (thyroid dermopathy) characterized by non-pitting edema, an orange-brown hue, and “peau d”orange.

Figure 2.

Pretibial myxedema. (Courtesy of Bryan Anderson, MD)

Figure 3.

Pretibial myxedema histology, low power. (Courtesy of Bryan Anderson, MD)

The most rare and severe form of TD is the elephantiasic variant, being observed in approximately 5% of cases. This is accompanied by severe lymphedema, leading to functional impairment. In any of the variants, hyperhidrosis and/or hypertrichosis may be appreciated. In the event of concomitant nerve compression, foot drop may be appreciated.

The term TD is preferred to pretibial myxedema because the latter is a misnomer. Rarely the disease may be seen in other locales other than the pretibial area, such as the arms (preradial), back, shoulders, ears, nose, within surgical scars and sites of prior vaccinations.

An examination of the eyes most commonly demonstrates upper eyelid retraction, conjunctival injection, edema, erythema of the periorbital region, and proptosis. If acropachy is present, clubbing of the fingers and toes (similar to that seen in pulmonary osteoarthropathy) accompanied by swelling of the fingers and toes is observed.

Laboratory studies should be directed at confirming the diagnosis of autoimmune thyroid disease by checking a TSH, T4, (T3 if the T4 is normal), and a TSH receptor antibody titer (which is positive in Graves disease). In clinical Graves disease, the TSH will be low with an elevated T4; in clinical Hashimoto’s thryoiditis, the TSH will be high with a low T4. In subclinical forms of the disease, the T4 will be in the normal range. Euthyroid TD, when TSH and T4/T3 levels are normal, is exceptionally rare. Antithryoglobulin and antithryoperoxidase (antimicrosomal) antibodies are more commonly observed in Hashimoto’s thyroiditis than Graves disease.

A skin biopsy is usually not necessary, as the diagnosis of TD may be made confidently on clinical grounds. In those equivocal cases where a biopsy is deemed necessary, one would expect to find increased amounts of glycosaminoglycans (hyaluronic acid and lesser amounts of chondroitin sulfate) in the reticular dermis. This is easily confirmed with an alcian blue stain. It is important to get adequate tissue to at least the deeper portion of the dermis by a punch or incisional biopsy to assure that other conditions in the differential diagnosis are ruled out.

There is little value in imaging studies such as an magnetic resonance imaging (MRI) or ultrasound, although it may be valuable to periodically assess thickness of the dermis by ultrasound to objectively determine response to treatment (as progress may be hard to measure on a clinical basis alone.)

Diagnosis confirmation

The differential diagnosis of TD includes the following entities:

Simple edema (characteristically pitting and associated with congestive heart failure, renal disease, liver disease, or venous insufficiency)

Hypertrophic lichen planus (readily distinguished by other features of lichen planus such as oral involvement and a distinct histology)

Other cutaneous mucinoses (lichen myxedematosus, scleromyxedema) which are unassociated with thyroid disease (with the exception of those rare associations with autoimmune thyroid disease). These disorders tend to involve other locations such as the face and upper extremities, and may be associated with a monoclonal gammopathy;

Nephrogenic systemic fibrosis (differentiated by a history of renal insufficiency and exposure to gadolinium, with normal thyroid studies)

Lower extremity bullous pemphigoid (differentiated by histology, direct immunofluorescence, and ELISA studies for bullous pemphigoid antigens 1 and 2)

Elephantiasis due to congenital disease or acquired lymphatic obstruction (secondary to malignancy, infection, radiation, or filarial disease)

Obesity-associated lymphedematous mucinosis (seen in the context of obesity with normal thyroid function; histologically the edema, mucin, and angioplasia is appreciated in the papillary dermis, not the reticular dermis which is characteristic of TD).

Who is at Risk for Developing this Disease?

Autoimmune thyroid disease is very common, being noted far more frequently in women than men. The overall incidence (clinical and subclinical) is 1.3% for hyperthyroidism and 4.6% for hypothyroidism. Ask the patient about a family history of thyroid disease because approximately 20% of patients with Graves disease have first-degree relatives with autoimmune thyroid disease. Seventy percent of those with Graves disease have at least subclinical ophthalmopathy. Up to approximately 4% of patients with Graves disease, and 13% of those with Graves ophthalmopathy will have TD. Twenty percent of those with significant TD have acropachy. The rare EMO syndrome (exophthalmia, myxedema, osteoarthropathy) is seen in less than 1% of cases.

Smoking is a major risk factor for all of the extrathyroidal manifestations of autoimmune thyroid diseases. Obesity may also be a contributing or aggravating factor for thyroid dermopathy.

What is the Cause of the Disease?

The etiology of autoimmune thyroid disease is unknown, but appears to occur in genetically predisposed patients triggered by undefined environmental antigens (with the exception of cigarette smoke). No precise genetic predisposition has been determined for the extrathyroidal manifestations of Graves disease. TD is due to immunologic and mechanical factors.


Immunologically, there appears to be activation of the TSH receptor on fibroblasts by circulating anti-TSH receptor antibodies in patients with Graves disease, resulting in the fibroblast producing hyaluronic acid (and lesser amounts of chondroitin sulfate), which is deposited in the dermis. It is possible that in Graves disease the receptor is overexpressed in pretibial tissues. This immunologic interplay occurs with the involvement of MHC class II antigens with helper T cells that become activated with autoreactive B cells through CD154-CD40 bridges, secreting IL-2 and interferon-gamma. There is increasing evidence that other cytokines and immunologic factors such as TNFα play a role in the pathogenesis of the disease.

Mechanical factors contribute to the pathogenesis of TD. Dependent edema may inhibit the return of lymphatic fluid, thereby reducing the clearance of those cytokines contributing to the deposition of glycosaminoglycans.

Systemic Implications and Complications

The importance of recognizing TD is in making sure that autoimmune thyroid disease has been diagnosed and appropriately treated. With the exception of nerve compression causing a foot drop, or functional disability observed in severe elephantiasic cases, there are no systemic complications related to TD per se.

Treatment Options

Treatment options are summarized in Table I.

Table I.
Medical Treatment Surgical Procedures Physical Modalities
Topical corticosteroids with or without occlusion Excisional surgery with grafting Complete decongestive physiotherapy
Intralesional corticosteroids
Pentoxyfilline, systemic corticosteroids, octreotide, IVIG (intravenous immunoglobulin), cytotoxic therapy

Optimal Therapeutic Approach for this Disease

If risk factors such as smoking and obesity are present, every effort should be made to help the patient cease smoking and/or lose weight. Thyroid function should be normalized with the assistance of the patient’s primary care physician or endocrinologist.

Inquire about any associated autoimmune diseases as patients with Graves disease (and Hashimoto’s thyroiditis) have an increased risk other immunologically-mediated diseases such as diabetes mellitus, immunobullous diseases, and collagen vascular diseases. Determine how severe the TD is, and what effect it is having on the patient’s quality of life. Mild cases of cosmetic concern will be managed less aggressively than those yielding functional impairment . Explain the natural history of the TD to the patient so that they understand that improvement may occur after a prolonged time without any treatment, and that most therapeutic modalities work slowly.

Encourage the use of combinations of therapeutic modalities for any potential synergistic effect.

Potent (betamethasone diproprionate 0.05%, or equivalent) and ultrapotent (clobetasol 0.05% or equivalent) topical steroids with or without occlusion are the cornerstones of treating pretibial myxedema. There is evidence that treating TD as early as possible after the diagnosis is made will yield a better response to topical corticosteroids than more chronic lesions.

When utilizing ultrapotent steroids under occlusion, consider a pulsed regimen to avoid excess systemic absorption and/or atrophic changes. Although the goal is to reduce dermal thickness, superficial epidermal/dermal atrophy may lead to undesirable ulceration, especially if the area is traumatized. For resistant or nodular areas, intralesional steroids, at a typical dose of triamcinolone 5mg/cc are very helpful.

Unless contraindicated (such as in patients with peripheral vascular disease). compression therapy utilizing compression stockings of at least 20-30 mm/Hg, should be utilized in all patients. This should be used in conjunction with all treatment modalities, if possible. If patients have access to a certified physiotherapist, complete decompressive physiotherapy (as used in patients with chronic lymphedema) may be very valuable.

If systemic treatments are necessary, pentoxyfylline at a dose of 400mg three times daily is recommended. This drug has mild anti-TNFα activity, and appears to be a useful adjunctive agent.

For severe cases of pretibial myxedema, there is no compelling evidence that any of the following agents are of benefit, despite the fact that some have been reported to be of value in case reports or small series: intravenous immunoglobulin (IVIG), octreotide, plasmapheresis, melphalan, surgical excision, and skin grafting. As scars may worsen TD, any surgical procedure must be approached with caution.

As pretibial myxedema is a relatively uncommon disorder, there has been more research on developing treatments for Graves ophthalmopathy. As the pathogenesis of the ophthalmopathy and thyroid dermopathy are analogous, perhaps some of the newer treatments that have been anecdotally reported in the ophthalmologic literature, such as anti-TNF therapies (infliximab, adalimumab, etanercept), rituximab, or anikinra may prove to be of value with further study. An intriguing possibility is the use of low molecular weight thyrotropin receptor antagonists that have been shown to decrease hyaluronic acid production in vitro.

Patient Management

Explain the natural history of thyroid dermopathy to the patient before beginning treatment. This is a chronic condition, which may improve without any treatment whatsoever, over the course of many years. Accordingly, treatments may help, but progress may be very slow.

Encourage patients to persist with treatment; they will improve over time. A high-resolution ultrasound or MRI performed at baseline, repeated annually, to measure dermal thickness, is of value in objectively determining if a patient is responding to therapy. As it is very difficult to see progress that occurs so slowly, documentation of improvement may provide incentive for the patient to continue treatment.

Tell the patient that pretibial myxedema is not dangerous in most cases, so that the risks of any potential systemic treatments must be carefully weighed against potential benefit. For mild disease requiring only topical treatment, patients need to be seen only periodically (every 4 to 6 months); for those patients requiring aggressive systemic treatments (systemic corticosteroids, IVIG, cytotoxic agents, etc), patients need to be seen in concordance with the appropriate monitoring for that drug or modality. An endpoint to treatment is based on what the patient hopes to have accomplished, be it cosmetic and/or functional improvement.

Unusual Clinical Scenarios to Consider in Patient Management

Remember that although rare, unusual presentations of TD may occur. Patients may be euthyroid. Under these circumstances, a careful assessment of other associated features (notably the ophthalmopathy) and checking for the TSH receptor antibody is essential.

The same approach holds true for deposition of mucin appearing as a plaque or nodule on atypical sites, such as the forehead or trunk. A valuable rule of thumb – if mucin deposition is found either clinically or histologically, at least a rudimentary assessment for autoimmune thyroid disease is warranted.

What is the Evidence?

Heymann, WR. “Thyroid disorders with cutaneous manifestations.”. 2008. pp. 1-193. (A thorough review of the relationship of the thyroid gland to skin, with detail on the diagnosis and management of specific thyroid skin lesions, the non-specific manifestations of hyperthyroidism and hypothyroidism, and the associations with other systemic diseases.)

Fatourechi, V, Heymann, WR. “Pretibial myxedema (Thyroid dermopathy)”. Thyroid disorders with cutaneous manifestations. 2008. pp. 103-119. (An outstanding review of the clinical presentations, pathogenesis, and management of all aspects of the extrathyroidal manifestations of autoimmune thyroid disease.)

Bahn, RS. “Graves’ ophthalmopathy”. N Engl J Med. vol. 362. 2010. pp. 726-38. (A comprehensive review of the pathophysiology of Graves ophthalmopathy, which is analogous to thyroid dermopathy. A highlight is an outline of the most recent treatments for the ophthalmopathy, many of which should be assessed for their potential value in pretibial myxedema.)

Fatourechi, V. “Pretibial myxedma: pathophysiology and treatment”. Am J Clin Dermatol. vol. 6. 2005. pp. 295-309. (An outstanding overview of therapeutic approaches appropriate for mild forms of pretibial myxedema to the most severe elephantiasic forms.)

Takasu, N, Higa, H, Kinjou, Y. “Treatment of pretibial myxedema”. (This series of six patients with pretibial myxedema demonstrated that the two who patients who responded to treatment (triamcinolone acetonide 0.1% ointment) began therapy within months of the diagnosis. There was no beneficial response for the remaining four patients who started treatment 5 to 10 years after being diagnosed with the condition, allowing the authors to conclude that implementing topical corticosteroid therapy should be as early as possible.)

Lang, PG, Sisson, JC, Lynch, PC. “Intralesional triamcinolone therapy for pretibial myxedema”. Arch Dermatol. vol. 111. 1975. pp. 197-202. (Although there have not been any recent studies to confirm the authors success in 7 of 9 patients, each receiving between 3 and 7 treatments, intralesional steroids remain an effective treatment for recalcitrant areas of thyroid dermopathy.)

Engin, B, Gumusel, M, Ozdemir, M, Cakir, M. “Successful combined pentoxifylline and intralesional triamcinolone acetonide treatment of severe pretibial myxedema”. Dermatol Online J. vol. 13. 2007. pp. 16(An excellent example of how a multimodality approach may improve patient outcome.)

Rotman-Pikielny, P, Brucker-Davis, Turner, ML, Sarlis, NJ, Skarulis, MC. “Lack of effect of long-term octreotide therapy in severe thyroid-associated dermopathy”. Thyroid. vol. 13. 2003. pp. 465-70. (Three patients with thyroid dermopathy did not demonstrate a statistically significant improvement with octreotide, in contrast to prior case reports. This paper, and virtually all studies of patients treated with systemic agents, is either a case report or very small case series. Until randomized, controlled trials are performed on an adequate number of patients with TD, systemic approaches to the condition must be considered anecdotal.)

Senel, E, Güleç, AT. “Euthyroid pretibial myxedema and EMO syndrome”. Acta Dermatoven. vol. 18. 2009. pp. 21-3. (The EMO syndrome (exophthalmia, myxedema, and osteoarthopathy) is rare, being noted in less than 1% of all cases of TD. This interesting case report reminds us that even in such rare presentations, patients may be euthyroid at the time of presentation.)

Rongioletti, F, Donati, P, Amantea, A, Gerardo, F, Montinari, M, Santoro, F, Parodi, A. “Obesity-associated lymphoedematous mucinosis”. J Cutan Pathol. vol. 36. 2009. pp. 1089-94. (This report of five patients details the clinical and histologic differences between obesity-associated mucin deposition and that seen with TD. As obesity has become a worldwide epidemic, it is essential that this condition, which occurs in euthyroid patients, be recognized as a distinct entity to be treated with a strict weight loss regimen. Such an approach may also be helpful in those patients with TD who are overweight, by improving the mechanical factors that tend to aggravate the condition.)