Flesh-colored nodules on the shins and feet

Pretibial myxedema

Pretibial myxedema, also called thyroid dermopathy or localized myxedema, is characterized by asymptomatic, cutaneous induration of the skin attributable to accumulation of acid mucopolysaccharides (mainly hyaluronic acid). This mucin deposition is also referred to as glycosaminoglycans. Pretibial myxedema is one of the cutaneous mucinoses, a diverse group of diseases having the common characteristic of mucin deposition in the dermis, epidermis, or follicle. Dermal mucin can be seen with or without systemic findings and can be a primary or secondary histologic feature dependent on the clinical entity. In the case of pretibial myxedema, one has a condition with diffuse dermal mucin and accompanying systemic findings.

Pretibial myxedema is one of the manifestations of Graves’ disease, an autoimmune disease manifested by hyperthyroidism, diffuse thyroid enlargement, infiltrative ophthalmopathy, acropachy, and serum autoantibodies.^1-3 A strong correlation exists between the presence of long-acting thyroid stimulator (LATS), autoantibody against the TSH receptor (also called thyroid-stimulating immunoglobulin), and localized myxedema. Signs and symptoms of Graves’ disease are varied and include emotional lability, weight loss, heat intolerance, tachycardia, angina, diarrhea, tremor, myopathy, fever, hypomenorrhea, goiter, and exophthalmos. The condition most commonly affects middle-aged women, with female-to-male ratio of approximately four-to-one.

Pretibial myxedema usually occurs symmetrically on the anterolateral aspect of the lower legs or feet, with pink, flesh-colored, yellow, or waxy induration. Prominent hair follicles give the lesions a peau d’orange appearance. Large plaques can be painful and pruritic. When present, hypertrichosis and hyperhidrosis are confined to the pretibial myxedematous skin. There are four clinical types that clearly overlap. Sixty percent of patients with pretibial myxedema present with solid, nonpitting, or brawny, edematous type.⁴ Another 20% of cases present with a sharply circumscribed, nodular variant.⁵ Almost the same percentage have a plaque type of pretibial myxedema. Fewer than 1% present with the elephantiasic morphology.⁶ All four morphological types have similar histologic features.

Pretibial myxedema is present in almost 5% of patients with Graves’ disease and in 15% of patients with Graves’ ophthalmopathy and exophthalmos. It is a late manifestation of Graves’ disease developing most often during the second year after hyperthyroidism has been diagnosed and treated. Pretibial myxedema is nearly always preceded by significant ophthalmopathy as well as diffuse thyroid-gland enlargement and thyroid acropachy. In 12% of patients, pretibial myxedema occurs four to 12 years after the diagnosis of thyrotoxicosis. Pretibial myxedema can occur in Hashimoto’s thyroiditis without thyrotoxicosis, in the setting of hypothyroidism following treatment of Graves’ disease, and, rarely, in euthyroid patients. All patients have elevated levels of thyroid-stimulating immunoglobulin. Diagnostic criteria for Graves’ ophthalmopathy include eyelid retraction, exophthalmos, optic nerve dysfunction, extraocular muscle involvement in the form of restrictive myopathy, or muscle enlargement detected by imaging studies. Common manifestations of thyroid acropachy are clubbing of the nails, edema and thickening of the fingers and hands, and occasionally periosteal reaction of the distal bone.

The pathogenesis of this condition is still under investigation. All patients with pretibial myxedema have high serum concentrations of TSH-receptor antibodies, indicating the distinct autoimmune aspect.⁷ These receptors of TSH in the connective tissue may be the antigen responsible for the immune process. Studies have shown that both humoral and cellular immune mechanisms take part in the stimulation of fibroblasts and production of large amounts of glycosaminoglycans. The occasional occurrence of lesions in areas other than pretibial skin indicates a systemic process.

The predilection for the lower legs with this condition also has not been fully explained. It has been suggested that the skin provides sites of frequent injury, and thus a form of Koebner phenomenon may be in place in which the skin lesions result from activation of fibroblasts by trauma. Gravitational, local circulatory, and immunologic factors may also be important.

Myxedema is not always confined to the pretibial area, as involvement can also involve the hands, arms, shoulders, ankles, ears, face, and sites of trauma and scars. This is why some prefer calling this entity thyroid dermopathy.

Differential diagnosis clinically includes severe stasis dermatitis, elephantiasis nostras, necrobiosis lipoidica, erythema nodusum, hypertrophic lichen planus, lichen simplex chronicus, and panniculitis. A skin biopsy is definitive and rules out all other possibilities. Pretibial myxedema differs from edema of the lower extremity in that it is indurated, has flesh- to orange-colored lesions, and does not show pitting edema of the ankles.

Apart from appearance, there is minimal associated morbidity with this condition. For example, the lesions can occasionally impair walking because of difficulty wearing shoes. Massive involvement of the feet and/or hands can lead to functional impairment. There have been reports of entrapment of peroneal nerves by mucinous connective tissue, which can result in foot drop or faulty dorsiflexion.

Treatment remains problematic. Unlike Graves’ ophthalmopathy, therapy for the associated hyperthyroidism does not directly improve the cutaneous lesions, and often, as in this case, the condition develops after treatment has been instituted. Most cases of pretibial myxedema do not require any treatment, especially in light of the fact that current treatment modalities are only palliative at best, and lesions can normally be covered by clothing.1 Topical corticosteroid applied under occlusion has proved usually beneficial in reducing the size of lesions.⁸ Additionally, local compressive therapy (i.e., gradient pneumatic compression) is beneficial when significant edema and/or elephantiasis is present. Intralesional and oral steroid therapies as well as plasmapheresis and IV immunoglobulin have produced varied responses.⁹ Skin grafting and local excision have not met with overwhelming results because of frequent relapses. Newer therapies under investigation include octrotide, which is an insulin analogue that suppresses TSH receptors, and pentoxifylline, which decreases glycosaminoglycan production by fibroblasts in vitro.⁸ Of note, 50 % of patients have their lesions resolve spontaneously after several years of persistence.¹ In this case, we initiated topical steroids with occlusion for three weeks, followed by weekly treatments thereafter with acceptable patient satisfaction.

Dr. Burkhart is clinical professor of dermatology at the University of Toledo College of Medicine and clinical assistant professor of dermatology at Ohio University College of Osteopathic Medicine in Athens, Ohio. He has no relationships to disclose relating to the content of this article.

References

1. Fatourechi V. Pretibial myxedema: pathophysiology and treatment options. Am J Clin Dermatol. 2005;6:295-309.
2. Kerns MJ, Mutasim DF. Focal cutaneous mucinosis in Graves’ disease: relation to pretibial myxedema. Am J Dermatopathol. 2010;32:196-197.
3. Veeranna S, Kushalappa S, Betkerur J. Pretibial myxedema, ophthalmopathy, and acropachy in a male patient with Graves’ disease. Indian J Dermatolo Venereol Leprol. 2004;70:380-382.
4. Dharmalingam M Seema G, Khaitan B. Plaque form of pretibial myxedema in hypothyroidism. Indian J Dermatolo Venereol Leprol. 2001;67:330-331.
5. Hunzeker CM, Kamino H, Walters RF, Kovich OI. Nodular pretibial myxedema. Dermatol Online J. 2008;14:8.
6. Bilen H, Atasoy M, Akcay G. Elephantiasic pretibial myxedem and cutis verticis gyrate caused by Graves’ disease. Thyroid. 2006;8:815-816.
7. Hadj-Kacem H, Rebuffat S, Mnif-Feki M. Autoimmune thyroid diseases: genetic susceptibility of thyroid-specific genes and thyroid autoantigens contributions. Int J Immunogenet. 2009;36:85-96.
8. Engin B, Gumusel M, Ozdemir M. Successfu combined pentoxifylline and intralesional triamcinolone acetonide treatment of sever prtibial myxedema. Dermatol Online J. 2007;13:16.
9. Jolles S, Hughes J. Use of IGIV in the treatment of atopic dermatitis, scleromyxedema, pydoderma gangranosum, psoriasis, and prtibial myxedema. Int Immunopharmacol. 2006;4:579-591.

From the May 01, 2010 Issue of Clinical Advisor