A 30-year-old woman presents to the clinic with a raised pink rash on her right lower leg. She says that she first noticed bumps on her shin approximately 2 months earlier. The rash is neither pruritic nor painful, and she has no other skin lesions elsewhere on her body. On examination, a waxy erythematous plaque is visualized on the anterior lower leg. On review of systems, the patient describes palpitations and unplanned weight loss over the past 4 months. She is otherwise healthy and has no family history of skin conditions.
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Pretibial myxedema (PTM) is an uncommon manifestation of autoimmune thyroid disease, occurring in 4% of patients with Graves disease (GD) and in 15% of patients with Graves-related ophthalmic disease.1 From 1% to 10% of individuals with hyperthyroidism experience PTM; it may also occur in euthyroid patients as well as those with chronic stasis dermatitis.2 PTM is an infiltrative lesion of the dermis and the subcutaneous tissue.1,3 The first well-documented association of a localized myxedema with Hashimoto thyroiditis was described in 1987.4 It classically presents with thickening of the skin most frequently localized to the pretibial region, earning this disorder its common name.5 PTM has also been described in other areas of the limbs, such as the toes or radial skin.5 In general, these lesions can be morphologically variable; however, they are most commonly pink and waxy with peau d’orange appearance.2
PTM has a gradual onset, typically developing 12 to 24 months after a diagnosis of thyrotoxicosis.5 This condition predominantly affects older adults, especially those in their 60s. Women are 3.5-times more likely to be affected than men.5 The prevalence of PTM is approximately 0.5% to 4% in patients with GD and as high as 15% in patients with severe Graves orbitopathy and markedly increased serum levels of thyrotropin receptor antibodies.5 To date, the exact pathogenesis of this condition is unknown, but it is widely understood that both mechanical and immunologic factors may be involved.6
Trauma to soft tissues or a lengthened duration of standing may induce PTM. For instance, edema, smoking, and arterial or venous insufficiency often lead to local hypoxia that may cause PTM.5 The pathophysiology of PTM is thought to involve the release of inflammatory cells and cytokines. Specifically, when the immune reaction is triggered, infiltrating T lymphocytes begin a cascade that leads to release of cytokines.6 This release causes cell proliferation and synthesis of glycosaminoglycans, particularly chondroitin sulfate and hyaluronic acid, from which PTM arises.7 Another possible trigger for PTM development is radioactive iodine.8
Light microscopic analysis of a localized myxedema biopsy specimen demonstrates abundant mucin in the reticular dermis but usually not in the papillary dermis.5 There may be a few lymphocytes in the perivascular spaces, but extensive infiltration with lymphocytes is not common.6 Compared with normal skin, PTM is associated with increased mast cells, and the amount of collagen fibers is relatively reduced with marked edema; acanthosis, papillomatosis, and hyperkeratosis are occasionally noted.5 Ultrastructural studies may demonstrate fibroblasts with dilated endoplasmic reticulum, which is a marker for active glycosaminoglycan synthesis and secretion.5
Clinically, PTM is classified into 3 forms: diffuse PTM, which is characterized by nonpitting edema and/or hyperpigmentation of the skin with dilated follicular openings; plaque-like or nodular myxedema, which is characterized by sharply circumscribed dermal lesions; and elephantiasic PTM, which is characterized by a combination of edema and nodules.5
Skin changes that appear in patients with PTM can look similar to those in patients with simple edema from venous insufficiency or fluid retention, chronic or lichenified dermatitis, hypertrophic lichen planus, generalized myxedema, or urticarial phases of certain blistering episodes.5 Accumulation of mucin in the dermis is also a prominent feature in several cutaneous mucinoses including scleromyxedema, reticular erythematous mucinosis, and follicular mucinosis.5 The location of these mucinoses in the upper extremities helps to differentiate them from PTM. Also, patients with cutaneous mucinoses usually lack thyroid dysfunction and ophthalmopathy.5
The diagnosis of PTM is usually readily apparent due to the typical pretibial lesions, but biopsy may be necessary in some situations9; in a recent report, diagnosis was confirmed by biopsy in 58% of 178 cases.9 Imaging studies, such as radiography, may also aid in diagnosis.5
In the majority of cases, PTM is mild with symptoms limited to aesthetics.5 In rare occasions, the lesions may be painful or pruritic.9 Generally no treatment is required as up to 50% of patients report experiencing complete spontaneous remission after several years, with an average time to resolution of nearly 9 years.5 In cases with significant discomfort and deformity, a number of therapies have been proposed, including hyaluronidase or glucocorticoid injections, compressive dressings, and topical corticosteroids.10 While the administration of hypodermal triamcinolone injections has not yet been extensively studied, adverse reactions including hypopigmentation and skin atrophy may hinder its use.10 Mesotherapy, also known as intradermotherapy, is a method of steroid administration originally used in chronic pain management with lower risk of skin atrophy than hypodermal injections.10 Although preliminary, one study demonstrated that mesotherapy in PTM is well tolerated and effective; however, future studies of greater scale are warranted.10
The patient in the case described above was diagnosed with Graves disease and treated by an endocrinologist. She elected not to treat her PTM.
Jessica Sheu, BS, is a medical student; Talia Noorily, BA, is a medical student; and Christopher Rizk, MD, is a dermatology fellow at Baylor College of Medicine, Houston, Texas.
- Kriss JP. Pathogenesis and treatment of pretibial myxedema. Endocrinol Metab Clin North Am. 1987;16:409-415.
- Rojanametin K, Masaru T. Dermoscopy of pretibial myxedema. J Am Acad Dermatol. 2015;73:e195-e196.
- Smith TJ, Bahn RS, Gorman CA. Hormonal regulation of hyaluronate synthesis in cultured human fibroblasts: evidence for differences between retroocular and dermal fibroblasts. J Clin Endocrinol Metab. 1989;69:1019-1023.
- Humbert P, Dupond JL, Carbillet JP. Pretibial myxedema: an overlapping clinical manifestation of autoimmune thyroid disease. Am J Med. 1987;83:1170-1171.
- Fatourechi V. Pretibial myxedema: pathophysiology and treatment options. Am J Clin Dermatol. 2005;6:295-309.
- Bahn RS. Clinical review 157: pathophysiology of Graves’ ophthalmopathy: the cycle of disease. J Clin Endocrinol Metab. 2003;88:1939-1946.
- Bull RH, Coburn PR, Mortimer PS. Pretibial myxoedema: a manifestation of lymphoedema? Lancet. 1993;341:403-404.
- Harvey RD, Metcalfe RA, Morteo C, et al. Acute pre-tibial myxoedema following radioiodine therapy for thyrotoxic Graves’ disease. Clin Endocrinol (Oxf). 1995;42:657-660; discussion 661.
- Schwartz KM, Fatourechi V, Ahmed DDF, Pond GR. Dermopathy of Graves’ disease (pretibial myxedema): long-term outcome. J Clin Endocrinol Metab. 2002;87:438-446.
- Vannucchi G, Campi I, Covelli D, et al. Treatment of pretibial myxedema with dexamethazone injected subcutaneously by mesotherapy needles. Thyroid. 2013;23:626-632.