AUTHOR AND EDITOR INFORMATION

Section 1 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

INTRODUCTION

Section 2 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Background

Pretibial myxedema (PTM) or, more appropriately, thyroid dermopathy is a term used to describe localized lesions of the skin resulting from the deposition of hyaluronic acid, usually as a component of thyroid disease. Although the condition is most often confined to the pretibial area, it may occur anywhere on the skin. It is nearly always associated with Graves disease (see Graves Disease for more information).
 
Additionally, a Medscape CME course related Graves disease is Therapy Insight: Management of Graves' Disease During Pregnancy.

Pathophysiology

PTM occurs as a result of the deposition of hyaluronic acid in the dermis and subcutis. The precise cause of this phenomenon remains uncertain. A leading theory proposes that fibroblasts are stimulated to produce abnormally high amounts of glycosaminoglycan due to exposure to thyroid hormones. Both thyrotropin and thyrotropin receptor antibody binding sites are found in the plasma membranes of fibroblasts derived from the skin of patients with PTM. Long-acting thyroid stimulator (LATS), an immunoglobulin G (IgG) antibody, is present in the serum of almost all patients with PTM, but it has also been found in the serum of patients without PTM. LATS was later demonstrated to represent thyrotropin receptor autoantibodies.  

Research published in 2006 suggests that it may be more than the high level of glycosaminoglycans, but the change in percentage of the constituents of the glycosaminoglycans in the blood that leads to the development of PTM. Thyroid hormones, by means of their influence on prostaglandin metabolism, alter the synthesis and degradation of glycosaminoglycans. Prostaglandin degradation may be what is changed in the course of Graves disease, based on findings that glycosaminoglycan synthesis is reduced, as is extracellular matrix assembly in vitro with exposure to T3 excess.¹

Cell-mediated immunity, using differentially expressed T-cell surface receptors in localized PTM, has also been proposed as having a causative role.² The fact that PTM frequently develops in areas of injury suggests that trauma may contribute to local fibroblast activation. In addition, extrathyroid manifestations of Graves disease often occur in the skin and eyes—fibroblasts within the orbits and skin were found to have phenotypic differences from other fibroblasts throughout the body.

Frequency

United States

PTM occurs in 0.5-4.3% of patients with Graves disease. PTM has also been reported in patients with Hashimoto thyroiditis, primary hypothyroidism, and euthyroidism. Peak incidence occurs in the fifth to sixth decades of life.

Mortality/Morbidity

PTM is primarily of cosmetic concern and rarely causes significant morbidity. Local discomfort and difficulty wearing shoes are expected.

Sex

Women are affected more frequently than men, with a female-to-male ratio of 3.5:1.

Age

PTM may occur in children and young adults, but most cases occur in older adults, with a peak age at onset in the fifth to sixth decades of life.

CLINICAL

Section 3 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

History

• The onset of PTM most commonly occurs 1-2 years after the diagnosis of Graves disease, but it may occur earlier or later. PTM in the absence of Graves disease is uncommon. Most patients who develop PTM also have Graves ophthalmopathy, with the onset of dermopathy typically following the onset of ophthalmopathy by 6-12 months. The natural history of PTM is not well defined. Available data indicate that about 10-26% of patients eventually experience complete remission, and about 24% have partial remission.
• Skin lesions or areas of nonpitting edema appear on the anterior or lateral aspects of the legs or in sites of old or recent trauma in patients with Graves disease.
• Otherwise unexplained skin lesions or areas of nonpitting edema occur in patients with thyroid disease.

Physical

Pertinent physical findings of PTM are limited to the skin. However, physical findings consistent with Graves thyrotoxicosis are significant because they are indicative of PTM as the etiology of the skin lesions. This observation is especially true regarding the finding of proptosis because nearly all patients who develop PTM have thyroid ophthalmopathy. Ophthalmopathy usually occurs prior to dermopathy.³ Thyroid acropachy occurs in 1% of patients with Graves disease. It is clinically characterized by clubbing of the fingers and the toes, periosteal proliferation of the shafts of the phalanges and other distal long bones, and swelling of the soft tissues overlying affected bony structures. When present, acropachy usually follows dermopathy. Graves dermopathy and acropachy appear to be markers of severe ophthalmopathy.

• Primary lesion
• • Early lesions are bilateral, firm, nonpitting, asymmetrical plaques or nodules.
  • Hair follicles are sometimes prominent, giving a peau d'orange texture.
  • Areas of nonpitting edema may develop.
  • In the elephantiasic form of PTM, lesions may coalesce to give the entire extremity an enlarged, verruciform appearance.
  • Overlying hyperhidrosis or hypertrichosis may be present in these cases.
• Distribution
• • Lesions characteristically appear on the lateral or anterior aspect of the legs, but they may occur on the thighs,⁴ the shoulders, the hands, the forehead, or any other skin surface.
  • Lesions often occur in areas of recent or prior trauma or skin graft donor sites.
• Color: Lesions are characteristically shiny pink to purple-brown.

Causes

• The cause is unknown.
• PTM is generally considered a cutaneous manifestation of thyroid disease.

DIFFERENTIALS

Section 4 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Other Problems to be Considered

Collagen-vascular disorders
Generalized pruritus (possibly severe with Graves disease)
Stasis mucinosis
Sweet syndrome

WORKUP

Section 5 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Lab Studies

• Thyrotropin levels may be abnormally high or low, depending on whether the underlying thyroid disease has been recognized and treated.
• LATS levels are elevated in about 50% of patients with PTM.

Histologic Findings

The characteristic histopathologic features consist of the deposition of mucin (glycosaminoglycans) throughout the reticular dermis and with attenuation of collagen fibers. Mucin may appear as individual threads and granules. With extensive deposition of mucin, the collagen fibers are frayed, fragmented, and widely separated. Stellate fibroblasts are often observed, but the number of fibroblasts is not increased. The overlying epidermis may show hyperkeratosis. The mucin is hyaluronic acid that stains blue with Alcian-blue at a pH of 2.5 and colloidal iron stains (see Media File 3); metachromasia is shown with toluidine blue stain. Findings of mucin deposition restricted to an expanded papillary dermis, nodular angioplasia, and hemosiderin deposition are more suggestive of stasis dermatitis.

TREATMENT

Section 6 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Medical Care

• The lesions of PTM are primarily of cosmetic concern, although severe elephantiasic forms may lead to significant limb enlargement and impair function.
• Surgical treatment should be avoided because scarring may aggravate the dermopathy, and benefits are equivocal.
• Local application of corticosteroids remains the mainstay of treatment.
• Compression wraps or stockings that provide 20-40 mm Hg of pressure can be useful as an adjunctive therapy.

Consultations

• Consult a dermatologist for an evaluation of lesions in suspected PTM.
• Consult an endocrinologist for an evaluation of possible underlying thyroid disease.

MEDICATION

Section 7 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Various medical treatments, including plasmapheresis and cytotoxic therapy, have been tried, but the efficacy of these therapies is unproven. Intralesional or topical therapy with corticosteroids is currently the only treatment that offers demonstrated efficacy. Systemic use should be avoided because of undesirable adverse effects.

Combinations reported as helpful include oral pentoxifylline and topical clobetasol propionate ointment⁵ and pentoxifylline with intralesional triamcinolone acetonide.⁶

Newer treatment regimens that are promising but require further investigation include octreotide, a somatostatin analog, and high-dose intravenous immunoglobulin (IVIG).⁷ The basis for use of octreotide stems from research of refractory PTM patients who had increased expression of insulinlike growth factor-1 receptor on up-regulated fibroblasts. Intralesional injections of octreotide have led to decreased amounts of hyaluronic acid within the lesion. Some studies report success with weekly injections, and patients have remained symptom free for up to 15 months^{8, 9}; however, others do not.¹⁰ Surgical removal is generally ill advised because scarring may worsen dermopathy; however, at least one patient with thick plaques prior to surgical shaving of the lesion and daily octreotide injections for 6 months did not have recurrence after 9 years of surveillance.¹¹

Drug Category: Corticosteroids

These agents are applied topically under an occlusive dressing, and they provide symptomatic relief in many patients. A variety of ointments, creams, and gels are available. The following are a few examples of topical preparations available (in order of decreasing potency).

Drug Name	Fluocinonide (Fluonex, Lidex)
Description	High-potency topical corticosteroid that inhibits cell proliferation; is immunosuppressive and anti-inflammatory. Use 0.05% ointment or gel. Similar potency to mometasone and fluticasone.
Adult Dose	Apply sparingly to affected areas bid and cover with occlusive dressing until lesions resolve or 4-6 wk have passed; plastic wrap may be used for occlusive dressing
Pediatric Dose	Apply as in adults
Contraindications	Documented hypersensitivity; herpes simplex infection; fungal, viral, or tubercular skin lesions
Interactions	None reported
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	May cause adverse systemic effects if used over large areas, on denuded areas, on occlusive dressings, or during prolonged treatment periods

Drug Name	Hydrocortisone (LactiCare HC, Westcort, Dermacort, DermaGel, Cortaid)
Description	An adrenocorticosteroid derivative suitable for application to skin or external mucous membranes. Has mineralocorticoid and glucocorticoid effects resulting in anti-inflammatory activity.
Adult Dose	Apply sparingly to affected areas bid
Pediatric Dose	Apply as in adults
Contraindications	Documented hypersensitivity; viral, fungal, and bacterial skin infections
Interactions	None reported
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Products may contain either tartrazine or sodium bisulfite, which may cause allergic reactions in susceptible individuals; prolonged use, application over large surface areas, and use of potent steroids and occlusive dressings may increase systemic absorption of corticosteroids and may cause Cushing syndrome, reversible HPA-axis suppression, hyperglycemia, and glycosuria

Drug Name	Triamcinolone (Kenalog)
Description	For inflammatory dermatosis responsive to steroids; decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing capillary permeability. Use 0.1% ointment.
Adult Dose	Apply thin film bid/tid until favorable response obtained
Pediatric Dose	Apply as in adults
Contraindications	Documented hypersensitivity; fungal, viral, and bacterial skin infections
Interactions	None reported
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Do not use on skin with decreased circulation; prolonged use, application over large areas, and use of potent steroids and occlusive dressings may result in systemic absorption and may cause Cushing syndrome, reversible HPA-axis suppression, hyperglycemia, and glycosuria

FOLLOW-UP

Section 8 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Complications

• PTM rarely causes significant morbidity.

Prognosis

• The prognosis is good. PTM may persist for months or years but often regresses spontaneously. About 10-26% of patients experience eventual complete remission.

Patient Education

• For excellent patient education resources, visit eMedicine's Endocrine System Center. Also, see eMedicine's patient education article Thyroid Problems.

MISCELLANEOUS

Section 9 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Special Concerns

• Most patients have underlying thyroid disease and ophthalmopathy.

ACKNOWLEDGMENTS

Section 10 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author, Purnima Sau, MD, to the development and writing of this article.

MULTIMEDIA

Section 11 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Media file 1:  Bilateral erythematous infiltrative plaques in the pretibial areas.
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Media type:  Photo

Media file 2:  Deposition of mucin in the reticular dermis (hematoxylin and eosin stain, original magnification X25).
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Media type:  Photo

Media file 3:  Blue staining of mucin with colloidal iron stain (original magnification X25).
	View Full Size Image
Media type:  Photo

REFERENCES

Section 12 of 12

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

1. Komosinska-Vassev K, Winsz-Szczotka K, Olczyk K, Kozma EM. Alterations in serum glycosaminoglycan profiles in Graves' patients. Clin Chem Lab Med. 2006;44(5):582-8. [Medline].
2. Heufelder AE, Bahn RS, Scriba PC. Analysis of T-cell antigen receptor variable region gene usage in patients with thyroid-related pretibial dermopathy. J Invest Dermatol. Sep 1995;105(3):372-8. [Medline].
3. Fatourechi V, Bartley GB, Eghbali-Fatourechi GZ, Powell CC, Ahmed DD, Garrity JA. Graves' dermopathy and acropachy are markers of severe Graves' ophthalmopathy. Thyroid. Dec 2003;13(12):1141-4. [Medline].
4. Missner SC, Ramsay EW, Houck HE, Kauffman CL. Graves' disease presenting as localized myxedema in a thigh donor graft site. J Am Acad Dermatol. Nov 1998;39(5 Pt 2):846-9. [Medline].
5. Pineda AM, Tianco EA, Tan JB, Casintahan FA, Beloso MB. Oral pentoxifylline and topical clobetasol propionate ointment in the treatment of pretibial myxoedema, with concomitant improvement of Graves' ophthalmopathy. J Eur Acad Dermatol Venereol. Nov 2007;21(10):1441-3. [Medline].
6. Engin B, Gümüsel M, Ozdemir M, Cakir M. Successful combined pentoxifylline and intralesional triamcinolone acetonide treatment of severe pretibial myxedema. Dermatol Online J. May 1 2007;13(2):16. [Medline].
7. Antonelli A, Navarranne A, Palla R, Alberti B, Saracino A, Mestre C, et al. Pretibial myxedema and high-dose intravenous immunoglobulin treatment. Thyroid. Winter 1994;4(4):399-408. [Medline].
8. Priestley GC, Aldridge RD, Sime PJ, Wilson D. Skin fibroblast activity in pretibial myxoedema and the effect of octreotide (Sandostatin) in vitro. Br J Dermatol. Jul 1994;131(1):52-6. [Medline].
9. Shinohara M, Hamasaki Y, Katayama I. Refractory pretibial myxoedema with response to intralesional insulin-like growth factor 1 antagonist (octreotide): downregulation of hyaluronic acid production by the lesional fibroblasts. Br J Dermatol. Nov 2000;143(5):1083-6. [Medline].
10. Rotman-Pikielny P, Brucker-Davis F, Turner ML, Sarlis NJ, Skarulis MC. Lack of effect of long-term octreotide therapy in severe thyroid-associated dermopathy. Thyroid. May 2003;13(5):465-70. [Medline].
11. Felton J, Derrick EK, Price ML. Successful combined surgical and octreotide treatment of severe pretibial myxoedema reviewed after 9 years. Br J Dermatol. Apr 2003;148(4):825-6. [Medline].
12. Fatourechi V, Pajouhi M, Fransway AF. Dermopathy of Graves disease (pretibial myxedema). Review of 150 cases. Medicine (Baltimore). Jan 1994;73(1):1-7. [Medline].
13. Heymann WR. Advances in the cutaneous manifestations of thyroid disease. Int J Dermatol. Sep 1997;36(9):641-5. [Medline].
14. Kriss JP. Pathogenesis and treatment of pretibial myxedema. Endocrinol Metab Clin North Am. Jun 1987;16(2):409-15. [Medline].
15. Malkinson FD, Furey N. Pretibial myxedema. Arch Dermatol. Dec 1967;96(6):737-8. [Medline].
16. Schwartz KM, Fatourechi V, Ahmed DD, Pond GR. Dermopathy of Graves' disease (pretibial myxedema): long-term outcome. J Clin Endocrinol Metab. Feb 2002;87(2):438-46. [Medline].
17. Smith TJ, Bahn RS, Gorman CA. Connective tissue, glycosaminoglycans, and diseases of the thyroid. Endocr Rev. Aug 1989;10(3):366-91. [Medline].
18. Somach SC, Helm TN, Lawlor KB, Bergfeld WF, Bass J. Pretibial mucin. Histologic patterns and clinical correlation. Arch Dermatol. Sep 1993;129(9):1152-6. [Medline].

Article Last Updated: Apr 24, 2008