Localized myxedema is an uncommon manifestation of autoimmune thyroiditis and in particular Graves' disease. It is almost always associated with Graves' ophthalmopathy (1,2,3). Although more than 91% of patients with localized myxedema have a history of thyrotoxicosis, it can occur in patients with ophthalmopathy who have never had thyrotoxicosis and also rarely in patients with chronic autoimmune thyroiditis with or without hypothyroidism (3,4,5). In a community-based epidemiologic study, 4% of patients with clinically evident ophthalmopathy had localized myxedema (6), and it occurs in 12% to 15% of patients with severe Graves' ophthalmopathy (2,4). The average age for females is 53 years and for males 54 years; patients younger than age 20 years rarely have the condition. The female-to-male ratio is 3.9:1 (3,5).
The characteristic abnormality of localized myxedema, skin thickening, usually is limited to the pretibial area. Thus, the disorder has been called pretibial myxedema. Because it can occur in other areas, however, localized myxedema, thyroid dermopathy, and dermopathy of Graves' disease are more appropriate terms. A subclinical form of the disorder can be identified by skin biopsy specimens that show deposition of glycosaminoglycans and activated fibroblasts in patients with Graves' disease without clinically evident skin changes (7,8), although no such abnormalities were seen in biopsy specimens of forearm skin from another group of patients with Graves' disease (9). Because most patients with localized myxedema have relatively severe ophthalmopathy (3,10) and high serum concentrations of thyrotropin (TSH) receptor–stimulating antibodies (11,12), localized myxedema most likely indicates more severe Graves' disease. When present, dermopathy is a marker for the existence or future development of severe ophthalmopathy and the likelihood of development of optic neuropathy, often requiring orbital decompression (10).
The lesions are characterized by an accumulation of glycosaminoglycans in the dermis and subcutaneous tissues (13,14,15,16). Although localized myxedema is uncommon, the histologic similarities between the fibroblast activation and glycosaminoglycan accumulation present in retroorbital tissue of patients with Graves' ophthalmopathy and in the dermal tissue of patients with localized myxedema suggest that insights into the pathogenesis of the latter would be helpful in the understanding and treatment of the more common and clinically important condition of ophthalmopathy (17).
The lesions of localized myxedema occur not only in the pretibial area but almost as often on the feet and toes (2,3) (Fig. 23C.1). Isolated cases of involvement of the upper extremities, shoulders, upper back, pinnae, and nose have been reported (18,19,20,21,22). When the lesions occur in unusual sites, a history of trauma to the area is often present. A patient who carried heavy objects suspended from a stick balanced across his shoulders developed localized myxedema of the shoulders (Fig. 23C.2) (19). Lesions also may develop in burn and surgical scars (Fig. 23C.3) (22) and in smallpox vaccination sites (23).
FIGURE 23C.1. Thyroid dermopathy involving the first toes.
FIGURE 23C.2. Localized myxedema involving both shoulders. The patient had carried heavy objects suspended from a stick balanced across his shoulders. (From Noppakun N, Bancheun K, Chandraprasert S. Unusual locations of localized myxedema in Graves' disease: report of three cases. Arch Dermatol 1986;122: 85, with permission.)
FIGURE 23C.3. Thyroid dermopathy (localized myxedema) in five patients. A: Nonpitting edema form in pretibial area. B: Plaque form in pretibial area. C: Nodular form in ankle and foot. D: Elephantiasic form. E: Occurrence of thyroid dermopathy in scar tissue. (From Schwartz KM, Fatourechi V, Ahmed DD, et al. Dermopathy of Graves' disease (pretibial myxedema): long-term outcome. J Clin Endocrinol Metab 2002;87:438, with permission.)
Localized myxedema commonly begins with raised waxy lesions in the pretibial area. They are usually light-colored, but may be flesh-colored or yellowish brown (2,3,24,25). Hyperpigmentation and hyperkeratosis may be present (2,3), as may hyperhidrosis (26,27). The latter may be caused by stimulation of sympathetic fibers by the surrounding mucin deposition (27). The lesions may be indurated and the hair follicles prominent, so that the lesions have an orange peel (peau d'orange) or pigskin appearance and texture. The lesions are usually asymptomatic and of only cosmetic importance, but they can impair function (for example, causing difficulty wearing shoes) and rarely may be painful or pruritic. Nerve entrapment and reversible footdrop were reported in one patient (28). The lesions usually are aggravated by trauma, and exuberant recurrence may ensue if they are surgically excised (29).
Localized myxedema may appear in several distinct clinical forms (Fig. 23C.3): diffuse, nonpitting edema, the most common form (3,5); raised plaque lesions on a background of nonpitting edema; sharply circumscribed tubular or nodular lesions; and the rare elephantiasic form, consisting of nodular lesions mixed with lymphedema. Rarely, the lesions are polypoid or fungating. They usually do not ulcerate.
In a review of 178 consecutive patients with pretibial myxedema, 4 patients had no evidence of Graves' ophthalmopathy (10). Similar patients and patients with localized myxedema as the presenting symptom have been reported (30,31,32,33). The most common time of onset of ophthalmopathy was 0 to 12 months after diagnosis of thyrotoxicosis. For localized myxedema, the onset was 12 to 24 months after the diagnosis of thyrotoxicosis, but 12% of the patients developed localized myxedema 4 to 12 years after the diagnosis of thyrotoxicosis (Fig. 23C.4) (3).
FIGURE 23C.4. Onset of localized myxedema in relation to time of diagnosis of thyrotoxicosis in 136 patients. Cross-hatched bar : Onset of localized myxedema within 3 months of diagnosis of thyrotoxicosis. (From Fatourechi V, Pajouhi M, Fransway AF. Dermopathy of Graves disease (pretibial myxedema): review of 150 cases. Medicine (Baltimore) 1994; 73:1, with permission.)
BIOCHEMICAL NATURE AND HISTOPATHOLOGY
Light microscopy of biopsy specimens of lesions of localized myxedema shows large amounts of glycosaminoglycans (a mucin-like substance) in the reticular part of the dermis, but not usually in the papillary dermis. A few lymphocytes may be seen in the perivascular spaces, but extensive infiltration with lymphocytes is unusual. The number of mast cells is moderately increased. Fragmentation and fraying of collagen fibers are seen when the tissue is stained with hematoxylin and eosin (Fig. 23C.5). Mucinous material with and without connective tissue separation is seen when the tissue is stained with Alcian blue and the periodic acid–Schiff stain. Collagen fibers are relatively reduced, and there is marked edema. Hyperkeratosis, acanthosis, and papillomatosis occasionally are seen (34).
FIGURE 23C.5. Photomicrograph of skin biopsy specimen from patient with localized myxedema showing separation and fraying of connective tissue fibers and edema. The epidermis (top) is normal. (Hematoxylin and eosin, 340× original magnification.) (From Fatourechi V, Pajouhi M, Fransway AF. Dermopathy of Graves disease (pretibial myxedema): review of 150 cases. Medicine (Baltimore) 1994;73:1, with permission.)
Ultrastructural studies show dilated endoplasmic reticulum in fibroblasts, indicative of active glycosaminoglycan synthesis and secretion. The epidermis is usually normal except for widened intercellular spaces. Amorphous electron-dense material is seen close to the surface of the fibroblasts.
Overall, the structural changes of localized myxedema can be distinguished from hypothyroid myxedema by hyperkeratosis, a greater abundance of mucin, and mononuclear cell infiltration (34,35,36,37). The characteristics that distinguish localized myxedema from mucinosis associated with stasis dermatitis include preservation of a zone of normal-appearing collagen in the superficial papillary dermis, mucin deposition in the reticular dermis, lack of angioplasia, and relative absence of hemosiderin (37).
Quantitative lymphoscintigraphy and fluorescence microlymphography have shown that the deposited mucin promotes dermal edema by retention of fluid, which in turn causes compression or occlusion of small peripheral lymphatics and lymphedema (38). In one study, immunofluorescent staining of specimens from areas of localized myxedema showed evidence of immunoglobulin (Ig) A deposition in 75% of patients, IgG in 57%, and complement in 43% (39).
Graves' disease is a multigenic condition that develops as a result of susceptibility genes and environmental factors (40). However, no unique susceptibility genes specific to localized myxedema or Graves' ophthalmopathy have been identified (41). Graves' hyperthyroidism results from direct stimulation of thyroid follicular cells by TSH receptor–stimulating antibodies (see section on pathogenesis in this chapter). All patients with localized myxedema have high serum concentrations of TSH receptor–stimulating antibodies (2,5,11,12,42,43,44). Polymerase chain reaction techniques have shown RNA encoding the extracellular domain of the TSH receptor in cultured orbital, abdominal skin, and peripheral skin fibroblasts from patients with ophthalmopathy or localized myxedema as well as in skin from normal subjects (45,46). Pretibial myxedema tissue and normal skin express TSH receptor protein (46). TSH receptor immunoreactivity and transcripts have been identified in fibroblast cultures of orbital and pretibial myxedema and normal skin (47,48,49). Not all studies have shown TSH receptor immunoreactivity in normal skin. In one study, TSH receptor immunoreactivity was demonstrated in pretibial hypodermis tissues of two patients with thyroid dermopathy but not in pretibial tissues of two control subjects. The immunoreactivity occurred in the cells resembling fibroblasts. It is not clear yet if this immunoreactivity is related to the receptor itself or to a crossreacting protein (50).
These results implicate TSH receptor–stimulating antibodies and TSH receptors in the pathogenesis of localized myxedema.
The serum of patients with localized myxedema may stimulate glycosaminoglycan production by fibroblasts in vitro (51,52). In other studies, however, serum IgG from patients with localized myxedema increased the synthesis of glycosaminoglycans, protein, and DNA by cultured FRTL-5 thyroid cells, but these IgGs and those of normal subjects were equally active in stimulating dermal fibroblasts (53).
If TSH receptors are expressed in normal skin, as shown by Rapoport et al (46), then how is it that the pretibial area is most commonly involved? There is a mechanical contribution to pathogenesis. Skin grafted to a lower extremity from areas that are not usually involved develops localized myxedema at the recipient site (46,54,55). Localized myxedema develops in areas exposed to repeated trauma (56), at the site of immunization (23), and after episodes of prolonged standing. Dependent edema because of a lower return of lymphatic fluid might reduce the clearance and increase the half-life of disease-related cytokines and chemokines within the affected tissue (46,57). This pooling of immune mediators increases the disease-producing effects. There is some evidence that trauma and injury may lead to activation of T cells and initiation of an antigen-specific response (58), in this case fibroblast activation and production of glycosaminoglycans.
Fibroblast activation in localized myxedema may occur indirectly, through sensitized T lymphocytes. T cells sensitized to antigens shared by thyroid follicular cells and fibroblasts, one candidate antigen being a portion of the TSH receptor, could infiltrate dermal tissue and release cytokines, including interleukin 1α and transforming growth factor-β, which then stimulate synthesis of glycosaminoglycans and activate immunomodulatory proteins in dermal fibroblasts (17,59,60,61). There is evidence of accumulation of thyroid-specific T cells in the retroorbital and pretibial tissues in patients with Graves' ophthalmopathy and localized myxedema, respectively, and these T cells express a limited number of genes for T-cell antigen receptors, as is characteristic of antigen-sensitized T cells (62). Thus, in both extrathyroidal manifestations of Graves' disease, similar antigens may be responsible for recruitment and expansion of T cells.
Whatever the proximate cause of increased dermal production of glycosaminoglycans, the local accumulation of these substances leads to accumulation of fluid and expansion of dermal connective tissue and thus the characteristic skin changes (17). Secondarily, obstruction of the lymphatic microcirculation may aggravate the immune process and the lesions (38,46).
Some evidence for differences in the regulation of synthesis of glycosaminoglycans by fibroblasts from various anatomic sites has been presented (63,64), but the mechanical theory seems to apply better to localization of thyroid dermopathy in the lower extremity (65).
In summary, with the demonstration of TSH receptor transcripts and protein in fibroblasts, recognition of the role of various cytokines in stimulation of fibroblast activity, demonstration of high concentrations of TSH receptor–stimulating antibodies in the serum of patients with localized myxedema, and elucidation of the role of mechanical factors contributing to the pathogenesis of localized myxedema, the reasons for its (usual) location on the pretibial region have become better recognized.
The diagnosis of localized myxedema is usually obvious because of the typical pretibial lesions, the presence of Graves' ophthalmopathy, and a history of thyrotoxicosis. Biopsy may be necessary in some cases, however (3,5,37). Although dermopathy can be the initial presentation of Graves' disease in rare cases (10,30,31,32,33), the diagnosis of Graves' disease should be considered doubtful if Graves' ophthalmopathy is not present.
Skin changes somewhat similar to those of localized myxedema can occur in patients with simple edema as a result of fluid retention or venous insufficiency (66), generalized myxedema, chronic or lichenified dermatitis, hypertrophic lichen planus, and the urticarial phases of certain blistering eruptions, such as bullous pemphigoid. Cutaneous mucinoses, such as lichen myxedematosus (papular mucinosis), reticular erythematous mucinosis, and follicular mucinosis, are relatively rare dermatologic conditions in which accumulation of mucin in the dermis is a prominent feature (2,67). Most of these mucinoses involve the upper extremities, and thyroid dysfunction and ophthalmopathy are absent. Mucin deposition in recently recognized nephrogenic fibrosing dermopathy has some similarities with thyroid dermopathy, but the clinical picture and manifestations are different (68).
Most patients require no therapy because the lesions are usually asymptomatic and not particularly unsightly, or they can be covered by clothing to the patient's satisfaction. Also, the lesions usually do not progress and may partially or completely regress with time (3). The natural course and long-term outcome of treated and untreated localized myxedema in a series of 178 patients were reported recently (5). Forty-six percent of these patients required no therapy for dermopathy.
When cosmetic concerns, functional impairment, or local discomfort necessitates treatment, topical application of a corticosteroid is the preferred therapy (5,69,70). The likelihood of therapeutic success decreases, however, as the extent of the lesions increases. The glucocorticoid is applied directly to the lesions, which for best results should be covered with a plastic film. In a group of 11 patients treated nightly or every other night by application of 0.2% midpotency corticosteroid fluocinolone acetonide cream to the lesions covered with occlusive plastic film dressings, all had substantial improvement (69). The improvement persisted after the frequency of treatment was gradually reduced to 2 to 4 times a month. A high-potency corticosteroid, such as clobetasol propionate, may also be used (71). Absorption of topical corticosteroid may be enhanced by hydrocolloid or plastic wrap occlusive dressing (71).
A trial of 4 to 10 weeks, followed by intermittent maintenance therapy (3,5), is usually needed. An occlusive dressing is kept in place for 12 hours. In the case of prolonged local therapy, skin should be watched for signs of adverse effects from the topical corticosteroid, such as atrophy, telangiectasia, and ecchymosis. Because of fluid accumulation, use of compressive bandages or an elastic stocking during the day offers additional benefit, especially in patients with the elephantiasic form of the disorder. Patients may require many months of therapy, the goal of which is to limit the degree of disfigurement, improve function, and avoid tissue breakdown and compressive complications. For patients with severe pretibial myxedema, such as the elephantiasic form, treatment similar to that used for patients with lymphedema may be required. In a recent report, complete decompressive physiotherapy resulted in sustained improvement in a patient with elephantiasic pretibial myxedema (72). This treatment, given by a certified physiotherapist, is a combination of manual lymphatic drainage and gentle massage, followed by the application of multilayered low-stretch bandaging, exercise, and scrupulous skin care (73,74). Intradermal injections of a glucocorticoid (75) and hyaluronidase have been used, but these are not recommended because their efficacy is limited and they may cause irregular, lumpy skin. Local excision of pseudotumorous localized myxedema of the dorsum of the foot resistant to medical therapy has been reported, with apparent success (76). Surgical excision of nodules and skin grafting should be avoided, however, because of the possibility of exuberant recurrence of localized myxedema at the site of a surgical scar (29).
When ophthalmopathy overshadows the localized myxedema, as is often the case, systemic corticosteroid or other immunosuppressive therapy for the former may cause regression of the skin lesions (3,77). These drugs are rarely, if ever, indicated for localized myxedema alone. Other treatments that have been reported to be beneficial in a few patients include plasmapheresis, the somatostatin analogue octreotide, and high-dose intravenous immunoglobulin (78,79,80,81,82). The rationale for a beneficial effect of octreotide is the presence of somatostatin receptors in lymphocytes (83). However, a recent report showed no benefit from octreotide therapy in four patients with severe pretibial myxedema (84). Lack of benefit from high-dose intravenous immunoglobulin in a patient with elephantiasic pretibial myxedema also was reported recently (85). Evaluation of the effects of these therapies is difficult because of the small number of patients reported, short follow-up periods, and lack of controlled studies.
The long-term outcome for patients with localized myxedema varies. About half of patients with mild disease who receive no therapy have complete remission in 17 years. Severely affected patients who receive local corticosteroid and other therapies fare no better than patients with milder cases who receive no specific therapy. After 25 years of follow-up, 70% of untreated patients with milder myxedema and 58% of patients with severe forms who received local therapy achieved either partial or complete remission (Figs. 23C.6 and 23C.7) (5). Long-term remission appears to depend on the severity of initial disease rather than on the effect of therapy. Patients with milder cases without therapy have a better chance of complete remission than do patients with severe cases despite therapy. The present therapeutic modalities are palliative at best, and better and safer means of immune modulation are needed to treat this extrathyroidal manifestation of autoimmune thyroid disease.
FIGURE 23C.6. Percentage of patients who had complete remission according to treatment group (Kaplan-Meier method). (From Schwartz KM, Fatourechi V, Ahmed DD, et al. Dermopathy of Graves' disease (pretibial myxedema): long-term outcome. J Clin Endocrinol Metab 2002;87:438, with permission.)
FIGURE 23C.7. Combined percentage of patients who had partial or complete remission according to treatment group (Kaplan-Meier method). (From Schwartz KM, Fatourechi V, Ahmed DD, et al. Dermopathy of Graves' disease (pretibial myxedema): long-term outcome. J Clin Endocrinol Metab 2002;87:438, with permission.)
Thyroid acropachy is the least common manifestation of Graves' disease. Similar to dermopathy, acropachy is a marker of a severe autoimmune process and a marker of severity of associated ophthalmopathy (10). A recently reported series of patients with localized myxedema indicated that 22% of patients had thyroid acropachy (86). The most common form of acropachy is clubbing of the fingers and toes. Less commonly, swelling of digits and toes and periosteal reaction of distal extremity bones are seen. Previous reports had suggested a female-to-male ratio of 1:1 in this condition (87). However, in a recent report of 40 patients with acropachy, the female-to-male ratio was 3.4:1 (86). Acropachy almost always occurs in association with ophthalmopathy and localized myxedema, although an isolated case without either has been reported (88).
Typically, the process involves soft-tissue swelling of the hands and feet, usually in association with clubbing of the fingers and toes (Figs. 23C.8 and 23C.9). The skin is commonly pigmented and hyperkeratotic. Joints are not involved in thyroid acropachy, and the local warmth and increased blood flow characteristic of pulmonary osteoarthropathy are usually absent. The upper and lower extremities are equally involved (87,89). The process may be asymmetric, and involvement of a single digit has been reported (90). Acropachy is often painless, but some patients have pain and loss of function because of extreme swelling (86,91).
FIGURE 23C.8. A, B: Photographs of the hands in two patients with thyroid acropachy, showing clubbing of the fingertips and soft tissue swelling. B: Note the asymmetric involvement of the fingers.
FIGURE 23C.9. Radiograph of the toes in a patient with thyroid acropachy. Note soft-tissue swelling (arrowhead) and mild, fluffy periosteal reaction of the first toe and distal end of the first metatarsal (arrows). (From Fatourechi V, Ahmed DD, Schwartz KM. Thyroid acropachy: report of 40 patients treated at a single institution in a 26-year period. J Clin Endocrinol Metab 2002;87:5435, with permission.)
It is unusual for acropachy to occur before thyroid dysfunction, and in general the developmental chronology is thyroid dysfunction, ophthalmopathy, localized myxedema, and, lastly, acropachy (87,89). Although it can occur as late as 40 years after the onset of thyrotoxicosis, the median interval between diagnosis of the latter and acropachy is 2 to 3 years (87).
Radiography shows fusiform soft-tissue swelling of the digits and subperiosteal bone formation, usually involving the metacarpals, the proximal and middle phalanges of the fingers, and the metatarsal and proximal phalanges of the toes. The subperiosteal reaction is unusual in the long bones of the forearms or the legs, in contrast to pulmonary osteoarthropathy. Only one of 40 patients who had severe extremity pain had a periosteal reaction in the femur (Fig. 23C.10) (86). The periosteal new bone formation is most marked in the midportion of the diaphysis, and it characteristically appears spiculated, leathery, frothy, lacy, or bubbled (Fig. 23C.11) (87,89), quite different from the laminal periosteal proliferation of classic pulmonary osteoarthropathy. In the earlier stages of acropachy, when bone radiographs may appear normal, technetium (99mTc)-pyrophosphate bone scans show focal accumulation of the radionuclide in the affected areas (92). Most patients have a combination of skin changes, clubbing, bone changes, and radiographic changes, but patients in whom radiographic findings were the only manifestation of acropachy have been reported (89,93). Skin pathologic features are similar to those of localized myxedema (87,93). Little is known about the pathologic characteristics and pathogenesis of thyroid acropachy. One study of bone histology revealed nodular fibrosis of the periosteal area, subperiosteal bone formation, and fibrosis of the marrow space (94). One can speculate that the process involves autoimmune activation of periosteal fibroblasts.
FIGURE 23C.10. Imaging of a patient with thyroid acropachy and marked lower extremity pain. A: Radiograph of the left femur is normal. B: Technetium-99m bone scan shows irregular increased uptake in the cortical area of both femurs (arrows) and tibae. (From Fatourechi V, Ahmed DD, Schwartz KM. Thyroid acropachy: report of 40 patients treated at a single institution in a 26-year period. J Clin Endocrinol Metab 2002;87:5435, with permission.)
FIGURE 23C.11. Radiograph of fingers of a patient with thyroid acropachy. Note the asymmetric frothy appearance of subperiosteal bone formation in the midportion of the proximal phalanx on the left.
Similar to patients with dermopathy and severe ophthalmopathy, a high percentage of patients with acropachy are current cigarette smokers. In a recent report, 81% of women and 75% of men were current smokers, respectively 3.7 and 2.6 times higher than the rate for the US general population (86). The association of acropachy with tobacco use, is also seen in patients with severe ophthalmopathy and dermopathy and is believed not to be related to pulmonary complications of tobacco use (86).
No specific treatment for thyroid acropachy is available. Systemic immunosuppressive therapy and local corticosteroid therapy are usually directed at associated ophthalmopathy and dermopathy. In most patients, clubbing is the only manifestation of acropachy, and it is asymptomatic and requires no specific therapy. After long-term follow-up, remission of acropachy may occur. It is not clear from the reported cases how often remission of clubbing occurs. Long-term follow-up has shown that dermopathy and ophthalmopathy, not acropachy, are common sources of functional problems and the patient's chief complaints (86).
1. Beierwaltes WH. Clinical correlation of pretibial myxedema with malignant exophthalmos. Ann Intern Med 1954;40:968–984.
2. Kriss JP. Pathogenesis and treatment of pretibial myxedema. Endocrinol Metab Clin North Am 1987;16:409–415.
3. Fatourechi V, Pajouhi M, Fransway AF. Dermopathy of Graves disease (pretibial myxedema): review of 150 cases. Medicine (Baltimore) 1994;73:1–7.
4. Fatourechi V, Garrity JA, Bartley GB, et al. Orbital decompression in Graves' ophthalmopathy associated with pretibial myxedema. J Endocrinol Invest 1993;16:433–437.
5. Schwartz KM, Fatourechi V, Ahmed DD, et al. Dermopathy of Graves' disease (pretibial myxedema): long-term outcome. J Clin Endocrinol Metab 2002;87:438–446.
6. Bartley GB, Fatourechi V, Kadrmas EF, et al. Clinical features of Graves' ophthalmopathy in an incidence cohort. Am J Ophthalmol 1996;121:284–290.
7. Wortsman J, Dietrich J, Traycoff RB, et al. Preradial myxedema in thyroid disease. Arch Dermatol 1981;117:635–638.
8. Salvi M, De Chiara F, Gardini E, et al. Echographic diagnosis of pretibial myxedema in patients with autoimmune thyroid disease. Eur J Endocrinol 1994;131:113–119.
9. Peacey SR, Flemming L, Messenger A, et al. Is Graves' dermopathy a generalized disorder? Thyroid 1996;6:41–45.
10. Fatourechi V, Bartley GB, Eghbali-Fatourechi GZ, et al. Graves' dermopathy and acropachy are markers of severe Graves' ophthalmopathy. Thyroid 2003;13:1141–1144.
11. Morris JC III, Hay ID, Nelson RE, et al. Clinical utility of thyrotropin-receptor antibody assays: comparison of radioreceptor and bioassay methods. Mayo Clin Proc 1988;63:707–717.
12. Schermer DR, Roenigk HH Jr, Schumacher OP, et al. Relationship of long-acting thyroid stimulator to pretibial myxedema. Arch Dermatol 1970;102:62–67.
13. Watson EM, Pearce RH. The mucopolysaccharide content of the skin in localized (pretibial) myxedema. Am J Clin Pathol 1947;17:507–512.
14. Sisson JC. Hyaluronic acid in localized myxedema. J Clin Endocrinol Metab 1968;28:433–436.
15. Smith TJ, Bahn RS, Gorman CA. Connective tissue, glycosaminoglycans, and diseases of the thyroid. Endocr Rev 1989;10: 366–391.
16. Hanke CW, Bergfeld WF, Guirguis MN, et al. Hyaluronic acid synthesis in fibroblasts of pretibial myxedema. Cleve Clin Q 1983;50:129–132.
17. Bahn RS, Heufelder AE. Pathogenesis of Graves' ophthalmopathy. N Engl J Med 1993;329:1468–1475.
18. Cohen BD, Benua RS, Rawson RW. Localized myxedema involving the upper extremities. Arch Intern Med 1963;111:641–646.
19. Noppakun N, Bancheun K, Chandraprasert S. Unusual locations of localized myxedema in Graves' disease: report of three cases. Arch Dermatol 1986;122:85–88.
20. Akasu F, Takazawa K, Akasu R, et al. Localized myxedema on the nasal dorsum in a patient with Graves' disease: report of a case. J Endocrinol Invest 1989;12:717–721.
21. Slater DN. Cervical nodular localized myxoedema in a thyroidectomy scar: light and electron microscopy and histochemical findings. Clin Exp Dermatol 1987;12:216–219.
22. Wright AL, Buxton PK, Menzies D. Pretibial myxedema localized to scar tissue. Int J Dermatol 1990;29:54–55.
23. Pujol RM, Monmany J, Bague S, et al. Graves' disease presenting as localized myxoedematous infiltration in a smallpox vaccination scar. Clin Exp Dermatol 2000;25:132–134.
24. Frisch DR, Roth I. Pretibial myxedema: a review of the literature and case report. J Am Podiatr Med Assoc 1985;75:147–152.
25. Truhan AP. Pretibial myxedema. Am Fam Physician 1985;31: 135–138.
26. Gitter DG, Sato K. Localized hyperhidrosis in pretibial myxedema. J Am Acad Dermatol 1990;23:250–254.
27. Kato N, Ueno H, Matsubara M. A case report of EMO syndrome showing localized hyperhidrosis in pretibial myxedema. J Dermatol 1991;18:598–604.
28. Siegler M, Refetoff S. Pretibial myxedema: a reversible cause of foot drop due to entrapment of the peroneal nerve. N Engl J Med 1976;294:1383–1384.
29. Chremos AN. Relentless localized myxedema, with exophthalmos, clubbing of the fingers and hypertrophic osteoarthropathy: observations on an unusual case. Am J Med 1965;38: 954–961.
30. Georgala S, Katoulis AC, Georgala C, et al. Pretibial myxedema as the initial manifestation of Graves' disease. J Eur Acad Dermatol Venereol 2002;16:380–383.
31. Cho S, Choi JH, Sung KJ, et al. Graves' disease presenting as elephantiasic pretibial myxedema and nodules of the hands. Int J Dermatol 2001;40:276–277.
32. Jabbour SA, Miller JL. Endocrinopathies and the skin. Int J Dermatol 2000;39:88–99.
33. Omohundro C, Dijkstra JW, Camisa D, et al. Early onset pretibial myxedema in the absence of ophthalmopathy: a morphologic evolution. Cutis 1996;58:211–214.
34. Konrad K, Brenner W, Pehamberger H. Ultrastructural and immunological findings in Graves' disease with pretibial myxedema. J Cutan Pathol 1980;7:99–108.
35. Kobayasi T, Danielsen L, Asboe-Hansen G. Ultrastructure of localized myxedema. Acta Derm Venereol 1976;56:173–185.
36. Ishii M, Nakagawa K, Hamada T. An ultrastructural study of pretibial myxedema utilizing improved ruthenium red stain. J Cutan Pathol 1984;11:125–131.
37. Somach SC, Helm TN, Lawlor KB, et al. Pretibial mucin: histologic patterns and clinical correlation. Arch Dermatol 1993;129: 1152–1156.
38. Bull RH, Coburn PR, Mortimer PS. Pretibial myxoedema: a manifestation of lymphoedema? Lancet 1993;341:403–404.
39. Antonelli A, Palla R, Casarosa L, et al. IgG, IgA and C3 deposits in the extra-thyroidal manifestations of autoimmune Graves' disease: their in vitro solubilization by intravenous immunoglobulin. Clin Exp Rheumatol 1996;14[Suppl 15]:S31–S35.
40. Tomer Y, Barbesino G, Greenberg DA, et al. Mapping the major susceptibility loci for familial Graves' and Hashimoto's diseases: evidence for genetic heterogeneity and gene interactions. J Clin Endocrinol Metab 1999;84:4656–4664.
41. Villanueva R, Inzerillo AM, Tomer Y, et al. Limited genetic susceptibility to severe Graves' ophthalmopathy: no role for CTLA-4 but evidence for an environmental etiology. Thyroid 2000;10:791–798.
42. Kriss JP, Pleshakov V, Chien JR. Isolation and identification of the long-acting thyroid stimulator and its relation to hyperthyroidism and circumscribed pretibial myxedema. J Clin Endocrinol Metab 1964;24:1005–1028.
43. Chang TC, Wu SL, Hsiao YL, et al. TSH and TSH receptor antibody-binding sites in fibroblasts of pretibial myxedema are related to the extracellular domain of entire TSH receptor. Clin Immunol Immunopathol 1994;71:113–120.
44. Tao TW, Leu SL, Kriss JP. Biological activity of autoantibodies associated with Graves' dermopathy. J Clin Endocrinol Metab 1989;69:90–99.
45. Heufelder AE, Dutton CM, Sarkar G, et al. Detection of TSH receptor RNA in cultured fibroblasts from patients with Graves' ophthalmopathy and pretibial dermopathy. Thyroid 1993;3: 297–300.
46. Rapoport B, Alsabeh R, Aftergood D, et al. Elephantiasic pretibial myxedema: insight into a hypothesis regarding the pathogenesis of the extrathyroidal manifestations of Graves' disease. Thyroid 2000;10:685–692.
47. Spitzweg C, Joba W, Hunt N, et al. Analysis of human thyrotropin receptor gene expression and immunoreactivity in human orbital tissue. Eur J Endocrinol 1997;136:599–607.
48. Ludgate M, Crisp M, Lane C, et al. The thyrotropin receptor in thyroid eye disease. Thyroid 1998;8:411–413.
49. Wu SL, Chang TC, Chang TJ, et al. Cloning and sequencing of complete thyrotropin receptor transcripts in pretibial fibroblast culture cells. J Endocrinol Invest 1996;19:365–370.
50. Daumerie C, Ludgate M, Costagliola S, et al. Evidence for thyrotropin receptor immunoreactivity in pretibial connective tissue from patients with thyroid-associated dermopathy. Eur J Endocrinol 2002;146:35–38.
51. Cheung HS, Nicoloff JT, Kamiel MB, et al. Stimulation of fibroblast biosynthetic activity by serum of patients with pretibial myxedema. J Invest Dermatol 1978;71:12–17.
52. Shishiba Y, Imai Y, Odajima R, et al. Immunoglobulin G of patients with circumscribed pretibial myxedema of Graves' disease stimulates proteoglycan synthesis in human skin fibroblasts in culture. Acta Endocrinol (Copenh) 1992;127:44–51.
53. Metcalfe RA, Davies R, Weetman AP. Analysis of fibroblast-stimulating activity in IgG from patients with Graves' dermopathy. Thyroid 1993;3:207–212.
54. Schwartz KM, Ahmed DD, Ahmed I, et al. Development of localized myxedema in a skin graft. Int J Dermatol 2002;41:401–403.
55. Missner SC, Ramsay EW, Houck HE, et al. Graves' disease presenting as localized myxedema in a thigh donor graft site. J Am Acad Dermatol 1998;39:846–849.
56. Westphal SA. Extrathyroidal manifestations of Graves' disease: pretibial myxedema and thyroid acropachy. Endocr Pract 1995;1: 116–122.
57. Bahn RS. Clinical review 157: pathophysiology of Graves' ophthalmopathy: the cycle of disease. J Clin Endocrinol Metab 2003;88:1939–1946.
58. Matzinger P. An innate sense of danger. Semin Immunol 1998;10:399–415.
59. Umetsu DT, Katzen D, Jabara HH, et al. Antigen presentation by human dermal fibroblasts: activation of resting T lymphocytes. J Immunol 1986;136:440–445.
60. Heufelder AE, Wenzel BE, Gorman CA, et al. Detection, cellular localization, and modulation of heat shock proteins in cultured fibroblasts from patients with extrathyroidal manifestations of Graves' disease. J Clin Endocrinol Metab 1991;73: 739–745.
61. Korducki JM, Loftus SJ, Bahn RS. Stimulation of glycosaminoglycan production in cultured human retroocular fibroblasts. Invest Ophthalmol Vis Sci 1992;33:2037–2042.
62. Heufelder AE. T-cell restriction in thyroid eye disease. Thyroid 1998;8:419–422.
63. 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.
64. Shishiba Y, Tanaka T, Ozawa Y, et al. Chemical characterization of high buoyant density proteoglycan accumulated in the affected skin of pretibial myxedema of Graves' disease. Endocrinol Jpn 1986;33:395–403.
65. Heufelder AE, Smith TJ, Gorman CA, et al. Increased induction of HLA-DR by interferon-gamma in cultured fibroblasts derived from patients with Graves' ophthalmopathy and pretibial dermopathy. J Clin Endocrinol Metab 1991;73:307–313.
66. Kim KJ, Kim HH, Chang SE, et al. A case of pretibial mucinosis without thyroid disease. J Dermatol 2002;29:383–385.
67. Truhan AP, Roenigk HH Jr. The cutaneous mucinoses. J Am Acad Dermatol 1986;14:1–18.
68. Mackay-Wiggan JM, Cohen DJ, Hardy MA, et al. Nephrogenic fibrosing dermopathy (scleromyxedema-like illness of renal disease). J Am Acad Dermatol 2003;48:55–60.
69. Kriss JP, Pleshakov V, Rosenblum A, et al. Therapy with occlusive dressings of pretibial myxedema with fluocinolone acetonide. J Clin Endocrinol Metab 1967;27:595–604.
70. Benoit FL, Greenspan FS. Corticoid therapy for pretibial myxedema: observations on the long-acting thyroid stimulator. Ann Intern Med 1967;66:711–720.
71. Volden G. Successful treatment of chronic skin diseases with clobetasol propionate and a hydrocolloid occlusive dressing. Acta Derm Venereol 1992;72:69–71.
72. Susser WS, Heermans AG, Chapman MS, et al. Elephantiasic pretibial myxedema: a novel treatment for an uncommon disorder. J Am Acad Dermatol 2002;46:723–726.
73. Connell M. Complete decongestive physiotherapy. Innov Breast Cancer Care 1998;3:93–96.
74. Smith JK. Oncology nursing in lymphedema management. Innov Breast Cancer Care 1998: 3:82–87.
75. Lang PG, Sisson JC, Lynch PJ. Intralesional triamcinolone therapy for pretibial myxedema. Arch Dermatol 1975;111:197–202.
76. Pingsmann A, Ockenfels HM, Patsalis T. Surgical excision of pseudotumorous pretibial myxedema. Foot Ankle Int 1996;17: 107–110.
77. Koshiyama H, Mori S, Fujiwara K, et al. Successful treatment of hypothyroid Graves' disease with a combination of levothyroxine replacement, intravenous high-dose steroid and irradiation to the orbit. Intern Med 1993;32:421–423.
78. Kuzuya N, DeGroot LJ. Effect of plasmapheresis and steroid treatment on thyrotropin binding inhibitory immunoglobulins in a patient with exophthalmos and a patient with pretibial myxedema. J Endocrinol Invest 1982;5:373–378.
79. Noppen M, Velkeniers B, Steenssens L, et al. Beneficial effects of plasmapheresis followed by immunosuppressive therapy in pretibial myxedema. Acta Clin Belg 1988;43:381–383.
80. Chang TC, Kao SC, Huang KM. Octreotide and Graves' ophthalmopathy and pretibial myxoedema. BMJ 1992;304:158.
81. Priestley GC, Aldridge RD, Sime PJ, et al. Skin fibroblast activity in pretibial myxoedema and the effect of octreotide (Sandostatin) in vitro. Br J Dermatol 1994;131:52–56.
82. Antonelli A, Navarranne A, Palla R, et al. Pretibial myxedema and high-dose intravenous immunoglobulin treatment. Thyroid 1994;4:399–408.
83. Colao A, Lastoria S, Ferone D, et al. Orbital scintigraphy with [111In-diethylenetriamine pentaacetic acid-D-phe1]-octreotide predicts the clinical response to corticosteroid therapy in patients with Graves' ophthalmopathy. J Clin Endocrinol Metab 1998;83:3790–3794.
84. Rotman-Pikielny P, Brucker-Davis F, Turner ML, et al. Lack of effect of long-term octreotide therapy in severe thyroid-associated dermopathy. Thyroid 2003;13:465–470.
85. Terheyden P, Kahaly GJ, Zillikens D, et al. Lack of response of elephantiasic pretibial myxoedema to treatment with high-dose intravenous immunoglobulins. Clin Exp Dermatol 2003;28: 224–226.
86. Fatourechi V, Ahmed DD, Schwartz KM. Thyroid acropachy: report of 40 patients treated at a single institution in a 26-year period. J Clin Endocrinol Metab 2002;87:5435–5441.
87. Winkler A, Wilson D. Thyroid acropachy: case report and literature review. Mol Med 1985;82:756–761.
88. Goette DK. Thyroid acropachy. Arch Dermatol 1980;116:205–206.
89. Kinsella RA Jr, Back DK. Thyroid acropachy. Med Clin North Am 1968;52:393–398.
90. Chapman ME, Beggs I, Wu PS. Case report: thyroid acropachy in a single digit. Clin Radiol 1993;47:58–59.
91. Rothschild BM, Yoon BH. Thyroid acropachy complicated by lymphatic obstruction. Arthritis Rheum 1982;25:588–590.
92. Seigel RS, Thrall JH, Sisson JC. 99mTc-pyrophosphate scan and radiographic correlation in thyroid acropachy: case report. J Nucl Med 1976;17:791–793.
93. Parker LN, Wu SY, Lai MK, et al. The early diagnosis of atypical thyroid acropachy. Arch Intern Med 1982;142:1749–1751.
94. King LR, Braunstein H, Chambers D, et al. A case study of peculiar soft-tissue and bony changes in association with thyroid disease. J Clin Endocrinol Metab 1959;19:1323–1330.