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Pretibial myxedema, more generally thyroid dermopathy, results from mucopolysaccharide accumulation in the dermis, typically between the knee and dorsal foot. Thyroid dermopathy presents in Graves disease, but can occur in Hashimoto thyroiditis, primary hypothyroidism, and euthyroid patients. Treatment of thyroid eye disease with teprotumumab is established in the literature, with few case reports also showing improvement in pretibial myxedema. Reported is a 76-year-old man with thyroid eye disease and pretibial myxedema treated with teprotumumab; improvement was demonstrated in both conditions. He developed "muffled" hearing as an adverse effect, a complication not widely published in the dermatology literature. At 18 months post-treatment, his symptoms are stable without recurrence, but hypoacusis persists. Given the long-term efficacy and side-effects, dermatologists should recognize the potential benefits and risks of using teprotumumab for thyroid dermopathy. A baseline audiogram may be considered prior to therapy. Additionally, longitudinal data is needed to document the benefits and risks of this novel therapy.

Introduction: Pretibial myxedema (PTM) is a rare manifestation of Graves' disease. There is paucity of data regarding long-term follow-up and response to treatment in PTM., Materials and Methods: Retrospective study wherein 30 patients of PTM presenting during 2001-2011 attending dermatology and endocrinology outpatient departments were analyzed., Results: Among 30 patients with PTM, 12 were males and 18 females with a ratio of 1 : 1.5 males/females. Four morphological forms were identified: plaques (18 patients), diffuse non-pitting edema of both lower legs (five), nodules (five), and elephantiasis lesions (two). Eighty percent were diagnosed with hyperthyroidism before the development of dermopathy. Twenty-six patients presented with ophthalmopathy. Fourteen patients with plaque had an excellent response to topical clobetasol propionate ointment and attained complete resolution by 3.6 years. Out of 16 patients treated with combination therapy, which included nine treated with topical corticosteroids/intralesional triamcinolone and seven treated with oral, intralesional, and topical corticosteroids, nine attained complete resolution in the lesions by 3.4 years, and none relapsed anytime during four years of post-treatment follow-up. However, the remaining patients (elephantiasis and diffuse forms) failed to achieve complete resolution., Conclusions: Plaques and nodules are common variants with a favorable clinical response to topical and intralesional corticosteroid; elephantine and diffuse forms responded poorly to therapy. Studies analyzing larger cohorts of patients with PTM and their long-term follow-up are limited, hence more such studies are required., (© 2015 The International Society of Dermatology.)

Cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) is a well-known molecule that regulates T cell activity, with polymorphisms at different regions of this gene having been associated with autoimmune conditions. Pretibial myxedema (PTM), also called Graves' dermopathy, is an autoimmune extrathyroidal manifestation of Graves' disease. We opted to investigate the relationship between three single nucleotide polymorphisms of the CTLA-4 gene (+49A/G, and -318C/T and -1147C/T) and PTM in Iranian patients with Graves' ophthalmopathy (GO). A total of 105 unrelated Iranian patients with GO from the outpatient endocrine clinic of a large university general hospital as well as 103 healthy controls were studied. The genomic DNA was extracted from venous blood samples by a salting out method, and the polymorphisms at +49, -318 and -1147 positions of the CTLA-4 gene were determined using the polymerase chain reaction-restriction fragment length polymorphism method. The GG genotype (OR = 6.000, 95% CI = 1.805-19.940, P = 0.005) and the G allele (OR = 2.653, 95% CI = 1.314-5.357, P = 0.009) at position +49 were significantly associated with PTM in the patient group. The same genotype and allele were also significantly more common among patients (with or without PTM) than controls. No significant association was found for the other two polymorphisms. In conclusion, the +49G allele is associated with increased risk of PTM in patients with GO. Studies with larger sample sizes are needed to confirm the results of the present study.

Introduction: Elephantiasic myxoedema is very rare. We report 5 pretibial myxoedema cases observed in the Dermatological department of Le Dantec hospital in Dakar., Patients and Methods: Our 5 cases were 3 women (age: 52, 45 and 18 years) and 2 men (age: 54 and 32 years)., Results: All the cases were enormous, multinodular pachydermic, bilateral, elephantiasis in the low leg and associated to Graves 'disease. The duration was 4 month to 12 year. In 3 cases there was a Diamond syndrome which is a severe form. The cutaneous lesions were not influenced by medical treatment of thyroid disease. Systemic steroids achieved improvement of the elephantiasis in 1 case., Conclusion: Elephantiasis is a very unusual presentation of pretibial myxoedema and its occurrence doesn't depend to the intensity of thyrotoxicosis and its evolution. However in our cases, it was a severity indicator factor, like Diamond syndrome. Local and systemic steroids give very rarely improvement.

Background: EMO syndrome, defined as a triad including exophthalmus, pretibial myxedema and osteoarthropathia, is a rare condition in patients suffering from hyperthyreosis., Case Presentation: We here describe an interesting case of EMO syndrome associated with unilateral fibromatosis of the hand and an initial stage of generalized myxedema of the skin. To our knowledge a similar case has not yet been described in literature though reports about associated fibromatosis, e.g. located retroperitoneally, already exist. Familiar explanations include its initiation by autoimmune processes or aberrant T-cell cytokine stimulation leading to an overwhelming production of glycosaminoglycans., Conclusion: Interpreting our case in context with previous reports we conclude that associated fibromatosis induced by autoimmune processes may affect a variety of different localizations and therefore requires careful monitoring. A therapeutical attempt by using UVA1 irridation for pretibial myxedema remained without a satisfying regression.

EMO syndrome, a rare complication of Graves' disease, exhibits exophthalmos, pretibial myxedema, and osteoarthropathy. The presence of functional thyrotropin receptors (TSHR) in adipocytes and osteoblasts, both of which we have recently observed, may be related to these extrathyroidal manifestations of Graves' disease. In addition, the expression of TSHR in the heart has recently been reported. We describe here a patient with Graves' disease exhibiting EMO syndrome with a papillary fibroelastoma in the left ventricle. Pathological examinations showed that the fibroelastoma contained Alcian blue-stained mucinous materials that were also observed in the subcutaneous tissue of pretibial myxedema.

The reason why soon after elimination of the thyroid gland protrusion of the bulbi does not recede and adequate regression of soft orbital tissue infiltration does not occur is at first the short time which has elapsed after elimination. The result usually is recorded only later. The long-term cause of minor improvement is the impossibility to combine surgery of the thyroid gland and radioiodine with corticoids, as well as incomplete thyroid elimination and presence of residues and finally pretibial myxoedema associated with a persisting high level of antibodies against the receptor for TSH. Hypothyroidism after the eliminating dose must not be left too long, so far a period of 3-4 weeks seems adequate.

We report a case of pretibial myxedema with Graves' disease in an 18-year-old Japanese woman. The physical examination revealed waxy indurated plaques with prominent hair follicle openings and nonpitting edema disseminated on her lower legs. Histology from an edematous lesion revealed that the dermis was markedly thickened with abundant mucin, especially hyaluronic acid, and the collagen fibers in this portion were splitting up into fibrils. We also reviewed 112 cases of pretibial myxedema reported in the Japanese literature.

We describe a patient with monoclonal gammopathy who subsequently developed thyrotoxicosis, pretibial myxedema and thyroid-associated ophthalmopathy. The pathogenesis of thyrotoxicosis in Graves' disease is due to the presence of autoantibodies that mimic the action of thyrotropin (TSH), called thyroid-stimulating antibodies (TS-ab); these antibodies may or may not inhibit the binding of TSH to the receptor (thyroid-binding inhibiting immunoglobulin, TBII). The patient's immunoglobulins were TS-ab positive and TBII negative when measured on CHO cells expressing the human TSH receptor. The pathogenetic link between the thyroid, orbit and skin is yet to be established but several candidate shared antigens have been proposed, including the TSH receptor itself. The monoclonal immunoglobulins were in evidence before the symptoms of pretibial myxedema, thyrotoxicosis and ophthalmopathy. In addition, the patient had no autoantibodies to thyroglobulin or thyroperoxidase, which are classic markers of thyroid autoimmunity. This combination led us to postulate that the monoclonal gammopathy could be the cause of all the observed pathology. One method to test this hypothesis would be to show that the monoclonal immunoglobulin is a TS-ab. Various methods were used to separate the monoclonal from the polyclonal components of the patient's serum. Preparative isoelectric focusing enabled us to obtain fractions containing only the monoclonal (as revealed by polyacrylamide gel electrophoresis), which were devoid of TS-ab activity (measured as cAMP accumulation in CHO cells expressing the human TSH receptor in a hypotonic bioassay). Subsequently, different oligoclonal fractions were shown to have varying degrees of TS-ab activity, with one fraction having faint biological activity and able to recognize a recombinant TSH receptor preparation in a Western blot. In conclusion, the monoclonal antibody does not seem to be responsible for the thyrotoxicosis, pretibial myxedema and ophthalmopathy. We confirm previous data showing that TSH receptor antibodies in patients with Graves' disease are heterogeneous in nature and we present the first demonstration of autoantibodies capable of binding the TSH receptor but devoid of TBII activity.

The myxomatous materials in cutis from a patient with pretibial myxedema (PTM) with Graves' disease were found to be mainly hyaluronic acid (HA), which had accumulated extensively in the upper dermis. Fibroblasts were increased in number in the mid to lower dermis. To clarify the mechanism of the deposition of HA in the dermis, we employed an antibody against serum-derived hyaluronan-associated protein (SHAP). This immunohistochemical study disclosed that the greater part of the fibroblasts in the mid to lower dermis stained positively, while the fibroblasts surrounded by fairly large amounts of HA in the upper dermis stained faintly or not at all. From these results, we suspect that the accumulation of HA progresses from the upper to the low dermis and that the interaction of fibroblasts and SHAP leads to development of the physiophathological cutaneous changes seen in our case.

Pretibial myxedema (thyroid dermopathy), an uncommon autoimmune manifestation of Graves' disease, is almost always associated with significant ophthalmopathy and may be a marker for an unusually prolonged or different course for the ophthalmopathy. However, it is not known if the response to therapy for eye disease is different in patients with pretibial myxedema. We compared the results of orbital decompression in 385 patients without and 52 patients with pretibial myxedema operated on between 1969 and 1989. Preoperative and postoperative characteristics of severe Graves' ophthalmopathy did not differ in patients with or without pretibial myxedema except for slightly, but not significantly, more proptosis and diplopia in the pretibial myxedema group. In response to a 1989-1990 questionnaire (83% response rate, n = 364), 89.1% without (n = 319) and 88.9% with (n = 45) pretibial myxedema reported satisfactory or acceptable appearance of the eyes. Self-assessment of visual acuity, eye comfort, diplopia, and overall rate of satisfaction with the status of the eyes did not differ between the groups. The presence of pretibial myxedema does not herald an unsatisfactory response to transantral orbital decompression.

We describe here a case of EMO syndrome, which is defined as a combination of exophthalmos, pretibial or localized myxedema, and hypertrophic osteoarthropathy. A 34-year-old Japanese man with Graves' disease developed the characteristic eye changes. He showed 22 mm protrusion of both eyes and hypertrophy of the right lateral rectus muscle as well as both superior rectus muscles by computerized tomography. He subsequently developed lightly erythematous, indurated, nonpitting, peau d'orange plaques and nodules on his lower legs. Finally, he developed Graves' acropathy with hypertrophic osteoarthropathy in the metacarpal bones. Histological examination of myxedematous skin showed typical deposition of mucin accompanied by changes in the amount and distribution of elastic fibers. In addition, the lesional skin showed localized hyperhidrosis, a rarely reported complication of pretibial myxedema. We speculate that this hyperhidrosis of the lesional skin was brought about by stimulation of peripheral sympathetic nerves by surrounding mucin deposition, in the setting of poorly controlled hyperthyroidism.

Two cases of spontaneous hyperhidrosis limited to pretibial myxedema lesions were studied. Quantitative measurements of stimulated eccrine sweat were made after the intradermal injection of methacholine. The sweat rate was two to four times greater in the lesional skin than in perilesional skin. Eccrine secretory glands in excisional biopsy specimens from the pretibial lesions were significantly larger than those in perilesional skin. To our knowledge, hyperhidrosis localized to areas of pretibial myxedema has not been reported.

Pretibial myxedema is considered an autoimmune complication or association of Graves' disease, Hashimoto's thyroiditis, and primary myxedema. The mechanism of lesion formation is unknown; the most plausible theory is that it arises as a result of a target cell in the skin, probably the fibroblast, being stimulated to produce abnormally high amounts of glycosoaminoglycans (especially hyaluronic acid) by autoantibodies directed against a thyroid antigen(s)--that is, by a cross reaction. One or more intermediary humoral agents may be involved in pathogenesis. The reason for the localization to the pretibial region is unknown; there is evidence that most patients with the disorder have similar abnormalities in the preradial skin. The condition may persist for months or years but often regresses spontaneously, accompanied by a parallel decline in, or disappearance of, serum anti-TSH-receptor autoantibody levels. Skin biopsies reveal evidence of increased amounts of hyaluronic acid and damage to collagen and elastic fibers. Local symptomatic treatment with corticosteroids is effective in most cases with slight to moderate severity of skin involvement. Repeated treatments are advised until such time that a spontaneous clinical remission occurs.

The effect of prednisone treatment and plasmapheresis was studied in two patients with Graves' disease complicated by severe exophthalmos and/or pretibial myxedema. Titers of Thyrotropin Binding Inhibitory Immunoglobulins (TBII), Long Acting Thyroid Stimulator (LATS), antithyroid antibodies, and serum gammaglobulin concentrations, as well as clinical changes in exophthalmos and pretibial myxedema, were observed during the course of treatment. Steroid treatment lowered all of the abnormal antibody titers. Plasmapheresis did not change the TBII activity when determined using a fixed amount of immunoglobulin G fraction. However, serum gammaglobulin concentration was reduced by plasmapheresis, and therefore, total TBII activity in a unit of serum was reduced. Plasmapheresis also partially and temporarily resolved the pretibial myxedema, whereas no significant change in exophthalmos was observed. These results suggest that both steroid and plasmapheresis treatment are useful for lowering abnormal antibody titers in sera of patients with Graves' disease, and that plasmapheresis can be of some value in the treatment of pretibial myxedema.