Pretibial Myxedema

Background

This is an uncommon complication of Grave's disease, occurring in 1-4% of patients. There is a diffuse, non-pitting edema and thickening of the skin usually on the anterior aspect of the lower legs spreading to the dorsum of the feet. Advanced cases may involve the upper trunk, upper extremities, face, neck, and ears. The lesions resolve very slowly. It occasionally occurs in non-thyrotoxic Grave's disease, autoimmune thyroiditis, and stasis dermatitis. The serum contains circulating factors which stimulate fibroblasts to increase synthesis of glycosaminoglycans.

Biopsy of the skin reveals mucin in the mid to lower dermis. There is no increase in fibroblasts. With time, there may be secondary hyperkeratosis which may become verruciform. Many of these patients may also have co-existing stasis dermatitis. Elastic stains will reveal a reduction in elastic tissue.

PATHOGENESIS CHARACTERIZATION

TSH and TSH receptor antibody-binding sites in fibroblasts of pretibial myxedema are related to the extracellular domain of entire TSH receptor.

Chang TC, Wu SL, Hsiao YL, Kuo ST, Chien LF, Kuo YF, Change CC, Chang TJ.

Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei, Republic of China.

Clin Immunol Immunopathol 1994 Apr;71(1):113-20 Abstract quote

The role of TSH receptor antibodies in the pathogenesis of pretibial myxedema is still unclear.

This study was designed to determine whether patients with pretibial myxedema had higher serum titers of TSH receptor antibodies, and whether there were TSH and TSH receptor antibody-binding sites on plasma membranes of fibroblasts derived from the skin of pretibial myxedema. If there were, were the binding sites similar to the TSH receptor?

The TSH receptor antibodies were determined with radioreceptor assay in 20 normal subjects, 18 hyperthyroid Graves' disease patients without ophthalmopathy, 26 hyperthyroid Graves' disease patients with ophthalmopathy, and 11 patients with pretibial myxedema associated with Graves' ophthalmopathy. TSH and TSH receptor antibody-binding sites were studied on plasma membranes of fibroblasts cultured from the skin of pretibial myxedema with radioreceptor assay. RNA was also extracted from the fibroblasts of pretibial myxedema and reverse transcribed using random primers as the primers for cDNA synthesis. The resulting cDNAs were subjected to amplification by polymerase chain reaction with the use of a set of primers spanning the 5' region (+256/+275 and +616/+635) and the 3' region (+1819/+1838 and +2405/+2424) of the TSH receptor cDNA (+1 transcription start codon). They were further identified by Southern blot hybridization, with the probe spanning the 5' region (+272/+612) and the 3' region (+1908/+2268) of the TSH receptor cDNA (+ 1 transcription start codon), and sequencing.

The results showed that patients with pretibial myxedema had higher titers of TSH receptor antibodies in the serum. TSH and TSH receptor antibody-binding sites were present on plasma membranes of fibroblasts derived from the skin of pretibial myxedema patients and related to the extracellular domain of the TSH receptor. These data suggest a common antigenic site in the skin and in the thyroid as a putative target for TSH receptor antibodies or lymphocytes of Graves' disease.

IgG, IgA and C3 deposits in the extra-thyroidal manifestations of autoimmune Graves' disease: their in vitro solubilization by intravenous immunoglobulin.

Antonelli A, Palla R, Casarosa L, Fallahi P, Baschieri L.

Institute of Clinical Medicine II, University of Pisa, Italy.

Clin Exp Rheumatol 1996 May-Jun;14 Suppl 15:S31-5 Abstract quote

OBJECTIVE: To study the involvement of antibodies in the extrathyroidal manifestations of autoimmune Graves' disease, we determined the presence of IgG, IgA and IgM antibodies and C3c in connective tissue samples from patients with Graves' disease and pretibial myxedema (PTM) or thyroid associated ophthalmopathy (TAO).

METHODS: Connective orbital tissue samples were obtained from 12 patients undergoing orbital decompression for TAO, and skin samples from lesions on the pretibial area were obtained in 7 patients with PTM. Sections from each tissue sample were stained with fluorescin-isothiocianate conjugated anti-human IgG, IgA, IgM and C3c and were examined by a fluorescence optical instrument. Other serial sections from each sample were incubated with human IgG solutions (concentration 6 mg/ml or 20 mg/ml), human albumin (40 mg/ml), PBS, myoglobin (40 mg/ml), or IgA (20 mg/ml), and were then processed by a standard direct immunofluorescence staining procedure.

RESULTS: Among the samples from TAO patients 8/12 (67%) were positive for IgG deposition, 4/9 (44%) were positive for IgA, 1/9 (11%) was positive for IgM and 4/9 (44%) were positive for C3c deposition. Orbital connective samples from 3 non-TAO patients were all negative. Among samples from PTM patients 4/7 (57%) were positive for IgG deposition, 3/ 4 (75%) were positive for IgA, 0/4 was positive for IgM and 3/7 (43%) were positive for C3c deposition. Skin samples from 5 control patients undergoing skin biopsy for non-autoimmune diseases were all negative. Incubation with human IgG (20 mg/ml) resulted in the complete disappearance of IgG and C3c deposition in all positive patients. No significant variation in IgG fluorescent staining after incubation with either 6 mg/ml of IgG solution, human albumin, PBS, myoglobin or IgA was observed.

CONCLUSION: The results of our study suggest that different classes of antibodies, mainly IgG and IgA, may be implicated in the disease process in autoimmune TAO and PTM. Activation of the complement cascade, via the classic or the alternative pathway, could take place in about 40% of these patients. IVIG in vitro may solubilize, by a specific mechanism, IgG and complement immune complex deposition in the extrathyroidal manifestations of autoimmune Grave's disease.

TSH receptor transcripts and TSH receptor-like immunoreactivity in orbital and pretibial fibroblasts of patients with Graves' ophthalmopathy and pretibial myxedema.

Stadlmayr W, Spitzweg C, Bichlmair AM, Heufelder AE.

Molecular Thyroid Research Unit, Klinikum Innenstadt, Ludwig-Maximilians-Universitat, Munchen, Germany

Thyroid 1997 Feb;7(1):3-12 Abstract quote

Several lines of experimental and clinical evidence favor a close etiologic link between Graves' disease and its associated extrathyroidal manifestations, ophthalmopathy and pretibial dermopathy. The human TSHR represents a candidate antigen shared between the thyroid gland and the involved extrathyroidal sites in Graves' disease.

Here, we demonstrate that ribonucleic acid encoding exons 1-10 of human TSHR can be detected in fibroblasts derived from the affected orbital and pretibial space in patients with Graves' ophthalmopathy and pretibial dermopathy. RNA prepared from cultured fibroblasts was reverse transcribed and the resulting cDNA amplified by the polymerase chain reaction using primers spanning exons 1 through 10 of TSHR. The predicted transcripts (1890 and 2092 bp, respectively) were obtained with cDNA derived from orbital and pretibial fibroblasts of all patients with GO and PTM, and orbital fibroblasts of one healthy individual, and confirmed by southern hybridization. Sequencing of TSHR transcripts confirmed their identity with the reported nucleotide sequence of the human TSHR. Immunostaining using both monoclonal and polyclonal antibodies directed against the recombinant human TSHR revealed specific TSHR-like immunoreactivity in fibroblasts and adipose/connective tissue derived from the orbital and pretibial space of patients with GO and PTD, but not in normal individuals or control tissues.

Detection, within the orbital and pretibial tissues, of RNA encoding nonvariant hTSHR and of immunoreactivity for this important autoantigen in Graves' disease suggests that the pathogenic role of the TSHR may extend beyond the thyroid gland, and may include the associated extrathyroidal manifestations.

ELEPHANTIASIS

Elephantiasic pretibial myxedema: insight into and a hypothesis regarding the pathogenesis of the extrathyroidal manifestations of Graves' disease.

Rapoport B, Alsabeh R, Aftergood D, McLachlan SM.

Autoimmune Disease Unit, Cedars-Sinai Research Institute and School of Medicine, University of California, Los Angeles, USA.

Thyroid 2000 Aug;10(8):685-92 Abstract quote

The basis for the extrathyroidal manifestations of Graves' ophthalmopathy (GO) and dermopathy are not well understood.

We describe immunohistochemical studies on the skin of a patient with an extreme, elephantiasic form of Graves' dermopathy that developed after periods of prolonged standing with dependent edema. Excision of part of the lesion with subsequent skin grafting from a normal donor site resulted in recurrence of the disease at the original site as well as in development of disease at the donor site. A murine monoclonal antibody reacted with the thyrotropin receptor (TSHR) or a cross-reacting protein in fibroblast-like cells in the patient's upper dermis and, surprisingly, with dermal cells from unaffected individuals. The patient's dermis containing lymphoid follicles comprising B cells and CD3+, CD4+ T cells, with few CD8+ T cells. CD21+ cells (most likely follicular dendritic cells) were also present in the dermis. Based on past and present observations, we raise an unifying hypothesis to explain the diverse extrathyroidal manifestations of Graves' disease and their apparent lack of association with TSHR autoantibodies.

As opposed to the present concept that these phenomena relate to site-specific properties on preadipocytes or fibroblasts, we suggest that clinically evidence GO and dermopathy are primarily caused by local factors (particularly in the orbit) superimposed on a systemic, low-grade connective tissue inflammation.

LABORATORY/RADIOLOGIC/
OTHER TESTS
CHARACTERIZATION

RADIOLOGIC

LABORATORY MARKERS

Clinical applications of assays for thyrotropin-receptor antibodies in Graves' disease.

Ginsberg J, von Westarp C.

CMAJ 1986 May 15;134(10):1141-7 Abstract quote

Graves' disease is characterized by hyperthyroidism, diffuse goitre, infiltrative ophthalmopathy and, rarely, pretibial myxedema.

In 1956 a substance capable of prolonged thyroid stimulation was discovered in the serum of some patients with Graves' disease and termed long-acting thyroid stimulator (LATS). It was shown to be an antibody that could interact with the receptor for thyroid-stimulating hormone (TSH). The term LATS is usually reserved for the activity measured in a laborious in-vivo bioassay in mice. Today the activity of TSH-receptor antibodies (TSH-R Ab) can be measured by in-vitro bioassays or by radioreceptor assays. These assays are now becoming commercially available.

TSH-R Ab assays may be useful in predicting the response to therapy for Graves' disease, investigating euthyroid ophthalmopathy and predicting the likelihood of neonatal hyperthyroidism.

GROSS APPEARANCE/
CLINICAL VARIANTS CHARACTERIZATION

GENERAL

EMO SYNDROME

Exophthalmus-myxoedema circumscriptum praetibiale-osteoarthropathia hypertrophicans (E.M.O.) syndrome in Graves' disease: a review of eight cases reported in Japan.

Saito S, Sakurada T, Yamamoto M, Yamaguchi T, Yoshida K.

Tohoku J Exp Med 1975 Feb;115(2):155-65 Abstract quote

Case 1 showed recurrence of hyperthyroidism accompanied by pretibial myxedema and digital clubbing 14 years after thyroidectomy for Graves' disease. Case 2 had had pretibial myxedema for the past 20 years and myxedema tuberosum at the right shoulder for the past 10 years, and on admission showed exophthalmos and digital clubbing with thyroid gland demonstrating histological picture of chronic thyroiditis. This case was in slight hypothyroidism and serum LATS was highly positive.

Eight cases of E.M.O. syndrome have so far been reported in Japan, including our own. Six cases of these were males. Two cases did not show any sign of hyperthyroidism throughout their entire courses, including our Case 2 described here. Three cases had never received treatment for Graves' disease prior to the occurrence of this syndrome. The serum LATS was positive in all 5 cases thus far reported.

A case report of EMO syndrome showing localized hyperhidrosis in pretibial myxedema.

Kato N, Ueno H, Matsubara M.

Department of Dermatology, Otaru City General Hospital, Japan.

J Dermatol 1991 Oct;18(10):598-604 Abstract quote

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.

Exophthalmos, pretibial myxedema, osteoarthropathy syndrome associated with papillary fibroelastoma in the left ventricle.

Suzuki H, Shimura H, Haraguchi K, Harii N, Endo T, Hosaka S, Yoshii S, Tada Y, Onaya T.

The Third Department of Internal Medicine, Yamanashi Medical University, Japan.

Thyroid 1999 Dec;9(12):1257-60 Abstract quote

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.

VARIANTS

LOCALIZED

Graves' disease presenting as localized myxedema in a thigh donor graft site.

Missner SC, Ramsay EW, Houck HE, Kauffman CL.

University of Maryland School of Medicine, Baltimore Campus, Department of Dermatology, USA.

J Am Acad Dermatol 1998 Nov;39(5 Pt 2):846-9 Abstract quote

Pretibial myxedema, exophthalmus, and thyroid acropachy are the classic manifestations of Graves' Disease. However, myxedema in Graves' Disease can occur in locations other than the pretibial surfaces. Furthermore, with systemic symptoms, localized myxedema may occur at sites of trauma or scarring.

We describe a patient with localized myxedema on the thigh at the site of a donor skin graft as the initial presentation of Graves' Disease.

Graves' disease presenting as elephantiasic pretibial myxedema and nodules of the hands.

Cho S, Choi JH, Sung KJ, Moon KC, Koh JK.

Department of Dermatology, Asan Medical Center, College of Medicine, University of Ulsan, 388-1 Poongnap-dong, Songpa-gu, Seoul 138-736, South Korea.

Int J Dermatol 2001 Apr;40(4):276-7 Abstract quote

A 67-year-old man presented with a 2-year history of asymptomatic, firm, multiple nodules and plaques and cerebriform hypertrophy of both lower legs and feet, and well-defined, skin-colored, firm nodules and tumors on both hands.

He had been diagnosed as having Graves' disease 3 years previously, and had been treated with 10 mg of methimazole and 100 microg of thyroxin (T4) daily for 2 years. Physical examination revealed nonpitting edema, flesh-colored to erythematous, firm, confluent, polypoid nodules and fissured plaques extending from the shins to the dorsa of both feet (Fig. 1), and round to oval, firm, skin-colored, walnut-to-egg-sized tumors on all 10 fingers and the ulnar side of the dorsum of the right hand (Fig. 2). The thyroid gland was diffusely enlarged; however, there was no exophthalmos, and extraocular movements were normal. There was no weight loss, loss of appetite, tremor, heat intolerance, diarrhea, or fatigue.

On laboratory evaluation, thyroid-stimulating hormone (TSH) had a markedly low titer of < 0.05 microU/mL (normal: 0.4-5.0), and the TSH receptor antibody was extremely high at 73.8% (normal: < 15%). Serum free triiodothyronine (T3), T4, antimicrosome, and antithyroglobulin antibodies were normal or negative. Skin biopsy samples from the shin and hand disclosed extensive mucin deposition throughout the dermis.

HISTOLOGICAL TYPES CHARACTERIZATION

GENERAL

Pretibial mucin. Histologic patterns and clinical correlation.

Somach SC, Helm TN, Lawlor KB, Bergfeld WF, Bass J.

Department of Dermatology, Cleveland Clinic Foundation, Ohio.

Arch Dermatol 1993 Sep;129(9):1152-6 Abstract quote

BACKGROUND AND OBJECTIVE: We identified several patients with a histologic diagnosis of pretibial myxedema in whom thyroid disease was not found. The purpose of this study was to investigate if histologic characteristics can distinguish between pretibial mucinosis secondary to Graves' disease and that unassociated with thyroid disease.

METHODS: Biopsy specimens interpreted as compatible with pretibial myxedema were reviewed; these included 12 cases of pretibial mucinosis with documented Graves' disease, and six cases of pretibial mucinosis without evidence of Graves' disease. Ten specimens interpreted as compatible with stasis dermatitis were also evaluated for histologic characteristics, including the possible presence of mucin.

RESULTS: Features that distinguish between pretibial mucinosis associated with Graves' disease and pretibial mucinosis without Graves' disease included preservation of a zone of normal-appearing collagen in the superficial papillary dermis (12/12 with Graves' disease, 0/6 without), mucin deposition in the reticular dermis (12/12 with Graves' disease, 0/6 without), lack of mucin deposition in the superficial papillary dermis (11/12 with Graves' disease, 1/6 without), angioplasia (2/12 with Graves' disease, 6/6 without), and the presence of hemosiderin (2/12 with Graves' disease, 6/6 without). Mucin deposition in the papillary dermis was found in six of 10 specimens interpreted as stasis dermatitis.

CONCLUSIONS: There are patients with pretibial mucinosis in whom there is no thyroid disease. Specimens from patients without Graves' disease have features of stasis dermatitis in addition to mucinosis. We conclude that pretibial mucinosis may result from stasis or Graves' disease and that histologic differences allow for accurate differentiation.

Dermopathy of Graves disease (pretibial myxedema). Review of 150 cases.

Fatourechi V, Pajouhi M, Fransway AF.

Division of Endocrinology, Metabolism, and Internal Medicine, Mayo Clinic, Rochester, MN 55905.

Medicine (Baltimore) 1994 Jan;73(1):1-7 Abstract quote

Pretibial myxedema is an uncommon manifestation of Graves disease, and little information is available regarding its natural course and its relation to other manifestations of Graves disease.

We reviewed 150 consecutive cases with the diagnosis of pretibial myxedema over a 20-year period in a referral center. Only 1 patient in this group did not have ophthalmopathy, whereas 88% had significant proptosis and 30% required orbital decompression surgery. Dermopathy was a late manifestation of Graves disease, and its onset usually followed the diagnosis of hyperthyroidism and ophthalmopathy. In a few patients, dermopathy preceded diagnosis of hyperthyroidism or onset of ophthalmopathy. Fourteen patients were never clinically hyperthyroid; spontaneous hypothyroidism had developed in 11 in this group. All cases involved the lower extremities, with only 1 patient having combined upper and lower extremity involvement.

The most common form of thyroid dermopathy was nonpitting edema, followed by nodular and plaque forms, which occurred with equal frequency. The polypoid form occurred in 1 patient and the elephantiasic form in another; 7.3% had thyroid acropachy. Follow-up was available for 120 patients (range, 3 mo to 19 yr; mean, 3.2 yr), and complete remission was observed in only 12 patients. Topically applied corticosteroid therapy was used in 76 patients, and in this group 38% had sustained long-term partial remission, as opposed to 18% in the group receiving no corticosteroid therapy.

SPECIAL STAINS/IMMUNOPEROXIDASE/
OTHER CHARACTERIZATION

SPECIAL STAINS

A case of pretibial myxedema associated with Graves' disease: an immunohistochemical study of serum-derived hyaluronan-associated protein.

Shishido M, Kuroda K, Tsukifuji R, Fujita M, Shinkai H.

Department of Dermatology, School of Medicine, Chiba University, Japan.

J Dermatol 1995 Dec;22(12):948-52 Abstract quote

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.

IMMUNOPEROXIDASE

DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES

Dermal mucinosis

PROGNOSIS AND TREATMENT CHARACTERIZATION

PROGNOSTIC FACTORS

TREATMENT

Effect of plasmapheresis and steroid treatment on thyrotropin binding inhibitory immunoglobulins in a patient with exophthalmos and a patient with pretibial myxedema.

Kuzuya N, DeGroot LJ.

J Endocrinol Invest 1982 Nov-Dec;5(6):373-8 Abstract quote

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.

Successful treatment of hypothyroid Graves' disease with a combination of levothyroxine replacement, intravenous high-dose steroid and irradiation to the orbit.

Koshiyama H, Mori S, Fujiwara K, Hayakawa K, Koh T.

Department of Medicine, Kyoto City Hospital, Japan.

Intern Med 1993 May;32(5):421-3 Abstract quote

A 46-year-old woman with hypothyroid Graves' disease (EMO syndrome) is reported. The patient had bilateral exophthalmos, conjunctival chemosis, periorbital edema and limitation of lateral gaze.

Laboratory examination revealed the presence of primary hypothyroidism with positive thyroid-stimulating hormone (TSH) binding inhibitory immunoglobulin and thyroid stimulation antibody. These findings indicated a diagnosis of hypothyroid Graves' disease or EMO syndrome. She received levothyroxine replacement and steroid pulse therapy followed by radiotherapy. Her visual symptoms showed marked improvement and pretibial myxedema disappeared.

Although several studies indicate that hypothyroid Graves' disease is a different entity from hyperthyroid Graves' disease, this report suggests that steroid pulse therapy combined with radiotherapy may be effective to treat ophthalmopathy in both diseases.

Pretibial myxedema and high-dose intravenous immunoglobulin treatment.

Antonelli A, Navarranne A, Palla R, Alberti B, Saracino A, Mestre C, Roger P, Agostini S, Baschieri L.

Institute of Clinical Medicine II, University of Pisa, Italy.

Thyroid 1994 Winter;4(4):399-408 Abstract quote

Seven patients affected by Graves' ophthalmopathy and pretibial myxedema (four patients with nodular form, two with diffuse, and one with elephanthiasic form) have been treated with high-dose intravenous immunoglobulins.

We have observed (a) clinical improvement of pretibial myxedema and Graves' ophthalmopathy in all patients, (b) a reduction of pretibial skin thickness, by ultrasonography evaluation, in four patients, (c) a reduction of mucopolysaccharide skin content in three patients, (d) disappearance of lymphocytic skin infiltration and IgG deposition in two patients, and (e) a parallel reduction of the titer of circulating autoantibodies as antithyroglobulin, antimicrosomal, anti-TSH receptor, and of non-organ-specific antibodies as antinuclear, anti-smooth muscle cells, and anti-mitochondrial. In comparison two patients with Graves' ophthalmopathy and pretibial myxedema treated with systemic corticosteroids did not present any improvement of the cutaneous ailment.

Therefore, this study suggests that intravenous immunoglobulins are effective in the treatment of pretibial myxedema and may have an immunomodulant action in patients with Graves' disease and related disorders.

Surgical excision of pseudotumorous pretibial myxedema.

Pingsmann A, Ockenfels HM, Patsalis T.

Department of Orthopedics, Essen University, Germany.

Foot Ankle Int 1996 Feb;17(2):107-10 Abstract quote

Pretibial myxedema is a well-known clinical feature of autoimmune thyroid malfunction and is classically associated with Graves' disease. Its clinical course is frequently not related to the clinical control of the underlying thyroid disease. Treatment is primarily medical, consisting of oral and topical corticosteroids.

We present a case of successful local excision of a pseudotumorous manifestation at the dorsum of the foot recalcitrant to multimodal medical and dermatological therapy.

Elephantiasic pretibial myxedema: A novel treatment for an uncommon disorder.

Susser WS, Heermans AG, Chapman MS, Baughman RD.

Section of Dermatology and the Department of Rehabilitation Medicine, Dartmouth-Hitchcock Medical Center.
J Am Acad Dermatol 2002 May;46(5 Pt 1):723-6 Abstract quote
Pretibial myxedema is a known manifestation of Graves' disease. Much less common is the elephantiasis nostras variant, which is often refractory to treatment.

We therefore elected to try a new therapy, often used for the management of chronic lymphedema, called complete decongestive physiotherapy. After 6 weeks of intensive treatment, our patient lost 37 pounds and had reduced her edema volume by 47%. Her skin softened with decreased lymph seepage and she became mobile for the first time in years. At a 2-year follow-up visit, she exhibited sustained improvement. This case demonstrates that complete decongestive physiotherapy can provide effective, long-term control of this disease process.

We suggest that complete decongestive physiotherapy be considered in patients with severe forms of pretibial myxedema, as well as those with refractory lymphedema.

Henry JB. Clinical Diagnosis and Management by Laboratory Methods. Twentieth Edition. WB Saunders. 2001.
Rosai J. Ackerman's Surgical Pathology. Eight Edition. Mosby 1996.
Sternberg S. Diagnostic Surgical Pathology. Third Edition. Lipincott Williams and Wilkins 1999.
Weedon D. Weedon's Skin Pathology. Churchill Livingstone. 1997.
Fitzpatrick's Dermatology in General Medicine. 5th Edition. McGraw-Hill. 1999.
Robbins Pathologic Basis of Disease. Sixth Edition. WB Saunders 1999.
Arch Dermatol 1993;129:1152.

Commonly Used Terms

Dermal mucinosis -See term.

Internet Links

Clinical Photo

Last Updated 6/12/2002

GROSS APPEARANCE/ CLINICAL VARIANTS	CHARACTERIZATION
GENERAL
EMO SYNDROME
Exophthalmus-myxoedema circumscriptum praetibiale-osteoarthropathia hypertrophicans (E.M.O.) syndrome in Graves' disease: a review of eight cases reported in Japan. Saito S, Sakurada T, Yamamoto M, Yamaguchi T, Yoshida K.	Tohoku J Exp Med 1975 Feb;115(2):155-65 Abstract quote Case 1 showed recurrence of hyperthyroidism accompanied by pretibial myxedema and digital clubbing 14 years after thyroidectomy for Graves' disease. Case 2 had had pretibial myxedema for the past 20 years and myxedema tuberosum at the right shoulder for the past 10 years, and on admission showed exophthalmos and digital clubbing with thyroid gland demonstrating histological picture of chronic thyroiditis. This case was in slight hypothyroidism and serum LATS was highly positive. Eight cases of E.M.O. syndrome have so far been reported in Japan, including our own. Six cases of these were males. Two cases did not show any sign of hyperthyroidism throughout their entire courses, including our Case 2 described here. Three cases had never received treatment for Graves' disease prior to the occurrence of this syndrome. The serum LATS was positive in all 5 cases thus far reported.
A case report of EMO syndrome showing localized hyperhidrosis in pretibial myxedema. Kato N, Ueno H, Matsubara M. Department of Dermatology, Otaru City General Hospital, Japan.	J Dermatol 1991 Oct;18(10):598-604 Abstract quote 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.
Exophthalmos, pretibial myxedema, osteoarthropathy syndrome associated with papillary fibroelastoma in the left ventricle. Suzuki H, Shimura H, Haraguchi K, Harii N, Endo T, Hosaka S, Yoshii S, Tada Y, Onaya T. The Third Department of Internal Medicine, Yamanashi Medical University, Japan.	Thyroid 1999 Dec;9(12):1257-60 Abstract quote 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.
VARIANTS
LOCALIZED
Graves' disease presenting as localized myxedema in a thigh donor graft site. Missner SC, Ramsay EW, Houck HE, Kauffman CL. University of Maryland School of Medicine, Baltimore Campus, Department of Dermatology, USA.	J Am Acad Dermatol 1998 Nov;39(5 Pt 2):846-9 Abstract quote Pretibial myxedema, exophthalmus, and thyroid acropachy are the classic manifestations of Graves' Disease. However, myxedema in Graves' Disease can occur in locations other than the pretibial surfaces. Furthermore, with systemic symptoms, localized myxedema may occur at sites of trauma or scarring. We describe a patient with localized myxedema on the thigh at the site of a donor skin graft as the initial presentation of Graves' Disease.
Graves' disease presenting as elephantiasic pretibial myxedema and nodules of the hands. Cho S, Choi JH, Sung KJ, Moon KC, Koh JK. Department of Dermatology, Asan Medical Center, College of Medicine, University of Ulsan, 388-1 Poongnap-dong, Songpa-gu, Seoul 138-736, South Korea.	Int J Dermatol 2001 Apr;40(4):276-7 Abstract quote A 67-year-old man presented with a 2-year history of asymptomatic, firm, multiple nodules and plaques and cerebriform hypertrophy of both lower legs and feet, and well-defined, skin-colored, firm nodules and tumors on both hands. He had been diagnosed as having Graves' disease 3 years previously, and had been treated with 10 mg of methimazole and 100 microg of thyroxin (T4) daily for 2 years. Physical examination revealed nonpitting edema, flesh-colored to erythematous, firm, confluent, polypoid nodules and fissured plaques extending from the shins to the dorsa of both feet (Fig. 1), and round to oval, firm, skin-colored, walnut-to-egg-sized tumors on all 10 fingers and the ulnar side of the dorsum of the right hand (Fig. 2). The thyroid gland was diffusely enlarged; however, there was no exophthalmos, and extraocular movements were normal. There was no weight loss, loss of appetite, tremor, heat intolerance, diarrhea, or fatigue. On laboratory evaluation, thyroid-stimulating hormone (TSH) had a markedly low titer of < 0.05 microU/mL (normal: 0.4-5.0), and the TSH receptor antibody was extremely high at 73.8% (normal: < 15%). Serum free triiodothyronine (T3), T4, antimicrosome, and antithyroglobulin antibodies were normal or negative. Skin biopsy samples from the shin and hand disclosed extensive mucin deposition throughout the dermis.

HISTOLOGICAL TYPES	CHARACTERIZATION
GENERAL
Pretibial mucin. Histologic patterns and clinical correlation. Somach SC, Helm TN, Lawlor KB, Bergfeld WF, Bass J. Department of Dermatology, Cleveland Clinic Foundation, Ohio.	Arch Dermatol 1993 Sep;129(9):1152-6 Abstract quote BACKGROUND AND OBJECTIVE: We identified several patients with a histologic diagnosis of pretibial myxedema in whom thyroid disease was not found. The purpose of this study was to investigate if histologic characteristics can distinguish between pretibial mucinosis secondary to Graves' disease and that unassociated with thyroid disease. METHODS: Biopsy specimens interpreted as compatible with pretibial myxedema were reviewed; these included 12 cases of pretibial mucinosis with documented Graves' disease, and six cases of pretibial mucinosis without evidence of Graves' disease. Ten specimens interpreted as compatible with stasis dermatitis were also evaluated for histologic characteristics, including the possible presence of mucin. RESULTS: Features that distinguish between pretibial mucinosis associated with Graves' disease and pretibial mucinosis without Graves' disease included preservation of a zone of normal-appearing collagen in the superficial papillary dermis (12/12 with Graves' disease, 0/6 without), mucin deposition in the reticular dermis (12/12 with Graves' disease, 0/6 without), lack of mucin deposition in the superficial papillary dermis (11/12 with Graves' disease, 1/6 without), angioplasia (2/12 with Graves' disease, 6/6 without), and the presence of hemosiderin (2/12 with Graves' disease, 6/6 without). Mucin deposition in the papillary dermis was found in six of 10 specimens interpreted as stasis dermatitis. CONCLUSIONS: There are patients with pretibial mucinosis in whom there is no thyroid disease. Specimens from patients without Graves' disease have features of stasis dermatitis in addition to mucinosis. We conclude that pretibial mucinosis may result from stasis or Graves' disease and that histologic differences allow for accurate differentiation.
Dermopathy of Graves disease (pretibial myxedema). Review of 150 cases. Fatourechi V, Pajouhi M, Fransway AF. Division of Endocrinology, Metabolism, and Internal Medicine, Mayo Clinic, Rochester, MN 55905.	Medicine (Baltimore) 1994 Jan;73(1):1-7 Abstract quote Pretibial myxedema is an uncommon manifestation of Graves disease, and little information is available regarding its natural course and its relation to other manifestations of Graves disease. We reviewed 150 consecutive cases with the diagnosis of pretibial myxedema over a 20-year period in a referral center. Only 1 patient in this group did not have ophthalmopathy, whereas 88% had significant proptosis and 30% required orbital decompression surgery. Dermopathy was a late manifestation of Graves disease, and its onset usually followed the diagnosis of hyperthyroidism and ophthalmopathy. In a few patients, dermopathy preceded diagnosis of hyperthyroidism or onset of ophthalmopathy. Fourteen patients were never clinically hyperthyroid; spontaneous hypothyroidism had developed in 11 in this group. All cases involved the lower extremities, with only 1 patient having combined upper and lower extremity involvement. The most common form of thyroid dermopathy was nonpitting edema, followed by nodular and plaque forms, which occurred with equal frequency. The polypoid form occurred in 1 patient and the elephantiasic form in another; 7.3% had thyroid acropachy. Follow-up was available for 120 patients (range, 3 mo to 19 yr; mean, 3.2 yr), and complete remission was observed in only 12 patients. Topically applied corticosteroid therapy was used in 76 patients, and in this group 38% had sustained long-term partial remission, as opposed to 18% in the group receiving no corticosteroid therapy.

LABORATORY/RADIOLOGIC/ OTHER TESTS	CHARACTERIZATION
RADIOLOGIC
LABORATORY MARKERS
Clinical applications of assays for thyrotropin-receptor antibodies in Graves' disease. Ginsberg J, von Westarp C.	CMAJ 1986 May 15;134(10):1141-7 Abstract quote Graves' disease is characterized by hyperthyroidism, diffuse goitre, infiltrative ophthalmopathy and, rarely, pretibial myxedema. In 1956 a substance capable of prolonged thyroid stimulation was discovered in the serum of some patients with Graves' disease and termed long-acting thyroid stimulator (LATS). It was shown to be an antibody that could interact with the receptor for thyroid-stimulating hormone (TSH). The term LATS is usually reserved for the activity measured in a laborious in-vivo bioassay in mice. Today the activity of TSH-receptor antibodies (TSH-R Ab) can be measured by in-vitro bioassays or by radioreceptor assays. These assays are now becoming commercially available. TSH-R Ab assays may be useful in predicting the response to therapy for Graves' disease, investigating euthyroid ophthalmopathy and predicting the likelihood of neonatal hyperthyroidism.

SPECIAL STAINS/IMMUNOPEROXIDASE/ OTHER	CHARACTERIZATION
SPECIAL STAINS
A case of pretibial myxedema associated with Graves' disease: an immunohistochemical study of serum-derived hyaluronan-associated protein. Shishido M, Kuroda K, Tsukifuji R, Fujita M, Shinkai H. Department of Dermatology, School of Medicine, Chiba University, Japan.	J Dermatol 1995 Dec;22(12):948-52 Abstract quote 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.
IMMUNOPEROXIDASE

DIFFERENTIAL DIAGNOSIS	KEY DIFFERENTIATING FEATURES
Dermal mucinosis