Pretibial myxoedema associated with Hashimoto's thyroiditis

JEADV

(2002)

16

, 625–627

© 2002 European Academy of Dermatology and Venereology

625

CAS E REPO R T

Blackwell Science, Ltd

Pretibial myxoedema associated with Hashimoto’s thyroiditis

SP

Cannavò,†*

F

Borgia,†

M

Vaccaro,†

F

Guarneri,†

E

Magliolo,‡

B

Guarneri†

†

Institute of Dermatology,

‡

Department of Human Pathology, University of Messina, Italy.

*

Corresponding author, Institute of Dermatology, University

Hospital, Via Consolare Valeria, Gazzi, 98125 Messina, Italy, tel. +39 90/2212891; fax +39 90/2927691; E-mail: [email protected]

ABSTRACT

Pretibial myxoedema is a cutaneous mucinosis typically associated with Graves’ disease, although it mayalso develop in subjects with non-thyrotoxic thyroid pathologies. This report presents a rare case of pretibialmyxoedema occurring in a 58-year-old woman with biopsy-proven Hashimoto’s thyroiditis. The hypotheticalpathogenetic link between the two disorders is discussed with particular attention to the role of thyroidstimulating hormone receptor antibodies.

Key words:

glycosaminoglycans, myxoedema, thyroid diseases, thyroid stimulating hormone receptor antibodies

Received: 2 January 2001, accepted 28 February 2002

Introduction

Pretibial myxoedema (PTM) is a rare form of cutaneous

mucinosis, characterized by mucin deposition in the preti-

bial skin; the pathogenesis is still unknown and treatment is

frequently unsatisfactory. It is considered an autoimmune

complication or association of Graves’ disease, although it may

develop in subjects with non-thyrotoxic thyroid disorders; in

particular, only a few cases of PTM associated with chronic

lymphocytic thyroiditis have been reported.

We report a rare case of PTM following onset of Hashimoto’s

thyroiditis, confirmed by thyroid biopsy, and discuss the

hypothetical pathogenetic link between these two diseases.

Case report

In 1997, a 58-year-old woman developed tenderness of the

thyroid gland and diffuse goitre. A clinical diagnosis of

thyroiditis was made in an Endocrinological Department. For

this reason, in July 1998, she was subjected to thyroid biopsy;

the thyroid specimen revealed atrophy of the parenchymal cells

and diffuse lymphocytic infiltration, showing chronic lym-

phocytic thyroiditis. Since then, the woman has been receiving

supplemental levothyroxine, 50–200 mg daily. Results of periodic

thyroid function tests show alternate patterns of hypothyroidism

and euthyroidism.

In November 1998, the woman developed exophthalmos

with ocular pain, lacrimation and photophobia. Four months

later, slowly growing skin papules and oedema were noted on

the lower part of her legs. These symptoms gradually worsened

and she was referred to the Institute of Dermatology, University

of Messina (Italy) in March 2000.

Clinical examination revealed reddish, indurated, non-

pitting plaques with an ‘orange peel-like’ appearance on both

pretibial surfaces and dorsal ankles (fig. 1). A skin biopsy

specimen showed dermal infiltrate of mucin with separation of

collagen bundles and changes in the amount and distribution of

elastic fibres (fig. 2); several stellate fibroblasts were also visible

(fig. 3).

Thyroid function tests showed depressed levels of

triiodothyronine (60 ng/dL; normal range 80–200), thyro-

xine (3.3 ng/dL; normal range 6.1–11.8), free triiodothyronine

(0.7 pg/mL; normal range 2.0–4.25) and free thyroxine

(4.3 pg/dL; normal range 7–18) and markedly elevated thyroid

stimulating hormone (TSH) level (40 nm/L; normal range

0.25–4.0), thyroglobulin antibodies (AbTG) titre (140;

normal range < 100) and throferoxidase antibodies (AbTPO)

titre (1222; normal range < 100). Radioreceptor assay did not

detect TSH receptor antibodies in the woman’s serum.

The clinical history and the laboratory results led us to

diagnose a hypothyroid state with exophthalmos and PTM,

determined by Hashimoto’s thyroiditis.

The woman was started on treatment with methylprednisone

emisuccinate (9 IU/mg in 4 weeks), with progressive improvement

of the cutaneous manifestations. No relapses were observed at

6 months follow-up.

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Discussion

PTM is a rare skin disease included in the heterogeneous group

of the cutaneous mucinoses, characterized by mucin deposition

in the skin or within the hair follicle.

1

It is considered an

autoimmune complication in association with Graves’ disease, a

thyroid pathology characterized by goitre, clinical hyperthyroidism,

exophthalmos, acropachy and peculiar cutaneous manifesta-

tions. PTM occurs in fewer than 3% of these subjects, with a

predilection for women in the fifth to sixth decades of life. Skin

involvement usually follows the diagnosis of hyperthyroidism

or onset of exophthalmos, and it is often secondary to surgical

or radio-iodine therapy of the goitre.

2

PTM may also, very rarely, occur in subjects with non-

thyrotoxic thyroid disease and even in euthyroid subjects.

3–5

Among this smaller group, only a few cases of PTM associated

with chronic lymphocytic thyroiditis, confirmed by thyroid

biopsy

6

, have been reported.

The cutaneous lesions are typically confined to the lower part

of the legs, with different morphological forms: these include,

in decreasing order of frequency, non-pitting oedema, nodular,

plaque-like, polypoid and elephantiasic variants.

7

PTM is usually asymptomatic; in a few cases spontaneous

hyperhidrosis, limited to the affected areas, has been described.

8

Unusual locations of the infiltrate, such as the lower abdomen,

arms, scalp, ears and forehead have been reported in the

literature; however, in all the cases described, the infiltrate

showed similar features, both clinically and histologically, to the

often associated pretibial form.

3–9

Histopathological hallmarks are the deposition of large

amounts of hyaluronic acid and glycosaminoglycans (GAG) in

the dermis, leading to extensive splaying of collagen fibres and

damage of elastic tissue, and the presence of several stellate,

spindle-shaped fibroblasts. Special stains, such as colloidal iron

or alcian blue, allow better localization of the mucinous

infiltrate in the dermis.

1

The pathogenesis is still unclear: many hypotheses have been

made, but the most plausible one is the presence in patient’s

serum of a circulating factor of unknown origin that is able to

stimulate selectively the activity of the fibroblasts from the

pretibial area. They have a higher basal rate of GAG production

(six- to 16-fold) than fibroblasts from other sites. Priestley

fig. 1 Reddish, indurated, non-pitting plaques with ‘orange peel-like’

appearance on both pretibial surfaces and dorsal ankles.

fig. 2 Dermal infiltrate of mucin with separation of collagen bundles

Haematoxylin and eosin; original magnification, × 25.

fig. 3 Stellate dendritic fibroblasts in the dermis. Haematoxylin and eosin;

original magnification × 100.


Pretibial myxoedema and Hashimoto’s thyroiditis

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et al

.’s experiments

10

demonstrated that sera from affected

subjects can stimulate the proliferation and GAG metabolism

of fibroblasts

in vitro

, regardless of their site of origin (pretibial

or other sites) and status (both patient and control). The lack

of site specificity does not permit an explanation of the

predominant localization of the mucinous infiltrate; it may

be due to an increased quantitative, rather than qualitative

response to stimulation.

Even the nature of the stimulating factor is still unknown:

first, long-acting thyroid stimulator and, then, insulin-like

growth factor 1 have been considered as the causative agents of

PTM, but their role has never been clearly demonstrated.

Recently, attention has been focused on the TSH receptor

antibodies. Chang

et al

.

11

have demonstrated that subjects

with Graves’ disease and PTM have high titres of TSH receptor

antibodies in their serum; moreover, the presence of TSH and

TSH receptor antibody-binding sites on fibroblasts derived

from the affected skin and the detection, within the pretibial

tissue, of RNA encoding non-variant human TSH receptor,

suggest the existence of a common antigenic site and seem

to provide evidence for the central pathogenetic role of

this autoantigen in both thyroidal and extrathyroidal

manifestations.

12

The woman in our case showed typical skin features of PTM

associated with chronic lymphocytic thyroiditis and exophthalmos;

the parallel course of both cutaneous and endocrinological

manifestations and the good response to corticosteroid therapy

confirm the presence of a close pathogenetic link between the

two diseases.

On the contrary, the absence of circulating TSH receptor

antibodies, as observed in our case, strongly suggests the

existence of a different autoimmune mechanism responsible

for such cutaneous features in subjects with Hashimoto’s

thyroiditis.

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Pretibial myxoedema associated with Hashimoto's thyroiditis