Asymmetrical anhidrosis with hyperpigmentation in a patient with type 1 diabetes

Dear Editor, Typically, the unaffected side in patients with asymmetrical sweating disorders, such as Harlequin syndrome, shows no skin abnormalities other than temporary hyperemia. Additionally, reductions in sweating associated with diabetes usually occur symmetrically on the distal extremities (1). Here, we present the case of a patient with type 1 diabetes who had asymmetrical segmental anhidrosis characterized by hyperpigmentation in areas where sweating function remained intact.A 48-year-old Japanese man first noticed a reduction in sweating in his palms and soles 6 years before presentation. Over time, the area of impaired sweating spread to his trunk, and he noticed the gradual development of hyperpigmentation where sweating remained. He had been diagnosed with type 1 diabetes 2 years previously, and this was suspected to be the acute-onset type, because high blood glucose concentrations had not previously been identified at annual medical checkups. Although he had been receiving insulin treatment since the diagnosis, his diabetes was not well controlled when he presented at our hospital with an HbA1c level of 8.9%. He also noticed asymmetrical pigmentation on his body, which gradually darkened. He visited the hospital because of heat intolerance and he presented with diffuse hyperpigmentation on his left shoulder, right chest and abdomen, and right back (Figure 1A andB). This pigmentation was particularly pronounced in the area of skin between his right armpit and right back.A thermal sweating test using Minor's method (the iodine-starch test; Figure 1C andD) and thermography (Figure 1E and F) revealed that the areas of hyperpigmentation largely corresponded to the areas where sweating function remained. Anhidrotic areas were detected on the right shoulder, left side of the chest and abdomen, and entire left and right lower back of the patient. The quantitative sudomotor reflex test was performed on his back, and revealed that sweat production in response to acetylcholine stimulation was lower on the left than on the right side (left back: 0.049 mg/cm 2 /min; right back: 0.159 mg/cm 2 /min). Magnetic resonance imaging of his brainstem and spine revealed no abnormalities. In addition, 123 I-meta-iodobenzylguanidine myocardial scintigraphy did not reveal any impairment of sympathetic nerve function in his heart. No orthostatic hypotension was identified during the active standing test, and no pupillary abnormalities were found. A neurological examination revealed no sensory or motor neuropathy, only a widespread impairment of sweating. Anti-nuclear and anti-Sjögren's syndrome type A and B antibodies were not detected.Skin biopsies were performed on the right side of the patient's back, where sweating function remained and hyperpigmentation was present, and on the left side of his back, where sweating was impaired. The eccrine glands in the area where sweating was impaired were slightly atrophied compared with those in the unaffected area (Figure 1G andH). Immunohistochemical staining for tubulin β3 suggested a reduction in the number of nerve fibers around the sweat glands in the area where sweating was impaired (Figure 1I-K). In contrast, the basal layer of the epidermis in the area where sweating function remained exhibited greater pigmentation of keratinocytes (Figure 1L andM), accompanied by slight epidermal thickening (epidermal thickness, excluding the stratum corneum and rete ridge: 52.8 ± 12.1 µm in the sweating area; 31.1 ± 6.7 µm in the non-sweating area [mean ± standard deviation]; Figure 1N andO). In addition, collagen fibers in the dermis were slightly thicker in the area where sweating function remained. There were no notable differences in the number of melanocytes in the epidermis of the two areas (Figure 1P andQ).Although hyperpigmentation of the unaffected area is rarely observed in patients with asymmetrical anhidrosis, it has been reported in some patients with Ross syndrome, which is characterized by segmental anhidrosis in combination with areflexia and a tonic pupil (2). The mechanism by which pigmentation develops in areas where the sweating function remains is unknown. In the present patient, because there was no apparent change in the number of melanocytes, it is likely that the difference in the amount of melanin deposition was the result of functional changes in the melanocytes. Differences in the skin environment, such as sweating, blood flow, temperature, and pH, may influence melanin production (3). Examination of the patient's biopsy indicated differences in the condition of keratinocytes and fibroblasts between affected and unaffected areas, which could affect melanocyte function through secreted factors and cell-to-cell contacts (3). On the basis of these findings, we presumed that the presence or absence of sweating altered the microenvironment of the melanocytes, affecting the signals they received from surrounding cells and altering melanin synthesis and deposition. Additionally, it has been reported that patients with type 1 diabetes lose melanin from their skin, according to the level of disease control and the presence or absence of neuropathy (4). The present case and this report suggest a possible connection between a neuropathy-associated reduction in sweating and hypopigmentation, which would have accentuated the hyperpigmentation of the sweating area of the present patient.Sweating dysfunction is a well-recognized complication of diabetes and may present with hyperhidrosis, gustatory sweating, and anhidrosis/hypohidrosis with variable distributions (1,5). Distal hypohidrosis associated with diabetic polyneuropathy is one of the most common patterns and is thought to result from hyperglycemia-induced damage to long peripheral axons (6). Sweating dysfunction is a common complication of diabetes and in most instances presents as a polyneuropathy that primarily affects the distal extremities. This condition is believed to result from hyperglycemia, which primarily damages the distal peripheral nerves with long axons (5). In the present case, a loss of sweating initially occurred in the distal extremities and gradually spread to the trunk in an asymmetrical pattern. Although the worsening of the patient's heat intolerance coincided with the onset of diabetes, it is thought that he first noticed a loss of sweating prior to the onset of diabetes. Progressive expansion of the areas with impaired sweating, as in the present patient, is occasionally observed in patients with segmental anhidrosis, including Ross syndrome (2). Additionally, the extensive nature of the sweating dysfunction and the absence of peripheral neuropathy other than that related to sweating probably distinguishes the present patient from those with typical diabetes-related peripheral neuropathy. Based on the distribution of the anhidrotic areas, revealed by thermography, and the reduction in the number of nerve fibers around the sweat glands, it can be inferred that there is a loss of postganglionic fibers at the level of the sympathetic ganglion. Furthermore, Minor's method revealed heterogeneity in the volume of sweat produced within the areas where sweating persisted. This heterogeneity may be explained by variations in the number of nerves remaining within each sympathetic ganglion. However, because the distribution of sweating appears not to correspond precisely to the sympathetic segments, it cannot be ruled out that sweat gland function is influenced by the local skin conditions.There is currently no established method for the restoration of sweating in patients with segmental or asymmetrical anhidrosis. For the present patient, therefore, the treatment focused on preventing heatstroke (1). Specifically, we advised him to take frequent breaks when in hot environments and when exercising, and to regularly apply a wet towel to help compensate for the lack of sweating.Figure 1. Pigmentation of areas of skin unaffected by asymmetrical anhidrosis. (A, B) Skin of the patient's anterior (A) and posterior trunk (B). He had hyperpigmentation on his left shoulder, right chest and abdomen, and right upper back. (C-F) Results of the thermal sweating test using Minor's method (C, anterior; D, posterior) and thermography (E, anterior; F, posterior). Areas that turned black using Minor's method (C, D) and areas that appeared to have a low temperature on thermography (E, F) indicated intact sweating. The areas of pigmentation (A, B) and sweating (C-F) largely coincided. (G, H) Hematoxylin and eosin (HE)-stained skin sections, showing the eccrine glands in the patient's right back, where sweating was present (G), and in his left back, where no sweating occurred (H). The glands in the areas where no sweating was observed were slightly atrophied (H) compared with those in the areas where sweating was observed (G). (I, J, K) Immunohistochemistry for tubulin β3 (BioLegend antibody #801213) in the skin of the right (I) and left (J, K) sides of the patient's back. (L, M) HE images of the epidermis and dermis in the right back (L) and the left back (M). In the right back (L), where sweating was observed, there was slightly more pigmentation in the basal layer of the epidermis and a slight thickening of the epidermis compared with the findings in the left back (M). In addition, the collagen fibers in the dermis of the right back (L) tended to be slightly thicker than those of the left back (M). (N, O) Thickness of the epidermis, measured at the five thinnest points between the rete ridges, as indicated by the double-headed arrows in the skin sections from the right (N) and left (O) sides of the patient's back. (P, Q) Immunohistochemistry for S100 (Abcam antibody #4066) in skin sections of the right (P) and left (Q) sides of the patient's back. Scale bars: 20 μm (G), 50 μm (L).