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Differences in skin lesions of endogenous and exogenous Cushing’s patients

Introduction Cushing’s syndrome is a rare condition characterized by increased glucocorticoid levels. Dermatologically, it causes a variety of skin conditions such as atrophy, striae, acne, plethora, hypertrichosis, hirsutism, acanthosis nigricans, hyperpigmentation, alopecia, purpura and fragile skin. Although skin lesions of Cushing’s syndrome have been described, exogenous and endogenous types have not been studied in detail. Aim To determine differences in possible skin lesions depending on the cause of Cushing’s syndrome. Material and methods A total of 35 patients – 16 iatrogenic Cushing’s syndrome patients and 19 endogenous Cushing’s syndrome patients – who were diagnosed in Erciyes University and 15 healthy individuals were included in this study. Results There was at least one skin finding in 34 (97.1%) of the patients with Cushing’s syndrome and 9 (60%) in the control group (p = 0.001). Comparison regarding skin findings in patient and control groups revealed that hypertrichosis, hyperpigmentation, and fungal infections were significantly more frequent in the patient group than the control group. Hirsutism was found more frequently in the endogenous group whereas stria, hypertrichosis and fungal infections were more frequent in the exogenous group. Conclusions Since Cushing’s syndrome is a rare disease and it is often diagnosed later in life, data on the frequency of skin findings are limited and sparse in the literature. In the comparison of endogenous Cushing’s and exogenous Cushing’s groups, acne, hypertrichosis, and fungal infections were found more frequently in the exogenous Cushing’s group and hirsutism more frequently in the endogenous Cushing’s group.


Introduction
Cushing' s syndrome (CS) is a rare condition characterized by increased glucocorticoid levels. This clinical picture may originate from excess production of glucocorticoids by the pituitary gland or adrenal gland (endogenous), as well as by ectopic secretion from other tissues or by cortisol-containing drug intake (exogenous) [1].

Aim
Although skin lesions of CS have been described, exogenous and endogenous types have not been studied in detail. In this study, our aim was to determine the possible differences of skin lesions depending on the cause of CS.

Material and methods
The study was carried out between November 2012 and August 2013 in Erciyes University Faculty of Medicine Department of Dermatology and Venereal Diseases.
This study was approved by the Erciyes University Faculty of Medicine Ethics Committee (Ethics Committee Approval number: 2012/628). Volunteers involved in the study were given information about the procedures to be applied and written approval was obtained.
In this study, the patient group consisted of 16 patients with the diagnosis of pemphigus and alopecia totalis and who developed iatrogenic CS after systemic steroid treatment for at least 3 months (0.5-1 mg/kg/day) at the Erciyes University Department of Skin and Venereal Diseases and 19 patients (35 patients in total) who were diagnosed with CS at the Erciyes University Department of Endocrine and Metabolism. Patients under 18 years of age and older than 65 years of age and patients who received treatment for the disease and achieved remission or were receiving treatment for this disease were not included in this study. The control group included 15 volunteers within the ages of 18-65 with no known and identified chronic disease.
Patients and controls were evaluated in terms of stria, acne, hirsutism, hypertrichosis, alopecia, ecchymosis, acanthosis nigricans and hyperpigmentation and present findings were recorded. Patients with endogenous CS and iatrogenic Cushing's were included in the study in the first period of diagnosis. The dermatological examinations of the patients were done in detail by the same doctor (FE). Acne severity was scored 0-3 (0: none, 1: mild, 2: moderate, 3: severe). The developing striae based on CS are pinker and wider, while the striae base on weight gain are paler and narrower. Taking this into account, the striae were evaluated according to their color: 0: none, 1: mild, 2: moderate and 3: severe [14]. Flexural areas such as axilla, inguinal, and neck were evaluated for acanthosis nigricans. For hyperpigmentation, the face region was evaluated together with the flexural areas. Alopecia was not typed. Hirsutism and hypertrichosis were recorded as either present or absent.

Statistical analysis
All statistical analyses were performed using the Statistical Package for Social Sciences (SPSS) 22 for Windows. The conformity of the data to the normal distribution was checked by the Shapiro-Wilk test. Measurable (quantitative) data were presented as mean ± standard deviation. Variables that did not fit a normal distribution were expressed as median and minimum-maximum values. Student's t test was used to evaluate the difference between the patient and the control group for the normal distribution-matched data.
The c 2 test was used for the evaluation of categorical variables of the patients' and the control group's find-ings. The distribution of countable data is defined as % (percent). In all tests p-values below 0.05 were considered statistically significant.

Demographic findings
Of the 50 people who were included in the study, 35 belonged to the patient group and 15 belonged to the control group. In the patient group, 19 (54.2%) patients had endogenous Cushing's whereas 16  There was at least 1 skin finding in 34 (97.1%) of the patients with CS and 9 (60%) in the control group (p = 0.001). The only case with no skin findings in patients with CS was in the endogenous group.

Evaluation of skin findings of the control and the patient groups
In comparison of patient and control group skin findings, hypertrichosis, hyperpigmentation and fungal infection were significantly more frequent in the patient group than in the control group (Table 2, p < 0.05). The frequency of skin tag lesions was significantly higher in the control group. There was no significant difference in other skin lesions ( Table 2, p > 0.05).

Evaluation of skin findings between endogenous, exogenous and control groups
In comparison of endogenous and exogenous groups' skin findings, frequency of hyperpigmentation was higher in the endogenous group than in the control group, whereas frequency of hypertrichosis, stria, hyperpigmentation and fungal infections was significantly higher in the exogenous group (p < 0.05). When endogenous and the exogenous groups were compared, there was a significant difference in stria, hirsutism, hypertrichosis and  Table 3). While hirsutism was higher in the endogenous group, stria, hypertrichosis and fungal infections were higher in the exogenous group. The stria evaluation of the endogenous group was as follows: 84.2% had no striae (0), 5.3% had moderate (2) striae and 10.5% had severe striae (3). These frequencies for the exogenous group were as follows: 50% had no striae (0), 37.5% had mild striae (2) and 12.5% had severe striae (3).
Glucocorticoids cause acne and seborrhea by the proliferation of sebocytes. Glucocorticoids also reduce the synthesis of dermal collagen and collagenous tissue by regulating the expression of matrix metalloproteinase (MMP) and other tissue inhibitors and thereby cause striae and skin atrophy by this dermal scarring. Hypertrichosis and hirsutism are the result of glucocorticoids formed by androgenic receptors and adrenal androgen increase or cortisol increase on terminal and veil hair [15,16].
In the European Registry on CS, the frequency of skin alteration was reported as 73.3% (311/424) for endogenous CS and 75% (18/24) for exogenous CS [13]. In our study, 97.1% of the patients with CS and 60% of the control group had at least 1 skin finding. In our study, the only patient without skin findings among the CS patients belonged to the endogenous group. The more frequent detection of skin findings in our study may be due to the detailed examination of skin findings by a dermatologist.
In a study of Stratakis et al. on 36 CS patients including children and adolescents between 6 and 21 years of age, striae were found in 77.7% of patients, acne in 58.3%, hirsutism in 63.7%, acanthosis nigricans in 27.7%, ecchymosis in 27.7%, hyperpigmentation in 16.6% and fungal infection in 11.1% [12].
In another study consisting of a total of 302 patients with 239 women and 63 men with CS, the results were reported as follows: acne and hirsutism 72%, skin atrophy 62% and fungal infection 6% [17].
In our study, fungal infection was found in 54.3% of patients, striae in 31.4%, ecchymosis in 42.9%, hypertrichosis in 42.9%, hyperpigmentation in 31.4%, alopecia in 28.6%, acne in 14.3%, hirsutism in 14.3 % and acanthosis nigricans in 11.4%. Compared to similar studies, striae, acne, acanthosis nigricans and hirsutism were less frequent; hyperpigmentation, ecchymosis and fungal infections were more frequent in our study [17]. Differences in skin finding frequencies can be attributed to similar studies being conducted on patients with free endog-  enous CS and the duration of exposure to cortisone in exogenous Cushing's patients on our follow-up [14].
In the comparison of endogenous and exogenous groups, rates of acne, hypertrichosis, and fungal infections were found to be higher in the exogenous group and hirsutism was more frequent in the endogenous group.
In addition, compared to the control group, hyperpigmentation in endogenous Cushing's patients and hyperpigmentation, hypertrichosis, stria and fungal infections in the exogenous Cushing's patients were found to be more frequent. As we observed in our study, patients with endogenous Cushing's had been diagnosed late because it took a long time for the clinical findings to become apparent, but patients with the disease of exogenous origin were referred earlier with more prominent clinical findings.
The most important limitation of our study was that we could not evaluate the clinical state after the treatment of the patients in the endogenous group and after the cessation of steroid therapy and the cortisol levels returned to baseline levels in the exogenous group. Another drawback of the study was the lower average age of the volunteers in the control group. Finally, the fact that the study was conducted in a small group of patients and single-centered was another limitation for us.

Conclusions
Since CS is a rare disease and it is often diagnosed late, data on the frequency of skin findings are limited and sparse in the literature. The single-center case series consisted of a small number of patients, but a high number of cases has only been achieved in multicenter studies. Another difference in our study is that we included cases with exogenous CS, but also observed clinical differences between endogenous and exogenous CS patients in terms of dermatological findings. More detailed studies on this topic on larger numbers of cases with longer follow-ups will make a bigger contribution to knowledge of the issue.