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We report here a 62-year-old man with long-standing Cushing’s disease. The patient had persistent hypercortisolaemia despite repeated resection of the pituitary adenoma. Pharmacological therapy was unsuccessful. Ultimately, he underwent bilateral adrenalectomy after which biochemical remission was achieved and symptoms resolved. Further follow-up was unremarkable, except that vitiligo appeared.
Two years postoperatively, he presented with severe headache, vision loss and hyperpigmentation of the skin areas not affected by vitiligo (Fig. 1). Laboratory testing showed a steep rise in adrenocorticotrophic hormone (ACTH) and magnetic resonance imaging (MRI) revealed a large sellar tumour. Debulking surgery was performed and tissue pathology was compatible with an aggressive ACTH-secreting pituitary tumour (Ki-67 > 50%, P53 > 50%).
Clinical presentation. Photograph of the patient’s head and neck showing a sharp demarcation between skin areas with depigmentation due to vitiligo, and skin areas not affected by vitiligo with profound hyperpigmentation. The patient is deceased. His son has given written informed consent to publication of his father’s case details.
Because the triad hyperpigmentation, excessive ACTH secretion, and an ACTH-secreting pituitary tumour was present, the diagnosis of Nelson’s syndrome was made (1). Nelson’s syndrome is a rare complication of bilateral adrenalectomy (1). Despite adjuvant radio-chemotherapy, the patient developed bone and liver metastases (Fig. 2). He opted for palliative care and died 1 month later.
The coexistence of 2 contrasting dermatological conditions, vitiligo and hyperpigmentation, forms a remarkable clinical image in which the patient’s normal skin colour is no longer visible.
As a reminder, Cushing’s disease occurs when the pituitary gland produces excessive levels of ACTH due to a benign pituitary tumour. In response, the adrenal glands produce too much cortisol, resulting in hypercortisolaemia.
We hypothesize that the appearance of vitiligo after treating Cushing’s disease is not an incidental finding. Due to hypercortisolaemia, the active phase of Cushing’s disease is associated with a state of immunosuppression (2, 3). After disease remission, and thereby normalization of hypercortisolaemia, rebound autoimmunity may occur (2, 3). A wide range of new-onset and exacerbations of autoimmune diseases during the remission phase of Cushing’s disease was reported, including autoimmune thyroiditis, Graves’ disease, coeliac disease, rheumatoid arthritis, sarcoidosis, and vitiligo, as illustrated by this case (2, 3). However, the exact mechanism leading to autoimmunity after remission of Cushing’s disease is not yet fully understood (2).
Bilateral adrenalectomy is an effective and definitive treatment for patients with Cushing’s disease refractory to pituitary surgery, radiotherapy, or pharmacological treatment (4). Although, it exposes patients to the risk of developing Nelson’s syndrome (4). In patients with Cushing’s disease, bilateral adrenalectomy resolves hypercortisolaemia, but also releases the hypothalamic–pituitary–adrenal axis from the negative feedback control of cortisol (5, 6). Without negative feedback, corticotrophin-releasing hormone levels rise, resulting in increased production of proopiomelanocortin and its subsequent products ACTH and alpha-melanocyte stimulating hormone (4–6). Both ACTH and alpha-melanocyte-stimulating hormone stimulate melanogenesis by binding melanocortin-1 receptors on melanocytes and keratinocytes (7, 8). Furthermore, it is hypothesized that excessive corticotrophin-releasing hormone levels after bilateral adrenalectomy can lead to the progression of a residual corticotroph tumour, contributing to the abundance of circulating ACTH (4, 6). Consequently, the profound hyperpigmentation characteristic of Nelson’s syndrome results from excessive ACTH secretion (8). In the current case, the hyperpigmentation is particularly visible in contrast to the skin areas affected by vitiligo.
To our knowledge this is the first published case of a patient with coexistence of vitiligo and hyperpigmentation due to underlying endocrine disorders. The development of vitiligo is an example of rebound autoimmunity after remission of Cushing’s disease, which underlines the necessity of close follow-up after treating Cushing’s disease to early detect autoimmune diseases. Moreover, this case demonstrates that hyperpigmentation after bilateral adrenalectomy may be an indication of Nelson’s syndrome as a rare, but potentially life-threatening, postoperative complication. In conclusion, it is vital to identify skin abnormalities as potential manifestations of endocrine diseases.
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