|Year : 2022 | Volume
| Issue : 1 | Page : 48-49
Mucocutaneous hyperpigmentation as a clue to diagnose Addison disease – Two case reports
Hsuan Chen1, Fu-Nien Hsieh2, Chao-Chun Yang3
1 Department of Dermatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
2 Department of Dermatology, St. Martin De Porres Hospital, Chiayi, Taiwan
3 Department of Dermatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University; International Center for Wound Repair and Regeneration, National Cheng Kung University, Tainan, Taiwan
|Date of Submission||17-Jun-2021|
|Date of Decision||21-Nov-2021|
|Date of Acceptance||09-Dec-2021|
|Date of Web Publication||10-Mar-2022|
Dr. Chao-Chun Yang
Department of Dermatology, National Cheng Kung University Hospital, No. 138, Sheng-Li Rd., Tainan 704
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Chen H, Hsieh FN, Yang CC. Mucocutaneous hyperpigmentation as a clue to diagnose Addison disease – Two case reports. Dermatol Sin 2022;40:48-9
Pigmentation in the oral cavity is commonly encountered in the clinic but very often a diagnostic dilemma for clinicians. The pattern and morphology of pigmentation are variable, including focal or diffuse distribution, and macular, popular, or nodular lesions. The underlying etiologies are diverse. Among all the etiologies, primary adrenal insufficiency, also known as Addison disease, can be life-threatening due to adrenal crisis. Therefore, early and prompt recognition of Addison disease is important when evaluating a patient with mucocutaneous pigmentation, as exemplified by the following two cases.
A 39-year-old female presented with progressive oral mucosal hyperpigmentation for 3–4 months. Physical examination showed multiple pigmented macules on the buccal mucosa, palate, gingiva, tip of the tongue, and lips [Figure 1]a and [Figure 1]b. Bilateral dorsal hands and feet, especially knuckles and periungual areas, nails, and palmar creases, also became pigmented [Figure 1]c and [Figure 1]d. She also suffered from chronic fatigue, poor appetite, and significant body weight loss for 4 months and amenorrhea for 1 year. There was no hypotension or hypoglycemia. She denied tobacco, medications, or heavy metal exposure history. Laboratory tests showed low morning serum cortisol level (0.06 μg/dL [normal, 6.2–19.4 μg/dL]), low serum aldosterone level (19.2 pg/ml), and elevated serum adrenocorticotropic hormone (ACTH) (994.7 pg/mL [normal, <46 pg/ml]), by which Addison disease was diagnosed. There was no electrolytes imbalance, and the sex hormone, prolactin, and HbA1c were within normal range. The thyroid function tests showed normal result and the abdominal ultrasound was unremarkable.
|Figure 1: (a and b) Multiple pigmented macules on oral mucosa, tongue, and lips. (c and d) Hyperpigmentation of bilateral hands, especially knuckles and periungual areas, nails, and palmar creases.|
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Another 57-year-old woman presented with a 2-year history of general weakness and pigmented patches over the lips, tongue, and buccal mucosa [Figure 2]a, [Figure 2]b, [Figure 2]c, [Figure 2]d. There were also pigmented macules over the face, upper back, palmar creases, fingers, finger nails, and peri-articular area of the extremities. Laboratory data showed elevated plasma ACTH level (1065 pg/ml), low morning cortisol level (5.14 μg/dL), and impaired adrenal function by insulin tolerance test (plasma cortisol level after insulin challenge, 1.52 μg/dL [normal, >18 μg/dL]), as the typical findings of Addison disease. The serum electrolytes, sex hormone, and thyroid hormone were within normal range. The abdominal ultrasound showed unremarkable results. Steroid replacement therapy with cortisone 37.5 mg daily was prescribed for the two cases, and their condition improved with decreased pigmentation of the skin and mucosa after 2-month treatment.
|Figure 2: Pigmented macules and patches over the (a) lips, (b) tongue, and (c and d) buccal mucosa.|
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Mucocutaneous hyperpigmentation, occurred in up to 92% of Addison disease patients, was reported to precede other manifestations of Addison disease by months to years. Pigmentation is homogeneous or blotchy and is more characteristic in sun-exposed areas and areas exposed to chronic mechanical stimulation, along with palmar creases, areolae, axillae, perineum, and umbilicus. Hair and nails may become darker as well. The oral cavity is also commonly affected with the pigmentation most commonly appeared on the gingiva, vermillion border of the lips, buccal mucosa, hard palate, and tongue.
The diagnosis of Addison disease is based on elevated serum ACTH concentration and an inability to stimulate serum cortisol levels in ACTH or insulin stimulation test. Mucocutaneous pigmentation in Addison disease results from over production of proopiomelanocortin due to the lack of cortisol feedback inhibition from adrenal glands. Proopiomelanocortin is then cleaved into ACTH, gamma-melanocyte stimulating hormone (MSH), and beta-lipotropin. The subunit ACTH undergoes further cleavage to produce alpha-MSH, which stimulates melanin synthesis via α-MSH receptor (MC1) causing hyperpigmentation.
The differential diagnosis of mucocutaneous pigmentation includes drugs, smoking, amalgam tattoo, or heavy metals exposure, which is summarized in [Supplementary Table 1], but these possibilities were excluded in our two cases by careful review of the personal and medical history. Laugier–Hunziker syndrome (LHS) is another important differential diagnosis in middle-aged women presenting as mucocutaneous hyperpigmentation. Hyperpigmentation in LHS is usually confined to the oral mucosa, and the nails involvement usually presents as longitudinal melanonychia, discrepant from the findings of our two cases.
After glucocorticoid replacement therapy, the pigmentation starts fading within several days, and completely disappears after a few months when the pigmented keratinocytes sloughing off. The timing of complete resolution of pigmentation depends on the turnover rate of normal keratinization cycle of skin and mucosa.
In summary, mucocutaneous hyperpigmentation may represent the first sign of primary adrenal insufficiency. Physicians, especially dermatologists, should be aware of this diagnosis when encountering patients with unexplained mucocutaneous pigmentation. Prompt clinical history taking and physical examination should be undertaken and, in highly suspicious case, confirmatory laboratory tests should be ordered. With appropriate steroid replacement therapy, not only the potential life-threatening events could be avoided but the pigmentation and other signs and symptoms could also be resolved.
Patient anonymity and informed consent
Written informed consent was obtained from the two patients for the publication of this report and any accompanying images.
Financial support and sponsorship
Conflicts of interest
Prof. Chao-Chun Yang, an editorial board member at Dermatologica Sinica, had no role in the peer review process of or decision to publish this article. The other authors declared no conflicts of interest in writing this paper.
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[Figure 1], [Figure 2]