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Increased skin pigmentation can be caused by excessive ACTH secretion in Addison’s disease and can occur after bilateral adrenalectomy for Cushing’s disease (Nelson’s syndrome). Pigmentation can be generalized or may be localized to palmar creases, extensor joint surfaces, tongue, nails, belt or bra lines, freckles, or new scars.

Pigmentation of the upper lip, forehead, or malar eminences, known as chloasma, can be caused by pregnancy (“mask of pregnancy”), oral contraceptives, or estrogen replacement therapy.

Acanthosis nigricans presents as velvety brown thickened skin of the neck and axillae. It may be associated with syndromes of severe insulin resistance type A (ovarian dysfunction and hirsutism) or type B (autoimmune). It may also be familial or associated with obesity, acromegaly, or thyroid disease. Acanthosis presenting after age 35 years is often a sign of an underlying malignancy, such as hepatocellular carcinoma.

Pretibial areas of pigmentation are common in diabetes (“diabetic shin spots”) as a result of minor trauma or following necrobiosis lipoidica diabeticorum.

Prominent lentigines can be a sign of Carney’s complex, an autosomal dominant condition associated with atrial myxomas, schwannomas, and endocrine overactivity (eg, tumors of the thyroid, gonads, or pigmented adrenal nodular hyperplasia). Similar skin pigmentation is seen in Peutz–Jeghers syndrome with an increased risk of intestinal polyposis, adenocarcinoma, breast cancer, and tumors of the gonads and thyroid.

Diffuse hyperpigmentation is seen in POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes) syndrome; adrenal insufficiency, hypoparathyroidism, diabetes, osteosclerotic bone lesions, or thiamine deficiency may occur.

Gray-brown (“bronze”) hyperpigmentation is caused by hemochromatosis, which can cause endocrine deficiencies such as diabetes mellitus. An orange skin discoloration is characteristic of jaundice and carotenodermia (caused by ingestion of large amounts of carotene in vegetables, seaweed, or vitamin preparations).

Patchy hypopigmentation can be due to vitiligo, a condition sometimes associated with Addison’s disease and with other endocrine deficiencies as part of the polyglandular autoimmune syndrome. Hypopigmentation can also be a manifestation of cobalamin deficiency, trisomy 13, and various dermatologic conditions.

Patients undergoing chronic hemodialysis frequently become hyperpigmented, and hypopigmentation has also been reported. Other causes of hyperpigmentation include sprue, malnutrition, HIV infection, and porphyria. Hyperpigmentation may be caused by certain drugs: amiodarone, arsenic, bleomycin, busulfan, clofazimine, hydroxychloroquine, chlorpromazine, doxorubicin (nail beds), imipramine, methimazole, minocycline, niacin, primaquine, propylthiouracil, topical tretinoin, and zidovudine (nails).