Hypopigmentation - treatment, symptoms and cause of Hypopigmentation

Disorders of hyperpigmentation are also divided into two groups¾localized and diffuse. The localized forms are due to an epidermal alteration, a proliferation of melanocytes, or an increase in pigment production. Both seborrheic keratoses and acanthosis nigricans belong to the first group. Seborrheic keratoses are common lesions, but in one clinical setting they are a sign of systemic disease, and that setting is the sudden appearance of multiple lesions, often with an inflammatory base and in association with acrochordons (skin tags) and acanthosis nigricans. This is termed the sign of Leser-Trelat and signifies an internal malignancy. Acanthosis nigricans can also be a reflection of an internal malignancy, most commonly of the gastrointestinal tract, and it appears as velvety hyperpigmentation, primarily in flexural areas. In the majority of patients, acanthosis nigricans is associated with obesity, but it may be a reflection of an endocrinopathy such as acromegaly, Cushing's syndrome, the Stein-Leventhal syndrome, or insulin-resistant diabetes mellitus (type A, type B, and lipoatrophic forms).

A proliferation of melanocytes results in the following pigmented lesions: lentigo, melanocytic nevus, and melanoma. In an adult, the majority of lentigines are related to sun exposure, which explains their distribution. However, in the Peutz-Jeghers and LEOPARD [lentigines; ECG abnormalities, primarily conduction defects, ocular hypertelorism; pulmonary stenosis and subaortic valvular stenosis; abnormal genitalia (cryptorchidism, hypospadias); retardation of growth; and deafness (sensorineural)] syndromes, lentigines do serve as a clue to systemic disease. In the multiple lentigines or LEOPARD syndrome, hundreds of lentigines develop during childhood and are scattered over the entire surface of the body. The lentigines in patients with Peutz-Jeghers syndrome are located primarily around the nose and mouth, on the hands and feet, and within the oral cavity. While the pigmented macules on the face may fade with age, the oral lesions persist. However, similar intraoral lesions are also seen in Addison's disease and as a normal finding in darkly pigmented individuals. Patients with this autosomal dominant syndrome (due to mutations in a novel serine threonine kinase gene) have multiple benign polyps of the gastrointestinal tract, testicular tumors, and an increased risk of developing gastrointestinal (primarily colon), breast, and gynecologic cancers.

Lentigines are also seen in association with cardiac myxomas and have been described in two syndromes whose findings overlap: LAMB (lentigines, atrial myxomas, mucocutaneous myxomas, and blue nevi) syndrome and NAME [nevus, atrial myxoma, myxoid neurofibroma, and ephelides (freckles)] syndrome. These patients can also have evidence of endocrine overactivity in the form of Cushing's syndrome, acromegaly, or sexual precocity.

The third type of localized hyperpigmentation is due to a local increase in pigment production, and it includes ephelides and cafe au lait macules (CALM). The latter are most commonly associated with two disorders¾neurofibromatosis (NF) and McCune-Albright syndrome. CALM are flat, uniformly light brown in color, and can vary in size from 0.5 to 12 cm. Approximately 80% of adult patients with type I NF will have six or more CALM measuring 1.5 cm or greater in diameter. Additional findings are discussed in the section on neurofibromas. In comparison with NF, the CALM in patients with McCune-Albright syndrome [polyostotic fibrous dysplasia with precocious puberty in females due to mosaicism for an activating mutation in a G protein (Gsa) gene] are usually larger, more irregular in outline, and tend to respect the midline. CALM have also been associated with pulmonary stenosis (Watson syndrome), tuberous sclerosis, the LEOPARD syndrome, and ataxia telangiectasia, but a few such lesions can be found in normal individuals.

In incontinentia pigmenti, dyskeratosis congenita, and bleomycin pigmentation, the areas of localized hyperpigmentation form a pattern¾swirled in the first, reticulated in the second, and flagellate in the third. Patients with the X-linked dominant disorder incontinentia pigmenti can have linear blisters and verrucous papules during infancy. During childhood, parallel swirls and streaks of hyperpigmentation appear on the trunk, and occasionally streaks of hypopigmentation appear on the extremities. Associated findings include seizures, mental retardation, retinal vascular abnormalities, and delayed or impaired dentition. Biopsy specimens of the streaks will show pigment within dermal macrophages ("incontinent pigment"). In dyskeratosis congenita, atrophic reticulated hyperpigmentation is seen on the neck, thighs, and trunk and is accompanied by nail dystrophy, pancytopenia, and leukoplakia of the oral and anal mucosa. The latter often develops into squamous cell carcinoma. In addition to the flagellate pigmentation (linear streaks) on the trunk, patients receiving bleomycin often have hyperpigmentation on the elbows, knees, and small joints of the hand.

Localized hyperpigmentation is seen as a side effect of several other systemic medications, including those that produce fixed drug reactions [phenolphthalein, nonsteroidal anti-inflammatory drugs (NSAIDs), sulfonamides, and barbiturates] and those that can complex with melanin (antimalarials). Fixed drug eruptions recur in the same location as circular areas of erythema that can become bullous and then resolve as brown macules. The eruption usually appears within hours of administration of the offending agent, and common locations include the genitalia, extremities, and perioral region. Chloroquine and hydroxychloroquine produce gray-brown to blue-black discoloration of the shins, hard palate, and face, while blue macules can be seen on the lower extremities and in sites of inflammation with prolonged minocycline administration. Estrogen in oral contraceptives can induce melasma¾symmetric brown patches on the face, especially the cheeks, upper lip, and forehead. Similar changes are seen in pregnancy, in patients receiving hydantoin, and in the adult form of Gaucher's disease. In the latter group there is also hyperpigmentation of the distal lower extremities.

In the diffuse forms of hyperpigmentation, the darkening of the skin may be of equal intensity over the entire body or may be accentuated in sun-exposed areas. The causes of diffuse hyperpigmentation can be divided into four groups¾endocrine, metabolic, autoimmune, and drugs. The endocrinopathies that frequently have associated hyperpigmentation include Addison's disease, Nelson syndrome, and ectopic ACTH syndrome. In these diseases, the increased pigmentation is diffuse but is accentuated in the palmar creases, sites of friction, scars, and the oral mucosa. An overproduction of the pituitary hormones a-MSH (melanocyte-stimulating hormone) and ACTH can lead to an increase in melanocyte activity. These peptides are products of the proopiomelanocortin gene and exhibit homology; e.g., a-MSH and ACTH share 13 amino acids. A minority of the patients with Cushing's disease or hyperthyroidism have generalized hyperpigmentation.

The metabolic causes of hyperpigmentation include porphyria cutanea tarda (PCT), hemochromatosis, vitamin B12 deficiency, folic acid deficiency, pellagra, malabsorption, and Whipple's disease. In patients with PCT (see "Vesicles/Bullae"), the skin darkening is seen in sun-exposed areas and is a reflection of the photoreactive properties of porphyrins. The increased level of iron in the skin of patients with hemochromatosis stimulates melanin pigment production and leads to the classic bronze color. Patients with pellagra have a brown discoloration of the skin, especially in sun-exposed areas, as a result of nicotinic acid (niacin) deficiency. In the areas of increased pigmentation, there is a thin varnish-like scale. These changes are also seen in patients who are vitamin B6 deficient, have functioning carcinoid tumors (increased consumption of niacin), or take isoniazid. Approximately 50% of the patients with Whipple's disease have an associated generalized hyperpigmentation in association with diarrhea, weight loss, arthritis, and lymphadenopathy. A diffuse slate-blue color is seen in patients with melanosis secondary to metastatic melanoma. Although there is a debate as to whether the color is due to single-cell metastases in the dermis or to a widespread deposition of melanin resulting from the high concentration of circulating melanin precursors, there is more evidence to support the latter.

Of the autoimmune diseases associated with diffuse hyperpigmentation, biliary cirrhosis and scleroderma are the most common, and occasionally, both disorders are seen in the same patient. The skin is dark brown in color, especially in sun-exposed areas. In biliary cirrhosis the hyperpigmentation is accompanied by pruritus, jaundice, and xanthomas, whereas in scleroderma it is accompanied by sclerosis of the extremities, face, and, less commonly, the trunk. Additional clues to the diagnosis of scleroderma are telangiectasias, calcinosis cutis, Raynaud's phenomenon, and distal ulcerations (see "Telangiectasias"). The differential diagnosis of cutaneous sclerosis with hyperpigmentation includes the POEMS [polyneuropathy; organomegaly (liver, spleen, lymph nodes); endocrinopathies (impotence, gynecomastia); M-protein; and skin changes] syndrome. The skin changes include hyperpigmentation, skin thickening, hypertrichosis, and angiomas.