Peutz-Jeghers syndrome

Hyperpigmentation may be the sign of a benign or relatively easily treated condition, or it may indicate the presence of a life-threatening condition such as melanoma. This two-part article presents a suggested approach to adult patients with increased pigmentation and reviews various underlying causes.

Melanocytes and Pigmentation

Melanocytes are derived embryonically from neural crest cells that migrate into the basal layer of the epidermis. In the skin, melanocytes continuously produce melanosomes--organelles that are transferred to keratinocytes. The melanosomes convert tyrosine to melanin, giving skin its color. Under the stimulus of hormones or irritation, the production of melanosomes increases, leading to hyperpigmentation. In response to sun exposure or idiopathically in some disorders, hyperplasia of melanocytes occurs and causes hyperpigmentation. (1)

The same melanocyte concentration is present in persons of all races who have normal skin. However, some races have larger melanosomes, giving their skin a darker color. (2,3)

Diagnostic Approach

A simple way to approach hyperpigmentation is to consider whether the increase in color is caused by an increase of melanin, an increase in melanocytes, or the deposition of another substance that adds color to the skin (Figure 1). Selected disorders and their characteristics are discussed in the following sections and summarized in Table 1; other disorders are discussed and summarized in part II of this article.

[FIGURE 1 OMITTED]

A directed history and physical examination offer clues to the underlying cause of hyperpigmentation. The history should address the time of onset of the lesion, because some disorders (e.g., neurofibromatosis) are congenital, while others develop in childhood (e.g., ephelides) or during pregnancy (e.g., melasma). Systemic symptoms may indicate the presence of hyperthyroidism, Addison's disease, or diabetes-related disorders. A review of medication use, supplement use, and exposure to plants and ultraviolet radiation can help determine whether hyperpigmentation is caused by a medication side effect or a phototoxic reaction.

The size and number of the lesions are useful in diagnosing neurofibromatosis, ephelides, and lentigines. The border, color, and character of a lesion help to distinguish melanoma from a benign lesion, while the distribution of skin changes assists in the diagnosis of melasma and acanthosis nigricans. Congenital Lesions: Cafe au Lait Macules

Cafe au lait (coffee with milk) macules can be congenital, or they may develop in childhood. These flat macules usually occur on the trunk and can have a smooth or irregular border (Figure 2). They range from 0.2 to 4 cm in diameter in infants but can reach 30 cm in diameter in adults. (3) The hyperpigmentation is caused by increased melanin in melanocytes and basal keratinocytes. (4)

Cafe au lait macules may be a sign of neurofibromatosis. The diagnosis of this disease requires the presence of at least two of seven criteria established at a National Institutes of Health (NIH) consensus development conference (Table 2). (5) The presence of six or more cafe au lait macules is one of the diagnostic criteria; axillary or groin freckling is another (Figure 3). Hence, the presence of axillary or groin freckling should prompt a search for cafe au lait macules, and vice versa. If neurofibromatosis is suspected or confirmed, an ophthalmologist can detect optic gliomas and iris hamartomas, which are additional criteria for the diagnosis of neurofibromatosis. The American Academy of Dermatology has practice guidelines based on the NIH definition. (5) [Evidence level C, consensus opinion]

Cafe au lait macules themselves require treatment only if cosmesis is requested. Surgical or laser treatment by a cosmetic dermatologist may be considered on an individual basis. From a practical standpoint, neurofibromas, which can occur throughout the body, pose more of a cosmetic and functional concern (Figure 4).

Consultation with a geneticist may be prudent because neurofibromatosis is an autosomal dominant condition, although spontaneous mutations cause 50 percent of cases. (6) Some patients have cafe au lait macules without neurofibromatosis; their children are not at increased risk for the disease.

Diffuse Hyperpigmentation

Diffuse hyperpigmentation may have a systemic cause, such as Addison's disease, hyperthyroidism, or hemochromatosis. It also may occur because of a medication side effect.

In Addison's disease, the adrenal glands fail to produce adequate amounts of mineralocorticoids and glucocorticoids. When elevations of melanocyte-stimulating hormone and adrenocorticotropic hormone (also referred to as corticotropin) levels occur as the pituitary gland tries to stimulate the adrenal glands, melanin production increases, causing hyperpigmentation with a "muddy" appearance. (7) The hyperpigmentation is diffuse, but more pronounced in sun-exposed areas and in the perineum, axillae, areolae, palms, and soles. (8) Patients with Addison's disease should be treated with mineralocorticoid and glucocorticoid replacement to reduce the drive for excess production of adrenocorticotropic hormone and melanocyte-stimulating hormone.

Hyperthyroidism causes a pattern of hyperpigmentation similar to that in Addison's disease, especially in patients with darker complexions. (9) Treatment is specific to the cause of hyperthyroidism and may involve antithyroid medications, surgical resection of the thyroid, or radioactive iodine therapy.

Hemochromatosis, a disorder of iron storage and deposition, can cause a slate-gray hyperpigmentation (because of hemosiderin deposition). Hyperpigmentation is present in 70 percent of affected patients at diagnosis. (10) Bronzing resulting from increased melanin production is common, although the mechanism for this effect is not known. (11) Hemochromatosis is treated with repeated phlebotomy to reduce excessive iron stores. (12)

Lesions from Chronic Sun Exposure

The normal response to solar radiation (or tanning beds) is an increase in melanin production, which causes uniform tanning in most persons but leads to freckling in some. Ephelides, or freckles, are small (usually less than 3 mm in diameter), red or light- to dark-brown macules that appear on sun-exposed areas of the body (Figure 5). Lentigines are tan, brown, or black macules, 2 to 20 mm in diameter, that occur anywhere on the body (Figure 6).

Lentigines have increased numbers of melanocytes that produce dense epidermal deposits of melanin. In contrast to lentigines, ephelides have a normal number of melanocytes but an increased number of melanosomes. (13) Because both lentigines and ephelides are benign, differentiation is not critical.

Ephelides and lentigines can be too numerous to count. This factor and their relative uniformity of color help to distinguish them from nevi, which have more serious implications. If lesions are larger than several millimeters or display abnormal coloration, the differential diagnosis includes nevi, which may require surgical removal because of possible malignancy.

Multiple lentigines in the skin, lips, and mucous membranes should raise suspicion for Peutz-Jeghers syndrome. This autosomal dominant syndrome is associated with polyposis of the gastrointestinal tract and an increased risk of cancers of the pancreas, lung, breast, ovary, and uterus. (14) [Evidence level B, retrospective cohort study]

Treatment of ephelides and lentigines is for cosmesis only. Avoidance of sun exposure and the use of sunscreens and make-up or moisturizers that contain sunscreens can decrease the development of additional lesions. If desired, patients can be treated with bleaching solutions or with peeling agents by a professional who is experienced in their use, such as a dermatologist. However, results are slow, and complications such as irritation and hyperpigmentation can occur. Bleaching agents include hydroquinone (Eldoquin Forte), which is available in 2 to 4 percent creams and gels. Laser therapy also is an option, but because of the frequency and broad distribution of these lesions, referral to a cosmetic dermatologist is appropriate.

Lesions from Phototoxic Reactions

Hyperpigmentation can be caused by phototoxic reactions from the use of systemic or topical medications (Table 3) (15) or from contact with certain plants or foods in conjunction with sun exposure (16) (phytophotodermatitis). Initially, patients develop an erythematous allergic reaction. There can be an inflammatory response with lymphocytes, eosinophils, and edema, which can result in a bullous reaction on sun-exposed skin. Over time, hyperkeratosis and melanocytic hyperplasia develop, causing hyperpigmentation. (1) Some medications result directly in hyperpigmentation, without sun exposure, in a diffuse pattern (17,18) (Table 4). (17,19,20) Examples of plant materials and foods that may be associated with phytophotodermatitis include lemons, limes, fig leaves or stems, celery, dill, parsnips, and carrot juice. (16)

Patients with phototoxic reactions should discontinue use of the offending medication or contact with the offending substance. If necessary, exposure to sunlight should be avoided. For cosmetic concerns, phototoxic reactions that fail to resolve spontaneously should be managed similarly to melasma, which is discussed in part II of this article.

TABLE 2

Diagnostic Criteria for Neurofibromatosis

Diagnosis requires the presence of two or more of the following:

1. Six or more cafe au lait macules larger than 5 mm in greatest diameter in prepubertal persons and larger than 15 mm in greatest diameter in postpubertal persons

2. Two or more neurofibromas of any type or one plexiform neurofibroma

3. Freckling in the axillary or inguinal region

4. Optic glioma

5. Two or more Lisch nodules (iris hamartomas)

6. A distinctive osseous lesion such as sphenoid dysplasia or thinning of long bone cortex with or without pseudoarthrosis

7. A first-degree relative (i.e., parent, sibling, child) with neurofibromatosis type 1 by the above criteria

Information from reference 5.

TABLE 4

Medications That May Cause Hyperpigmentation

Amiodarone (Cordarone)

Amitriptyline (Elavil)

Arsenic

Bismuth

Bleomycin (Blenoxane)

Busulfan (Myleran)

Clofazimine (Lamprene)

Cyclophosphamide (Cytoxan)

Daunorubicin (DaunoXome, Cerubidine)

Doxorubicin (Adriamycin)

Gold (may cause chrysiasis)

Mercury

Minocycline (Minocin)

Nitrogen mustard (topical)

Phenothiazines

Silver (may cause argyria)

Zidovudine (Retrovir)

Information from references 17, 19, and 20.

REFERENCES

(1.) Crowson AN, Magro CM. Recent advances in the pathology of cutaneous drug eruptions. Dermatol Clin 1999;17:537-60,viii.

(2.) Jimbow K, Quevedo WC Jr, Fitzpatrick TB, Szabo G. Biology of melanocytes. In: Freedberg IM, Fitzpatrick TB, eds. Fitzpatrick's Dermatology in general medicine. 4th ed. New York: McGraw-Hill, 1993:261-89.

(3.) Landau M, Krafchik BR. The diagnostic value of cafe-au-lait macules. J Am Acad Dermatol 1999; 40(6 pt 1):877-90.

(4.) Ortonne JP, Brocard E, Floret D, Perrot H, Thivolet J. Diagnostic value of cafe-au-lait spots [in French]. Ann Dermatol Venereol 1980;107:313-27.

(5.) Eichenfield LF, Levy ML, Paller AS, Riccardi VM. Guidelines of care for neurofibromatosis type 1. American Academy of Dermatology Guidelines/ Outcomes Committee. J Am Acad Dermatol 1997;37:625-30.

(6.) Friedman JM. Epidemiology of neurofibromatosis type 1. Am J Med Genet 1999;89:1-6.

(7.) Ten S, New M, Maclaren N. Clinical review 130: Addison's disease 2001. J Clin Endocrinol Metab 2001;86:2909-22.

(8.) Thiboutot DM. Clinical review 74: Dermatological manifestations of endocrine disorders. J Clin Endocrinol Metab 1995;80:3082-7.

(9.) Leonhardt JM, Heymann WR. Thyroid disease and the skin. Dermatol Clin 2002;20:473-81,vii.

(10.) Niederau C, Strohmeyer G, Stremmel W. Epidemiology, clinical spectrum and prognosis of hemochromatosis. Adv Exp Med Biol 1994;356:293-302.

(11.) Ward SK, Roenigk HH, Gordon KB. Dermatologic manifestations of gastrointestinal disorders. Gastroenterol Clin North Am 1998;27:615-36,vi.

(12.) Brandhagen DJ, Fairbanks VF, Baldus W. Recognition and management of hereditary hemochromatosis. Am Fam Physician 2002;65:853-60.

(13.) Hyperpigmented lesions. In: Behrman RE, Kliegman R, Jenson HB, eds. Nelson Textbook of pediatrics. 16th ed. Philadelphia: Saunders, 2000:1983-4.

(14.) Boardman LA, Thibodeau SN, Schaid DJ, Lindor NM, McDonnell SK, Burgart LJ, et al. Increased risk for cancer in patients with the Peutz-Jeghers syndrome. Ann Intern Med 1998;128:896-9.

(15.) Gould JW, Mercurio MG, Elmets CA. Cutaneous photosensitivity diseases induced by exogenous agents. J Am Acad Dermatol 1995;33:551-73.

(16.) Friedlander SF. Contact dermatitis. Pediatr Rev 1998;19:166-71.

(17.) Pepine M, Flowers FP, Ramos-Caro FA. Extensive cutaneous hyperpigmentation caused by minocycline. J Am Acad Dermatol 1993;28(2 pt 2):292-5.

(18.) Kelly AP. Aesthetic considerations in patients of color. Dermatol Clin 1997;15:687-93.

(19.) Goroll AH, Mulley AG Jr, eds. Primary care medicine: office evaluation and management of the adult patient. 4th ed. Philadelphia: Lippincott Williams & Wilkins, 2000.

(20.) Skin diseases of general importance--part II. In: Cecil RL, Goldman L, Bennett JC. Cecil Textbook of medicine. 21st ed. Philadelphia: Saunders, 2000: 2288-98.

The authors indicate that they do not have any conflicts of interest. Sources of funding: none reported.

Figures 2 through 6 from the Utah Valley Family Practice Residency Program, Provo.

This is part I of a two-part article on hyperpigmentation in adults. Part II, "Melanoma, Seborrheic Keratoses, Acanthosis Nigricans, Melasma, Diabetic Dermopathy, Tinea Versicolor, and Postinflammatory Hyperpigmentation," appears in this issue on page 1963.

This article is one in a series coordinated by Daniel L. Stulberg, M.D., director of dermatology curriculum at the Utah Valley Family Practice Residency Program, Provo, Utah.

DANIEL L. STULBERG, M.D., directs the dermatology curriculum and publishes the Dermatology E-mail Quiz Series at the Utah Valley Family Practice Residency Program, Utah Valley Regional Medical Center, Provo. Dr. Stulberg received his medical degree from the University of Michigan Medical School, Ann Arbor, where he also completed a family practice residency.

NICOLE CLARK, M.D., is on the faculty of the Utah Valley Family Practice Residency Program. Dr. Clark received her medical degree from the University of Vermont College of Medicine, Burlington, and completed a residency at the Utah Valley Family Practice Residency Program.

DANIEL TOVEY, M.D., is in private practice with Intermountain Health Care Health Center, Springville, Utah. He received his medical degree from Tulane University School of Medicine, New Orleans, and completed a residency at the Utah Valley Family Practice Residency Program.

Address correspondence to Daniel L. Stulberg, M.D., Utah Valley Family Practice Residency, 1134 N. 500 West, Provo, UT 84604 (e-mail: daniel.stulberg@ihc.com). Reprints are not available from the authors.

COPYRIGHT 2003 American Academy of Family Physicians
COPYRIGHT 2003 Gale Group