Acanthosis nigricans: A practical approach to evaluation and management1. Division of Dermatology, Department of Internal Medicine, Duke University Medical Center, Durham, North Carolina. firstname.lastname@example.org
Steven P Higgins MD1, Michael Freemark MD2, Neil S Prose MD3
Dermatology Online Journal 14 (9): 2
2. Division of Endocrinology and Diabetes, Department of Pediatrics, DUMC, Durham, North Carolina
3. Departments of Medicine (Dermatology) and Pediatrics, DUMC, Durham, North Carolina
Acanthosis nigricans is a dermatosis characterized by thickened, hyperpigmented plaques, typically of the intertriginous surfaces and neck. Common in some populations, its prevalence depends on race. Clinicians should recognize acanthosis nigricans; it heralds disorders ranging from endocrinologic disturbances to malignancy. In this review, we discuss the pathogenesis of acanthosis nigricans and its clinical implications and management.
|Figure 1a||Figure 1b|
|Figure 1. (a) Right neck and (b) left axilla in a 10-year-old Asian male with acanthosis nigricans|
Acanthosis nigricans (AN) is a dermatosis characterized by velvety, papillomatous, brownish-black, hyperkeratotic plaques, typically of the intertriginous surfaces and neck (Fig. 1) [1, 2, 3, 4, 5]. Although AN is associated with malignancy, the recognition of its more common connection to obesity and insulin resistance allows for diagnosis of related disorders including type 2 diabetes, the metabolic syndrome, and polycystic ovary syndrome [6, 7, 8, 9]. Early recognition of these conditions is essential for prevention of disease progression.
Clinically, the neck is the most commonly affected area in children . Ninety-nine percent of children with AN have neck involvement, compared to 73 percent with axillary involvement . Acanthosis nigricans may also affect eyelids, lips, vulva, mucosal surfaces, dorsal hands, and flexural areas in the groin, knees and elbows . While usually asymptomatic, AN is occasionally pruritic [1, 2].
|Figure 2. Histology of acanthosis nigricans, demonstrating papillomatosis and hyperkeratosis. (Hematoxylin and eosin, original magnification x40). Reproduced with permission from Lee HW et al . (with permission of the author)|
Histopathology (Fig. 2) reveals a thickened stratum corneum with minimal involvement of the dermis except for thickened and elongated dermal projections . Despite the term "acanthosis," the actual amount of acanthosis, or thickening of the stratum spinosum, is variable and typically mild [2, 3]. The dark color of AN is likely due to hyperkeratosis rather than to a mild increase in melanin pigmentation . A subtle infiltrate composed of lymphocytes, plasma cells, or neutrophils may be present, as well as horn pseudocyst formation . Tissue staining with colloidal iron often shows infiltration of the papillary dermis with glycosaminoglycans such as hyaluronic acid, particularly in patients with gonadal disease such as polycystic ovarian syndrome (PCOS) .
Acanthosis nigricans is linked to a variety of syndromes (Table 1). Most are associated with insulin resistance or fibroblast growth factor receptor (FGFR) mutations. Acanthosis nigricans may also appear as an adverse effect of several medications that promote hyperinsulinemia, such as glucocorticoids , niacin [40, 41, 42], insulin , oral contraceptives , and protease inhibitors [45, 46, 47].
Acanthosis nigricans is common, although the exact prevalence depends on the racial makeup of the population studied. While obesity increases the risk for development of AN, the differences in prevalence of AN between racial groups cannot be explained solely by differing rates of obesity . For example, African Americans are 25 times as likely to have AN as patients of European descent . In a 1988 Texas school system population of 1412 adolescents, the general prevalence of AN was 7.1 percent, but was only 0.45 percent among Caucasian students . An additional study of over 100,000 children in Texas performed 11 years later revealed a prevalence of AN in 14.4 percent . Also, a random sample of 2205 Cherokee Nation members found 34.2 percent had AN . In general, AN seems to be most common in Native Americans, followed by African Americans, Hispanics, and Caucasians.
|Figure 3. Proposed mechanisms for the pathogenesis of acanthosis nigricans|
Elevated insulin concentrations result in direct and indirect activation of IGF-1 receptors on keratinocytes and fibroblasts, leading to proliferation. Other mediators may also contribute, including other tyrosine kinase receptors such as EGFR and FGFR. (IGF = insulin-like growth factor, BP = binding protein, IGF-1R = insulin-like growth factor 1 receptor, EGFR = epidermal growth factor receptor, FGFR = fibroblast growth factor receptor)
Acanthosis nigricans is most commonly associated with disorders associated with insulin resistance, including obesity, type 2 diabetes, and the polycystic ovary syndrome . In these cases, hyperinsulinemia is thought to play a pivotal role (Fig. 3). At low concentrations, insulin regulates carbohydrate, lipid, and protein metabolism and can weakly promote growth by binding to "classic" insulin receptors [9, 51]. At high concentrations, however, insulin can exert more potent growth-promoting effects through binding to insulin-like growth factor 1 receptors (IGF-1Rs), which are similar in size and subunit structure to insulin receptors, but bind IGF-1 with 100- to 1000-fold greater affinity than insulin [51, 52].
A number of observations suggest that insulin-dependent activation of IGF-1Rs can promote cellular proliferation and facilitate the development of AN. First, IGF receptors are found in cultured fibroblasts and keratinocytes . Second, insulin can cross the dermoepidermal junction, and at high concentrations can stimulate growth and replication of fibroblasts [2, 53]. Finally, the severity of AN in obesity correlates positively with the fasting insulin concentration [48, 54]. Thus, insulin may promote AN through direct activation of the IGF-1 signaling pathway.
The true pathogenesis of AN, however, is likely to be more complex. Obese patients rarely, if ever, achieve levels of insulin high enough (10 nM) to activate IGF-1Rs [55, 56]. The predilection of AN for areas such as the neck and axillae suggests that perspiration and/or friction also may be necessary cofactors [6, 57].
Hyperinsulinemia may also facilitate the development of AN indirectly by increasing the levels of free IGF-1 in the circulation. The activity of IGF-1 is regulated by IGF binding proteins (IGFBPs), which increase IGF-1 half life, deliver IGFs to target tissues, and regulate the levels of the metabolically active "free" IGF-1 [58, 59]. Insulin-like growth factor 1 binding protein and IGFBP-2 are both decreased in obese subjects with hyperinsulinemia, increasing plasma concentrations of free IGF-1 . An increase in bioactive IGF-1 promotes cell growth and differentiation .
Insulin-like growth factor 1 is expressed within the stratum granulosum and by dermal fibroblasts, but not by epidermal basal keratinocytes . In theory, an insulin-induced systemic reduction of IGFBP-1 and IGFBP-2 could increase local levels of free IGF-1, thereby facilitating the development of hyperkeratosis and papillomatosis.
Curiously, therapy with IGF-1 has resulted in improvement of extreme insulin resistance syndromes, including improvement of AN in 5 of 7 patients . Insulin-like growth factor 1 may reduce serum insulin concentrations and downregulate expression of IGF-1R [58, 63]. Since insulin binds with lower affinity to the IGF-1 receptor than IGF-1 itself, it is possible that insulin may be less proficient than IGF-1 at downregulating IGF-1Rs.
Hyperinsulinemia does not mediate all forms of acanthosis nigricans. As mentioned previously, certain AN syndromes are due to FGFR defects (Table 1). Some malignancies may be associated with insulin receptor antibodies, as in one reported case of metastatic pheochromocytoma; however, no insulin resistance is described for most cases of paraneoplastic AN . Malignancy-associated AN might be explained by elevated levels of growth factors such as transforming growth factor (TGF-α), which exerts effects on epidermal tissue via the epidermal growth factor receptor (EGFR) . One patient experienced a decrease in urinary TGF-α and improvement of AN after resection of a melanoma .
Insulin-like growth factor 1 receptor, FGFR, and EGFR are all tyrosine kinase receptors and acanthosis nigricans seems to be a final common manifestation of a variety of processes . The post-receptor intracellular pathways likely converge, although they have not been fully elucidated . Other perplexing aspects of AN include its predilection for certain races and anatomic sites, as well as the fact that only some people with predisposing states develop the condition.
Understanding the connection between acanthosis nigricans and insulin resistance is critical for clinicians. Patients with AN are at risk for all of the components of the metabolic syndrome: obesity, hypertension, elevated triglycerides, low high-density lipoprotein, and glucose intolerance [66, 67]. The metabolic syndrome, present in 34 percent of American adults, yields a risk of heart disease equivalent to smoking and in adults increases the risk of the development of diabetes 3.5-fold within 5 years [68, 69].
Like obesity, PCOS is associated with insulin resistance, hyperinsulinemia, and AN. Between 5 and 33 percent of patients with PCOS have AN [70, 71]. This syndrome includes increased synthesis of ovarian and adrenal androgens and inhibition of hepatic synthesis of sex hormone-binding globulin . Insulin resistance is also hypothesized to have a role in the development of acne, skin tags, male vertex balding, myopia, and epithelial cell cancers.
Evaluation and Management
|Figure 4. Recommended evaluation for patients with acanthosis nigricans, with potential etiologies.|
Patients may have multiple underlying diseases. The first step in evaluation should be identification of the underlying condition. We recommend obtaining certain basic studies (Fig. 4), particularly in all overweight adults and children without a known history of insulin resistance. Overweight in adults is defined as a body mass index (BMI, weight in kilograms divided by height in meters squared) of 25 kg/m² or greater [73, 74]. In children and adolescents, overweight is defined as at least the 85th percentile of the sex-specific BMI-for-age growth chart; the child is considered obese when the BMI z score exceeds the 95th percentile for age and gender. Studies should include blood pressure (BP), fasting lipoprotein profile, fasting glucose, hemoglobin A1C, fasting insulin, and alanine aminotransferase (ALT). Any abnormalities should prompt communication with the primary provider or referral to an endocrinologist.
The prevalence of obesity in the US has grown at an alarming rate [73, 74]. While detection of AN is unnecessary for obesity screening, counseling patients about AN provides an excellent opportunity to initiate treatment for obesity or overweight. Nonpharmacologic lifestyle modifications with diet and exercise can be initiated. Pharmacologic therapy may be required for patients with hypertension, hypercholesterolemia, hypertriglyceridemia, low levels of high density lipoprotein (HDL), or elevated fasting glucose [75, 76, 77].
Warning flags that should trigger a careful evaluation for malignancy in patients presenting with acanthosis nigricans include unintentional weight loss and rapid onset of extensive AN . Mucosal involvement is more common in patients who have AN in association with a malignancy, as are tripe palms, florid cutaneous papillomatosis, and the sign of Leser-Trélat . Acanthosis nigricans that appears after initiation of one of the causative medications should prompt discontinuation, when possible, or consideration of an alternative agent.
Improvement of the skin lesions is often the patient's primary concern. No randomized, controlled trials exist for any treatment of AN. Multiple case reports suggest that acanthosis nigricans improves with treatment of its underlying condition (Table 2).
A randomized, open-label trial that compared the insulin sensitizers metformin and rosiglitazone in 30 overweight Mexican patients for 12 weeks demonstrated only minimal improvement in AN lesions with either agent . Whether the duration of therapy was sufficient to see a clinical change is uncertain. A smaller, 6-month trial of metformin in obese patients resulted in improvement of AN in 3 of 5 patients .
Retinoids have been successfully used to treat AN. Topical 0.1 percent tretinoin caused improvement of AN in two case reports. One 18-year-old woman with AN experienced clearing of her neck in 10 days, with improvement in color and hyperkeratosis of her axillae within 2 weeks . Another patient had clearing of AN of the left axilla after tretinoin 0.1 percent gel was applied twice daily for 2 weeks. The right axilla, used as a control, did not show any improvement . In another case report, the combination of 0.05 percent tretinoin cream and 12 percent ammonium lactate cream led to resolution of AN .
Oral retinoids, such as isotretinoin and acitretin, also can be effective [92, 93, 94]. Improvement required large doses and extended courses, and relapse was described. One obese woman improved with isotretinoin 3 mg/kg/day, but relapsed when this was stopped . An 18-year-old man with generalized idiopathic AN experienced complete recovery after 45 days with acitretin 0.8 mg/kg (50 mg) divided into 2 daily doses. After starting maintenance therapy of 25 mg daily for 2 months, lesions recurred that subsequently resolved with topical retinoic acid 0.1 percent . An obese man taking isotretinoin 80 mg/day noted 90 percent improvement of his palms and 50 percent improvement of his axillae within 2 months. After gradually tapering this dose over more than a year and receiving over 30g, he experienced an exacerbation of his skin lesions that improved with metformin 1000 mg twice daily . Use of systemic retinoids for AN may be inappropriate given their side effect profile and potential for toxicity.
Other therapies found beneficial in case reports include calcipotriol, fish oil, and laser. One obese man had AN in the flexural areas that improved after 3 months of calcipotriol 0.005 percent cream twice daily . Another obese woman improved with calcipotriol ointment twice daily, also for 3 months . Fish oil containing omega-3 fatty acids effectively reduced hyperpigmentation and normalized skin texture in one woman with acquired generalized lipodystrophy and AN . This occurred after 6 months of taking 10 to 20g per day of fish oil. Long-pulsed (5 msec) alexandrite laser treatment led to resolution of AN in one woman . Greater than 95 percent clearance of the left axilla was observed after 7 treatments, spaced 4 to 8 weeks apart (fluence was 16 to 23 J/cm2, with spot sizes of 10 or 12.5 mm). The right axilla, initially used as a control, showed no improvement until it was treated.
Multiple anecdotal reports suggest that acanthosis nigricans is reversible. Given their ease of use and safety profile, topical retinoids are a reasonable first-line treatment. However, whether another therapy is superior remains unclear. Randomized, controlled trials of lifestyle intervention and other therapies are needed.
References1. Schwartz RA. Acanthosis nigricans. J Am Acad Dermatol 1994;31:1-19. PubMed
2. Rogers DL. Acanthosis nigricans. Semin Dermatol 1991;10:160-3. PubMed
3. Schwartz RA, Janniger CK. Childhood acanthosis nigricans. Cutis 1995;55:337-41. PubMed
4. Torley D, Bellus GA, Munro CS. Genes, growth factors, and acanthosis nigricans. Br J Dermatol 2002;147:1096-101. PubMed
5. Lee HW, Suh HS, Choi JC, Lee MW, Choi JH, Moon KC, Koh JK. Hyperkeratosis of the nipple and areola as a sign of malignant acanthosis nigricans. Clin Exp Dermatol 2005;30:721-2. PubMed
6. Stuart CA, Gilkison CR, Smith MM, Bosma AM, Keenan BS, Nagamani M. Acanthosis nigricans as a risk factor for non-insulin dependent diabetes mellitus. Clin Pediatr 1998;37:73-9. PubMed
7. Matsuoka LY, Wortsman J, Gavin JR, Goldman J. Spectrum of endocrine abnormalities associated with acanthosis nigricans. Am J Med 1987;83:719-25. PubMed
8. Cruz PD Jr, Hud JA Jr. Excess insulin binding to insulin-like growth factor receptors: proposed mechanism for acanthosis nigricans. J Invest Dermatol 1992;98:82S-5S. PubMed
9. Rendon MI, Cruz PD Jr, Sontheimer RD, Bergstresser PR. Acanthosis nigricans: a cutaneous marker of tissue resistance to insulin. J Am Acad Dermatol 1989;21:461-9. PubMed
10. Sherertz EF. Improved acanthosis nigricans with lipodystrophic diabetes during dietary fish oil supplementation. Arch Dermatol 1988;124:1094-6. PubMed
11. Flier JS, Young JB, Landsberg L. Familial insulin resistance with acanthosis nigricans, acral hypertrophy, and muscle cramps. New Engl J Med 1980;303:970-3. PubMed
12. Nabarro JD. Acromegaly. Clin Endocrinol 1987;26:481-512. PubMed
13. Akiyama M, Sasaki Y, Takahashi S, Hayakawa K, Suzuki H, Nishikawa T. Coexistent urticaria pigmentosa, acromegaly and acanthosis nigricans. Dermatologica. 1991;182:52-5. PubMed
14. Koc E, Bayrak G, Suher M, Ensari C, Aktas D, Ensari A. Rare case of Alström syndrome without obesity and with short stature, diagnosed in adulthood. Nephrology (Carlton) 2006;11:81-4. PubMed
15. Bar RS, Levis WR, Rechler MM, Harrison LC, Siebert C, Podskalny J, et al. Extreme insulin resistance in ataxia telangiectasia: defect in affinity of insulin receptors. New Engl J Med 1978;298:1164-71. PubMed
16. Jabbour SA. Cutaneous manifestations of endocrine disorders: a guide for dermatologists. Am J Clin Dermatol 2003;4:315-31. PubMed
17. Maitra SK, Rowland Payne CM. The obesity syndrome and acanthosis nigricans. Acanthosis nigricans is a common cosmetic problem providing epidemiological clues to the obesity syndrome, the insulin-resistance syndrome, the thrifty metabolism, dyslipidaemia, hypertension and diabetes mellitus type II. J Cosmet Dermatol 2004;3:202-10. PubMed
18. Annos T, Taymor ML. Ovarian pathology associated with insulin resistance and acanthosis nigricans. Obstet Gynecol 1981;58:662-4. PubMed
19. Cochran E, Young JR, Sebring N, DePaoli A, Oral EA, Gorden P. Efficacy of recombinant methionyl human leptin therapy for the extreme insulin resistance of the Rabson-Mendenhall syndrome. J Clin Endocrinol Metab 2004;89:1548-54. PubMed
20. Flier JS. Lilly Lecture: syndromes of insulin resistance. From patient to gene and back again. Diabetes 1992;41:1207-19. PubMed
21. Agarwal AK, Garg A. Genetic basis of lipodystrophies and management of metabolic complications. Annu Rev Med 2006;57:297-311. PubMed
22. Pope E, Janson A, Khambalia A, Feldman B. Childhood acquired lipodystrophy: a retrospective study. J Am Acad Dermatol 2006;55:947-50. PubMed
23. Seemanova E, Rudiger HW, Dreyer M. Morfan: a new syndrome characterized by mental retardation, pre- and postnatal overgrowth, remarkable face and acanthosis nigricans in 5-year-old boy. Am J Med Genet 1993;45:525-8. PubMed
24. Shohat M, Shohat T, Rimoin DL, Mohandas T, Heckenlively J, Magenis RE, et al. Rearrangement of chromosome 15 in the region q11.2----q12 in an individual with obesity syndrome and her normal mother. Am J Med Genet 1990;37:173-7. PubMed
25. Magsino CH Jr, Spencer J. Insulin receptor antibodies and insulin resistance. South Med J 1999;92:717-9. PubMed
26. Przylepa KA, Paznekas W, Zhang M, Golabi M, Bias W, Bamshad MJ, et al. Fibroblast growth factor receptor 2 mutations in Beare-Stevenson cutis gyrata syndrome. Nat Genet 1996;13:492-4. PubMed
27. Wilkes D, Rutland P, Pulleyn LJ, Reardon W, Moss C, Ellis JP, et al. A recurrent mutation, ala391glu, in the transmembrane region of FGFR3 causes Crouzon syndrome and acanthosis nigricans. J Med Genet 1996;33:744-8. PubMed
28. Bellus GA, Bamshad MJ, Przylepa KA, Dorst J, Lee RR, Hurko O, et al. Severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN): phenotypic analysis of a new skeletal dysplasia caused by a Lys650Met mutation in fibroblast growth factor receptor 3. Am J Med Genet 1999;85:53-65. PubMed
29. Baker KM, Olson DS, Harding CO, Pauli RM. Long-term survival in typical thanatophoric dysplasia type 1. Am J Med Genet 1997;70:427-36. PubMed
30. Hafner C, van Oers JM, Vogt T, Landthaler M, Stoehr R, Blaszyk H, et al. Mosaicism of activating FGFR3 mutations in human skin causes epidermal nevi. J Clin Invest 2006;116:2201-2207. PubMed
31. Scott RW, Klein AW, Leyden JJ. Acanthosis nigricans associated with a benign encephalopathy. Arch Dermatol 1974;109:78-80. PubMed
32. Kurtoğlu S, Atabek ME, Keskin M, Canöz O. Acanthosis nigricans in association with congenital adrenal hyperplasia: resolution after treatment. Case report. Turk J Pediatr 2005;47:183-7. PubMed
33. Costello JF. Acanthosis nigricans, congenital heart disease and other congenital defects. Proc R Soc Med 1972;65:751-2. PubMed
34. Nguyen V, Buka RL, Roberts BJ, Eichenfield LF. Cutaneous manifestations of Costello syndrome. Int J Dermatol 2007;46:72-6. PubMed
35. Thaipisuttikul Y. Acanthosis nigricans associated with hepatolenticular degeneration. J Dermatol 1997;24:395-400. PubMed
36. Dix JH, Levy WJ, Fuenning C. Remission of acanthosis nigricans, hypertrichosis, and Hashimoto's thyroiditis with thyroxine replacement. Pediatr Dermatol 1986;3:323-6. PubMed
37. Fahim SS, Adam JE. Acanthosis nigricans in Kabuki syndrome. J Cutan Med Surg 2004;8:157-61. PubMed
38. Maldonado RR, Tamayo L, Carnevale A. Neuroichthyosis with hypogonadism (Rud's syndrome). Int J Dermatol 1975;14:347-52. PubMed
39. Pham TH, Kaushik S, Lin BP, Jones DB. Case report: acanthosis nigricans in association with primary biliary cirrhosis: resolution after liver transplantation. J Gastroenterol Hepatol 1996;11:1021-3. PubMed
40. Stals H, Vercammen C, Peeters C, Morren MA. Acanthosis nigricans caused by nicotinic acid: case report and review of the literature. Dermatology 1992;128:941-4. PubMed
41. Kahn SE, Beard JC, Schwartz MW, Ward WK, Ding HL, Bergman RN, et al. Increased beta-cell secretory capacity as mechanism for islet adaptation to nicotinic acid-induced insulin resistance. Diabetes 1989;38:562-8. PubMed
42. McKenney JM, Proctor JD, Harris S, Chinchili VM. A comparison of the efficacy and toxic effects of sustained- vs immediate-release niacin in hypercholesterolemic patients. JAMA 1994;271:672-7. PubMed
43. Fleming MG, Simon SI. Cutaneous insulin reaction resembling acanthosis nigricans. Arch Dermatol 1986;122:1054-6. PubMed
44. Skouby, SO. Update on the metabolic effects of oral contraceptives. J Obstet Gynaecol 1986;6 Suppl 2:S104-9. PubMed
45. Mur A, Seidel V, López-Vílchez MA, Bonet M, Gilaberte M. Acanthosis nigricans as an adverse effect of highly active antiretroviral therapy in an adolescent girl with human immunodeficiency virus infection. Pediatr Infect Dis J 2005;24:742-3. PubMed
46. Mellor-Pita S, Yebra-Bango M, Alfaro-Martínez J, Suárez E. Acanthosis nigricans: a new manifestation of insulin resistance in patients receiving treatment with protease inhibitors. Clin Infect Dis 2002;34:716-7. PubMed
47. Walli R, Herfort O, Michl GM, Demant T, Jager H, Dieterle C, et al. Treatment with protease inhibitors associated with peripheral insulin resistance and impaired oral glucose tolerance in HIV-1-infected patients. AIDS 1998;12:F167-73. PubMed
48. Stuart CA, Pate CJ, Peters EJ. Prevalence of acanthosis nigricans in an unselected population. Am J Med 1989;87:269-72. PubMed
49. King-Tryce K, Garza L, Ozias JM. Acanthosis nigricans and insulin resistance. Disease Prevention News 2002;62:1-3. Available at http://www.dshs.state.tx.us/idcu/health/dpn/2002/ . Accessed October 17, 2007.
50. Stoddart ML, Blevins KS, Lee ET, Wang W, Blackett PR, Cherokee Diabetes Study. Association of acanthosis nigricans with hyperinsulinemia compared with other selected risk factors for type 2 diabetes in Cherokee Indians: the Cherokee Diabetes Study. Diabetes Care 2002;25:1009-14. PubMed
51. Flier JS, Usher P, Moses AC. Monoclonal antibody to the type I insulin-like growth factor (IGF-I) receptor blocks IGF-I receptor-mediated DNA synthesis: clarification of the mitogenic mechanisms of IGF-I and insulin in human skin fibroblasts. Proc Natl Acad Sci USA 1986;83:664-8. PubMed
52. Jain S, Golde DW, Bailey R, Geffner ME. Insulin-like growth factor-I resistance. Endocr Rev 1998;19:625-646. PubMed
53. Verrando P, Ortonne JP. Insulin binding properties of normal and transformed human epidermal cultured keratinocytes. J Invest Dermatol 1985;85:328-32. PubMed
54. Hud JA Jr, Cohen JB, Wagner JM, Cruz PD Jr. Prevalence and significance of acanthosis nigricans in an adult obese population. Arch Dermatol 1992;128:941-4. PubMed
55. Lee JM, Okumura MJ, Davis MM, Herman WH, Gurney JG. Prevalence and determinants of insulin resistance among U.S. adolescents: a population-based study. Diabetes Care 2006;29:2427-32. PubMed
56. Blakesley VA, Scrimgeour A, Esposito D, Le Roith D. Signaling via the insulin-like growth factor-I receptor: does it differ from insulin receptor signaling? Cytokine Growth Factor Rev 1996;7:153-9. PubMed
57. Barbieri RL, Ryan KJ. Hyperandrogenism, insulin resistance, and acanthosis nigricans syndrome: a common endocrinopathy with distinct pathophysiologic features. Am J Obstet Gynecol 1983;147:90-101. PubMed
58. Le Roith D. Seminars in medicine of the Beth Israel Deaconess Medical Center. Insulin-like growth factors. New Engl J Med 1997;336:633-640. PubMed
59. Nam SY, Lee EJ, Kim KR, Cha BS, Song YD, Lim SK, et al. Effect of obesity on total and free insulin-like growth factor (IGF)-1, and their relationship to IGF-binding protein (BP)-1, IGFBP-2, IGFBP-3, insulin, and growth hormone. Int J Obes Relat Metab Disord 1997;21:355-9. PubMed
60. Siddle K, Urso B, Niesler CA, Cope DL, Molina L, Surinya KH, et al. Specificity in ligand binding and intracellular signalling by insulin and insulin-like growth factor receptors. Biochem Soc Trans 2001;29:513-25. PubMed
61. Rudman SM, Philpott MP, Thomas GA, Kealey T. The role of IGF-I in human skin and its appendages: morphogen as well as mitogen? J Invest Dermatol 1997;109:770-7. PubMed
62. Kuzuya H, Matsuura N, Sakamoto M, Makino H, Sakamoto Y, Kadowaki T, et al. Trial of insulinlike growth factor I therapy for patients with extreme insulin resistance syndromes. Diabetes 1993;42:696-705. PubMed
63. Downs AM, Kennedy CT. Somatotrophin-induced acanthosis nigricans. Br J Dermatol 1999;141:390-391. PubMed
64. Matsuoka LY, Goldman J, Wortsman J, Kleinsmith D, Kupchella CE. Antibodies against the insulin receptor in paraneoplastic acanthosis nigricans. Am J Med 1987;82:1253-6. PubMed
65. Ellis DL, Kafka SP, Chow JC, Nanney LB, Inman WH, McCadden ME, et al. Melanoma, growth factors, acanthosis nigricans, the sign of Leser-Trelat, and multiple acrochordons. A possible role for alpha-transforming growth factor in cutaneous paraneoplastic syndromes. New Engl J Med 1987;317:1582-7. PubMed
66. Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes 1988;37:1595-607. PubMed
67. Third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III) final report. Circulation 2002;106:3143-421. PubMed
68. Ford ES. Prevalence of the metabolic syndrome defined by the International Diabetes Federation among adults in the U.S. Diabetes Care 2005;28:2745-9. PubMed
69. Sattar N, Gaw A, Scherbakova O, Ford I, O'Reilly DS, Haffner SM, et al. Metabolic syndrome with and without C-reactive protein as a predictor of coronary heart disease and diabetes in the West of Scotland Coronary Prevention Study. Circulation 2003;108:414-9. PubMed
70. Flier JS, Eastman RC, Minaker KL, Matteson D, Rowe JW. Acanthosis nigricans in obese women with hyperandrogenism. Characterization of an insulin-resistant state distinct from the type A and B syndromes. Diabetes 1985;34:101-7. PubMed
71. Dunaif A, Graf M, Mandeli J, Laumas V, Dobrjansky A. Characterization of groups of hyperandrogenic women with acanthosis nigricans, impaired glucose tolerance, and/or hyperinsulinemia. J Clin Endocrinol Metab 1987;65:499-507. PubMed
72. Cordain L, Eades MR, Eades MD. Hyperinsulinemic diseases of civilization: more than just Syndrome X. Comp Biochem Physiol A Mol Integr Physiol 2003;136:95-112. PubMed
73. Ogden CL, Carroll MD, Curtin LR, McDowell MA, Tabak CJ, Flegal KM. Prevalence of overweight and obesity in the United States, 1999-2004. JAMA 2006;295:1549-55. PubMed
74. Hedley AA, Ogden CL, Johnson CL, Carroll MD, Curtin LR, Flegal KM. Prevalence of overweight and obesity among US children, adolescents, and adults, 1999-2002. JAMA 2004;291:2847-50. PubMed
75. National High Blood Pressure Education Program Working Group on Hypertension Control in Children and Adolescents. Update on the 1987 Task Force Report on high blood pressure in children and adolescents. Pediatrics 1996;98:649-658. PubMed
76. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003;289:2560-72. PubMed
77. Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. New Engl J Med 2002;346:393-403. PubMed
78. Kuroki R, Sadamoto Y, Imamura M, Abe Y, Higuchi K, Kato K, et al. Acanthosis nigricans with severe obesity, insulin resistance and hypothyroidism: improvement by diet control. Dermatology 1999;198:164-6. PubMed
79. Lunetta M, Di Mauro M, Le Moli R, Burrafato S. Long-term octreotide treatment reduced hyperinsulinemia, excess body weight and skin lesions in severe obesity with acanthosis nigricans. J Endocrinol Invest 1996;19:699-703. PubMed
80. Manco M, Castagneto M, Nanni G, Guidone C, Tondolo V, Greco AV, et al. Biliopancreatic diversion as a novel approach to the HAIR-AN syndrome. Obes Surg 2005;15:286-9. PubMed
81. Pasquali R, Antenucci D, Casimirri F, Venturoli S, Paradisi R, Fabbri R, et al. Clinical and hormonal characteristics of obese amenorrheic hyperandrogenic women before and after weight loss. J Clin Endocrinol Metab 1989;68:173-9. PubMed
82. Tercedor J, Ródenas JM, Herranz MT, Vidal A, Munoz-Torres M. Effect of ketoconazole in the hyperandrogenism, insulin resistance and acanthosis nigricans (HAIR-AN) syndrome. J Am Acad Dermatol 1992;27:786. PubMed
83. Stratakis CA, Mastorakos G, Mitsiades NS, Mitsiades CS, Chrousos GP. Skin manifestations of Cushing disease in children and adolescents before and after the resolution of hypercortisolemia. Pediatr Dermatol 1998;15:253-8. PubMed
84. Eberting CL, Javor E, Gorden P, Turner ML, Cowen EW. Insulin resistance, acanthosis nigricans, and hypertriglyceridemia. J Am Acad Dermatol 2005;52:341-4. PubMed
85. Greenspan AH, Shupack JL, Foo SH, Wise AC. Acanthosis nigricans-like hyperpigmentation secondary to triazinate therapy. Arch Dermatol 1985;121:232-5. PubMed
86. Anderson SH, Hudson-Peacock M, Muller AF. Malignant acanthosis nigricans: potential role of chemotherapy. Br J Dermatol 1999;141:714-6. PubMed
87. Bellot-Rojas P, Posadas-Sanchez R, Caracas-Portilla N, Zamora-Gonzalez J, Cardoso-Saldana G, Jurado-Santacruz F, et al. Comparison of metformin versus rosiglitazone in patients with Acanthosis nigricans: a pilot study. J Drugs Dermatol 2006;5:884-9. PubMed
88. Tankova T, Koev D, Dakovska L, Kirilov G. Therapeutic approach in insulin resistance with acanthosis nigricans. Int J Clin Pract 2002;56:578-81. PubMed
89. Berger BJ, Gross PR. Another use for tretinoin--pseudoacanthosis nigricans. Arch Dermatol 1973;108:133-4. PubMed
90. Darmstadt GL, Yokel BK, Horn TD. Treatment of acanthosis nigricans with tretinoin. Arch Dermatol 1991;127:1139-40. PubMed
91. Blobstein SH. Topical therapy with tretinoin and ammonium lactate for acanthosis nigricans associated with obesity. Cutis 2003;71:33-4. PubMed
92. Katz RA. Treatment of acanthosis nigricans with oral isotretinoin. Arch Dermatol 1980;116:110-1. PubMed
93. Ozdemir M, Toy H, Mevlitoglu I, Demirkesen C. Generalized idiopathic acanthosis nigricans treated with acitretin. J Dermatolog Treat 2006;17:54-6. PubMed
94. Walling HW, Messingham M, Myers LM, Mason CL, Strauss JS. Improvement of acanthosis nigricans on isotretinoin and metformin. J Drugs Dermatol 2003;2:677-81. PubMed
95. Böhm M, Luger TA, Metze D. Treatment of mixed-type acanthosis nigricans with topical calcipotriol. Br J Dermatol 1998;139:932-4. PubMed
96. Lee HW, Chang SE, Lee MW, Choi JH, Moon KC, Koh JK. Hyperkeratosis of the nipple associated with acanthosis nigricans: treatment with topical calcipotriol. J Am Acad Dermatol 2005;52:529-30. PubMed
97. Rosenbach A, Ram R. Treatment of acanthosis nigricans of the axillae using a long-pulsed (5-msec) alexandrite laser. Dermatol Surg 2004;30:1158-60. PubMed
© 2008 Dermatology Online Journal