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Atypical localization of acanthosis nigricans in an obese patient with increased leptin level: Is there an association?

2006; Elsevier BV; Volume: 55; Issue: 2 Linguagem: Inglês

10.1016/j.jaad.2005.08.005

1097-6787

Ayça Cordan Yazıcı, Ümit Türsen, Güliz İkizoğlu, Esen Akbay, Canten Tataroğlu, Mehmet Çimen,

Hippo pathway signaling and YAP/TAZ

To the Editor: Acanthosis nigricans (AN) is characterized by velvety and papillomatous pigmented hyperkeratosis of the flexures and neck in both inherited and acquired forms in association with endocrine disorders, drugs, obesity, and malignancies.1Munoz-Perez M.A. Camacho F. Acanthosis nigricans: a new cutaneous sign in severe atopic dermatitis and Down syndrome.J Eur Acad Dermatol Venereol. 2001; 15: 325-327PubMed Google Scholar We report a case of AN and discuss the possible role of increased leptin level in the pathogenesis.A 42-year-old woman presented with a 5-year history of hyperpigmentation and thickening of the skin on both knees, elbows, and over the back of both feet and flexural areas such as axillae and groin. On physical examination, her blood pressure was 130/90 mm Hg. Body mass index was calculated as 38 kg/m2. Dermatologic examination revealed brownish-black hyperpigmented patches covered with papillomatous elevations on her knees, elbows, and extensor surface of feet (Fig 1). Microscopic examination of biopsy specimen revealed features consistent with AN (Fig 2). An oral glucose tolerance test produced normal findings and did not demonstrate insulin resistance (IR) by homeostasis model assessment. Homeostasis model assessment for IR index was calculated as 1.9. Serum analysis for total testosterone, sex hormone binding globulin, prolactin, insulin-like growth factor-1, and thyroid function tests, liver function tests, cholesterol, triglycerides, and IgE levels, except increased leptin level of 309, 2 ng/mL (normal limits, 10-100 ng/mL for obese women) were all within normal limits. Stool examination for occult blood done 3 days after admission produced negative results. The abdominopelvic ultrasonography and endoscopy of the upper gastrointestinal tract revealed normal findings. The patient was advised to use topical application of 0.05% retinoic acid. Medical treatment for obesity was started and she was put on a diet program.Fig 2Papillomatosis and hyperkeratosis of epidermis. (Hematoxylin-eosin stain; original magnification ×250.)View Large Image Figure ViewerDownload (PPT)AN is most commonly seen in flexural areas, the posterior and lateral neck, and the umbiliculus.2Uyttendaele H. Koss T. Bagheri B. Schneiderman P. Silfen M.E. Gallagher M.P. et al.Generalized acanthosis nigricans in an otherwise healthy young child.Pediatr Dermatol. 2003; 20: 254-256Crossref PubMed Scopus (16) Google Scholar AN has also been reported as being observed over the knees and elbows.1Munoz-Perez M.A. Camacho F. Acanthosis nigricans: a new cutaneous sign in severe atopic dermatitis and Down syndrome.J Eur Acad Dermatol Venereol. 2001; 15: 325-327PubMed Google Scholar, 2Uyttendaele H. Koss T. Bagheri B. Schneiderman P. Silfen M.E. Gallagher M.P. et al.Generalized acanthosis nigricans in an otherwise healthy young child.Pediatr Dermatol. 2003; 20: 254-256Crossref PubMed Scopus (16) Google Scholar In our patient, extensor surfaces of the feet, known to be a rare localization for AN, were also involved.The pathogenesis of AN remains unknown. One proposed mechanism is IR with reactive hyperinsulinemia and downstream binding of excess insulin to insulin-like growth factor receptors that can stimulate growth and proliferation of cells, including keratinocytes and fibroblasts.2Uyttendaele H. Koss T. Bagheri B. Schneiderman P. Silfen M.E. Gallagher M.P. et al.Generalized acanthosis nigricans in an otherwise healthy young child.Pediatr Dermatol. 2003; 20: 254-256Crossref PubMed Scopus (16) Google Scholar, 3Pote A. Cruz P.D. What causes acanthosis nigricans?.J Eur Acad Dermatol Venereol. 2001; 15: 302PubMed Google Scholar IR may be a result of genetic abnormalities of the insulin receptor or its function, obesity, or autoimmune diseases associated with antibodies to the insulin receptor.2Uyttendaele H. Koss T. Bagheri B. Schneiderman P. Silfen M.E. Gallagher M.P. et al.Generalized acanthosis nigricans in an otherwise healthy young child.Pediatr Dermatol. 2003; 20: 254-256Crossref PubMed Scopus (16) Google Scholar We could not detect IR in our patient, which made us think that mechanisms other than these could play a role in the formation of AN in obese patients.The concentration of leptin in the blood is higher in obese individuals. It was announced that leptin could play a paracrine role in cell proliferation, differentiation, growth, and apoptosis of epithelial cells.4Baratta M. Leptin–from a signal of adiposity to a hormonal mediator in peripheral tissues.Med Sci Monit. 2002; 8: 282-292Google Scholar Close regulation of leptin and its receptor obRb was shown during wound healing. Leptin action is targeted toward the epithelial compartment, as proliferating keratinocytes express the functional obRb receptor subtype. In vitro studies clearly supported a mitogenic effect of leptin on primary epidermal keratinocytes.5Stallmeyer B. Kämpfer H. Podda M. Kaufmann R. Pfeilschifter J. Frank S. A novel keratinocyte mitogen: regulation of leptin and its functional receptor in skin repair.J Invest Dermatol. 2001; 117: 98-105Crossref PubMed Google Scholar Thus, one may speculate that AN in our patient was related to the high level of leptin.In conclusion, when hyperkeratotic plaques appear on the elbows or knees, AN should be considered. The association of leptin levels and AN remains to be clarified with future studies in larger patient groups. To the Editor: Acanthosis nigricans (AN) is characterized by velvety and papillomatous pigmented hyperkeratosis of the flexures and neck in both inherited and acquired forms in association with endocrine disorders, drugs, obesity, and malignancies.1Munoz-Perez M.A. Camacho F. Acanthosis nigricans: a new cutaneous sign in severe atopic dermatitis and Down syndrome.J Eur Acad Dermatol Venereol. 2001; 15: 325-327PubMed Google Scholar We report a case of AN and discuss the possible role of increased leptin level in the pathogenesis. A 42-year-old woman presented with a 5-year history of hyperpigmentation and thickening of the skin on both knees, elbows, and over the back of both feet and flexural areas such as axillae and groin. On physical examination, her blood pressure was 130/90 mm Hg. Body mass index was calculated as 38 kg/m2. Dermatologic examination revealed brownish-black hyperpigmented patches covered with papillomatous elevations on her knees, elbows, and extensor surface of feet (Fig 1). Microscopic examination of biopsy specimen revealed features consistent with AN (Fig 2). An oral glucose tolerance test produced normal findings and did not demonstrate insulin resistance (IR) by homeostasis model assessment. Homeostasis model assessment for IR index was calculated as 1.9. Serum analysis for total testosterone, sex hormone binding globulin, prolactin, insulin-like growth factor-1, and thyroid function tests, liver function tests, cholesterol, triglycerides, and IgE levels, except increased leptin level of 309, 2 ng/mL (normal limits, 10-100 ng/mL for obese women) were all within normal limits. Stool examination for occult blood done 3 days after admission produced negative results. The abdominopelvic ultrasonography and endoscopy of the upper gastrointestinal tract revealed normal findings. The patient was advised to use topical application of 0.05% retinoic acid. Medical treatment for obesity was started and she was put on a diet program. AN is most commonly seen in flexural areas, the posterior and lateral neck, and the umbiliculus.2Uyttendaele H. Koss T. Bagheri B. Schneiderman P. Silfen M.E. Gallagher M.P. et al.Generalized acanthosis nigricans in an otherwise healthy young child.Pediatr Dermatol. 2003; 20: 254-256Crossref PubMed Scopus (16) Google Scholar AN has also been reported as being observed over the knees and elbows.1Munoz-Perez M.A. Camacho F. Acanthosis nigricans: a new cutaneous sign in severe atopic dermatitis and Down syndrome.J Eur Acad Dermatol Venereol. 2001; 15: 325-327PubMed Google Scholar, 2Uyttendaele H. Koss T. Bagheri B. Schneiderman P. Silfen M.E. Gallagher M.P. et al.Generalized acanthosis nigricans in an otherwise healthy young child.Pediatr Dermatol. 2003; 20: 254-256Crossref PubMed Scopus (16) Google Scholar In our patient, extensor surfaces of the feet, known to be a rare localization for AN, were also involved. The pathogenesis of AN remains unknown. One proposed mechanism is IR with reactive hyperinsulinemia and downstream binding of excess insulin to insulin-like growth factor receptors that can stimulate growth and proliferation of cells, including keratinocytes and fibroblasts.2Uyttendaele H. Koss T. Bagheri B. Schneiderman P. Silfen M.E. Gallagher M.P. et al.Generalized acanthosis nigricans in an otherwise healthy young child.Pediatr Dermatol. 2003; 20: 254-256Crossref PubMed Scopus (16) Google Scholar, 3Pote A. Cruz P.D. What causes acanthosis nigricans?.J Eur Acad Dermatol Venereol. 2001; 15: 302PubMed Google Scholar IR may be a result of genetic abnormalities of the insulin receptor or its function, obesity, or autoimmune diseases associated with antibodies to the insulin receptor.2Uyttendaele H. Koss T. Bagheri B. Schneiderman P. Silfen M.E. Gallagher M.P. et al.Generalized acanthosis nigricans in an otherwise healthy young child.Pediatr Dermatol. 2003; 20: 254-256Crossref PubMed Scopus (16) Google Scholar We could not detect IR in our patient, which made us think that mechanisms other than these could play a role in the formation of AN in obese patients. The concentration of leptin in the blood is higher in obese individuals. It was announced that leptin could play a paracrine role in cell proliferation, differentiation, growth, and apoptosis of epithelial cells.4Baratta M. Leptin–from a signal of adiposity to a hormonal mediator in peripheral tissues.Med Sci Monit. 2002; 8: 282-292Google Scholar Close regulation of leptin and its receptor obRb was shown during wound healing. Leptin action is targeted toward the epithelial compartment, as proliferating keratinocytes express the functional obRb receptor subtype. In vitro studies clearly supported a mitogenic effect of leptin on primary epidermal keratinocytes.5Stallmeyer B. Kämpfer H. Podda M. Kaufmann R. Pfeilschifter J. Frank S. A novel keratinocyte mitogen: regulation of leptin and its functional receptor in skin repair.J Invest Dermatol. 2001; 117: 98-105Crossref PubMed Google Scholar Thus, one may speculate that AN in our patient was related to the high level of leptin. In conclusion, when hyperkeratotic plaques appear on the elbows or knees, AN should be considered. The association of leptin levels and AN remains to be clarified with future studies in larger patient groups.