Doi:10.1016/j.jaad.2004.10.867

Insulin resistance, acanthosis nigricans, and Cheryl Lee D. Eberting, MD,a Edward Javor, MD,b Phillip Gorden, MD,b Maria L. Turner, MD,a arms and legs. Dermatologic examination identified facial hirsutism as well as prominent terminal hair A 23-year-old white female was seen in consulta- growth on the central chest and abdomen. Tan tion in the Dermatology Clinic at the National velvety plaques were prominent on the neck ( Institutes of Health, in Bethesda, Maryland for Thicker tan plaques were visible in the axillary plaques involving the neck, axillae, and inguinal vaults bilaterally and extended onto the anterior areas. At 4 months of age, she was noted to have shoulders . Plaques overlying the proximal hepatomegaly and hypertriglyceridemia with values medial thighs resulted in a papillomatous texture to as high as 6000 mg/dL. The patient described a the skin in this area. Hyperpigmentation with very ravenous appetite from a young age. Type 2 diabetes fine small papules created a ‘‘pebbling’’ appearance mellitus was diagnosed at age 12 and, despite over the joints of the dorsal hands. Numerous attempts at dietary modification, her blood glucose discrete exophytic fleshy papules consistent with levels remained poorly controlled. Treatment with acrochordons were noted in the axillae.
metformin was initiated at age 14, followed shortlythereafter by insulin because of continued poor control. Menarche occurred at age 15, and the patient A glucose tolerance test showed a fasting blood described a history of oligomenorrhea. A liver biopsy sugar of 70 mg/dL and a 2-hour glucose level of 229 at age 18 prompted by elevated transaminases mg/dL. HbA1c was 8.7% (normal range, 4.8-6.4%).
yielded a diagnosis of nonalcoholic steatohepatitis Other elevated values included: triglycerides, 702 (NASH) with early cirrhosis. The patient’s medica- mg/dL (normal range, \150 mg/dL); free testoster- tions at the time of presentation included metformin one, 63 pg/dL (normal range, 3-19 pg/dL); alanine 850 mg three times a day and U-500 insulin totaling aminotransferase, 54 u/L (normal range, 6-41 u/L); and aspartate aminotransferase, 40 u/L (normalrange, 9-34 u/L). Serum leptin was decreased at 1.44 ng/mL (normal range, [6 ng/mL). Assessment Physical examination was remarkable for a tall, of body composition by dual energy radiograph muscular-appearing woman with prominent fore- absorptiometry showed 7.8% body fat (normal head and mandible, a systolic ejection murmur, a protuberant abdomen with a liver span 12 cm belowthe subcostal arch, and an umbilical hernia The patient’s muscular appearance was furtherenhanced by prominent enlarged veins on her Congenital generalized lipodystrophy (CGL) withprominent acanthosis nigricans.
From the Dermatology Branch, Center for Cancer Research, National Cancer Institute,a and the Clinical Endocrinology Branch, National Institute of Diabetes and Digestive and KidneyDiseases,b National Institutes of Health.
The patient was enrolled in a protocol evaluating the efficacy of recombinant human leptin replace- Conflicts of interest: None disclosed.
ment in patients with lipodystrophy. Within 4 Reprint requests: Edward W. Cowen, MD, Dermatology Branch, months of initiating therapy, her appetite normalized CCR, NCI Building 10/Room 12N238, 10 Center Dr MSC 1908, patient’s menstrual cycle became regular and her insulin requirement decreased dramatically. The Fig 1. A and B, Prominent muscular appearance with paucity of subcutaneous fat (A) anddramatic change in body habitus after one year of leptin therapy (B). C-F, Prominent acanthosisnigricans on the neck (C) and right axilla (E) is significantly improved (D and F) followingleptin treatment.
HbA1c decreased from 8.7% to 4.7%, and triglycer- partial lipodystrophy, hyperinsulinemia and an ides normalized (75 mg/dL). The liver enzymes also increase in the IGF-1/IGF-1 binding protein ratio normalized. The patient’s insulin was discontinued appear to contribute to an unopposed biological ef- after 4 months of treatment and metformin was fect of IGF-1 on IGF-1 receptors, leading to the devel- withdrawn after 6 months. The acanthosis nigricans also diminished remarkably in concert with the other obesity-associated acanthosis nigricans, includingmetformin,isotretinoin,and topical tretinoin CGL is a rare autosomal recessive disorder that demonstration of the effect of leptin treatment on is characterized by a dramatic paucity of adipose acanthosis nigricans in patients with CGL. We believe tissue, extreme insulin resistance, hyperandrogen- that improvement in AN following leptin replace- ism, acanthosis nigricans, hypertriglyceridemia, he- ment results from normalization of the metabolic patic steatosis, and early-onset diabetes.CGL abnormalities characteristic of this syndrome.
patients also have voracious appetites, acceleratedgrowth, and low serum leptin Two gene loci exhibiting autosomal recessive inheritance for CGLhave been identified. Mutations in some patients CGL is associated with paucity of adipose tissue, with CGL have been localized to the gene encod- extreme insulin resistance, hyperandrogenism, ing 1-acylglycerol-3-phosphate O-acyltransferase2 and acanthosis nigricans, hypertriglyceridemia, (AGPAT2) on chromosome 9q34. The AGPAT2 pro- hepatic steatosis and early-onset diabetes.
tein is an acyltransferase that catalyzes an essential There are two known mutations that cause con- reaction in the biosynthetic pathway of glycerophos- genital generalized lipodystrophy: 1-acylglycerol- pholipids and triacylglycerol in eukaryotes. Pertur- 3-phosphate O-acyltransferase2 (AGPAT2) and bations in triacylglycerol synthesis in adipose tissue may lead to triglyceride-depleted adipocytes.Other The generalized lack of adipose tissue in CGL patients with CGL have a mutation in the Berar- results in decreased leptin levels, whereas sub- dinelli-Seip congenital lipodystrophy 2 (BSCL2) gene sequent fat accumulation in ectopic areas such as located on chromosome 11q13. This gene is highly skeletal muscle and liver leads to insulin resis- expressed in the brain and testes and encodes a tance, diabetes, and steatohepatitis.
protein of unknown function called seipA third Leptin replacement in patients with CGL results group of CGL patients has mutations in neither in remarkable improvement in the physical and AGPAT2 nor BSCL2.Our patient was found to have endocrinologic manifestations of the disorder, in- Leptin is a hormone or adipocytokine which is Editor’s note: Dr Gorden (philg@mail.nih.gov) is a leading produced primarily in white adipose tissue and authority on lipodystrophies and is actively involved in which signals satiety,curbs appetite,and stimu- clinical, therapeutic, and genetic studies of CGL patients at lates oxidation of fat.Because patients with gener- the National Institutes of Health in Bethesda, Maryland.
alized lipodystrophy lack significant adipose tissue,they are consequently deficient in leptin, and haveno signal for satiety. Fat accumulation in ectopic areas such as skeletal muscle and liver leads to 1. Zhu S, Wang Z, Shen W, Heymsfield SB, Heshka S. Percentage body fat ranges associated with metabolic syndrome risk: insulin resistance, diabetes,and steatohepatitis.
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