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Acanthosis nigricans and the metabolic syndrome
Acanthosis nigricans and metabolic syndrome Ayse Serap Karada˘g, Yi You, Retno Danarti, Safaa Al-Khuzae, WenChieh Chen PII: DOI: Reference:
S0738-081X(17)30163-3 doi: 10.1016/j.clindermatol.2017.09.008 CID 7186
To appear in:
Clinics in Dermatology
Please cite this article as: Karada˘g Ayse Serap, You Yi, Danarti Retno, Al-Khuzae Safaa, Chen WenChieh, Acanthosis nigricans and metabolic syndrome, Clinics in Dermatology (2017), doi: 10.1016/j.clindermatol.2017.09.008
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ACCEPTED MANUSCRIPT Acanthosis nigricans and metabolic syndrome Ayse Serap Karadağ, MDa, Yi You, MD, PhDb, Retno Danarti, MDc, Safaa
a
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Al-Khuzae, MDd, WenChieh Chen, MDe,f*
Department of Dermatology, Goztepe Research and Training Hospital, School of
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Medicine, Istanbul Medeniyet University, Fahrettin Kerim Gökay cad., 34722
b
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Goztepe, Kadıkoy, Istanbul, Turkey
Department of Dermatology, Southwest Hospital, The Third Military Medical
University, 30 Gaotanyan Street, Chongqing 400038, P.R. China c
Department of Dermatology and Venereology, Faculty of Medicine, Universitas
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Gadjah Mada/Dr. Sardjito Hospital, Jalan Farmako Sekip Utara, Yogyakarta 55281,
d
PT
Indonesia
Department of Dermatology, Rumaillah Hospital, Hamad Medical Cooperation, Al
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Rumaila, Off Al Istiolal Street, P.O. Box 3050, Doha, Qatar IZZ-Immunologie Zentrum Zürich, Walchestr. 11, CH 8006 Zurich, Switzerland
f
Department of Dermatology and Allergy, Technische Universität München,
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e
Biedersteinerstr. 29, D-80802 Munich, Germany *Corresponding author. Tel.: + 41 (0) 44 434 10 00 Email-address: [email protected] Karadağ AS and You Yi share the first authorship.
1
ACCEPTED MANUSCRIPT Abstract Acanthosis nigricans (AN) describes clinically a darkly pigmented thickening
skin,
which
demonstrates
epidermal/dermal
hyperplasia
with
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orthokeratotic hyperkeratosis and papillomatosis of stratum spinosum with basal layer
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hyperpigmentation, in the absence of actual acanthosis and melanocytosis in histology. It is a reactive cutaneous change closely associated with obesity/insulin endocrinopathy,
gastrointestinal adenocarcinoma.
malignancy
in
particular
The prevalence varies, and ethnicity seems an
Evidence shows that AN is a useful clinical marker to identify
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independent factor.
or
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resistance/hyperinsulinemia,
patients susceptible to insulin resistance, the metabolic syndrome, and type 2 diabetes.
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Whether AN can be regarded as one of the risk factors for the diagnosis of metabolic syndrome, like large waist circumference and elevated blood pressure, is unclear.
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Correlation between AN and degree of hyperglycemia, insulin resistance, impaired glucose tolerance and dyslipidemia remains to be confirmed. Classification of AN is
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inconsistent, and assessment of its severity is less studied. Several monogenic
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diseases are known to present extensive AN of early onset and can act as models for a better understanding of its pathogenesis.
Therapeutic options are limited and results
are unsatisfactory. Retinoids seem to be the most effective topical treatment, while insulin sensitizers, represented by metformin to target insulin resistance, are promising, but controlled studies are lacking. Change of lifestyle to diminish the manifestations of the metabolic syndrome is beneficial, but the influence remains unclarified. Spontaneous remission seems more complete in the paraneoplastic AN than in the form associated with obesity/insulin resistance.
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ACCEPTED MANUSCRIPT Introduction The term acanthosis nigricans (AN) was first described by Sigmund Pollitzer
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(1859-1937), Victor Janowsky (1847-1925) and Paul Gerson Unna (1850-1929) from
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Hamburg Germany in Unna´s eminent International Atlas of Rare Skin Diseases published in 1890.1 It commonly manifests as symmetrical, hyperpigmented, dark,
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rough patches/plaques typically in the intertriginous areas, flexures, and the neck.2 Elbows and knees, dorsal joints of hands/fingers (knuckles), external genitalia, and
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occasionally face and eyelids can be involved.3 Lesions may develop over the areolae, umbilicus, anus, lips, and rarely the conjunctiva and oral mucosa, with delicate smooth furrows and verrucous changes.3 The skin lesions begin with brown in
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fair-skinned or grey pigmentation in dark-skinned people, accompanied by dryness and roughness, then become palpably thickened and covered with small
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papillomatous elevations with a velvety texture.4 The distribution and severity are not always symmetrical, while the sequence of involvement varies individually.
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Superimposed skin tags (acrochordon) are commonly seen in advanced lesions.
Epidemiology and prevalence The prevalence of AN varies significantly, depending on age, ethnicity, skin type, degree of obesity, and concomitant diseases especially endocrinopathy, which can reach up to 25% in general surveys and above 60% in studies of overweight/obese children (Figure 1). Individuals with dark skin display this sign more commonly,5 with native Americans and African Americans being most commonly affected, followed by Hispanics, Asians, and much less Caucasians.3,6 In overweight/obese children, the ethnic influence on the prevalence rates appears less obvious.7 Occurrence of AN increases with age and shows no gender difference, whereas some 3
ACCEPTED MANUSCRIPT studies reveal a higher prevalence in girls of school age and in women with obesity or diabetes.8,9
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In most epidemiologic surveys of AN, only the nape was examined, which very
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likely underestimate the prevalence and severity of the disease. This may be why some studies show the presence of AN to be less sensitive than body index percentile
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for identification of youth with insulin resistance.10
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Classification
Different classifications of AN have been proposed, mainly based on the etiologic factors.11-13 Helen Ollendorff Curth (1899-1982) classified AN as malignant,
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benign/true, pseudo (related to endocrinopathies), and drug-induced.11 Enrioue Hernandez-Perez proposed a simple AN unrelated to malignancy and paraneoplastic
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AN.12 Smeeta Sinha and Robert A Schwartz combined etiology and localization and divided AN into obesity-associated, benign, syndromic, malignant, unilateral, acral,
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drug-induced, and mixed type.13 Many of the proposed nomenclatures are overlapping,
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unclear and confusing (e.g. benign, pseudo/true, malignant, mixed), reflecting the complexity of the disease pathogenesis. We would suggest discarding the use of benign, pseudo/true, malignant to describe AN, because AN itself is a reactive skin change in its nature, and a malignant transformation has so far never been observed. Overlapping is also met in acral AN which can be idiopathic,14 drug- or malignancy associated.15 Repeated insulin injection is known to induce local AN.16 The term familial AN refers to diverse presentations caused by mutations in insulin receptor gene or fibroblast growth factor receptor (FGFR)3,17,18 idiopathic or indeterminate cases with unclarified genetics.19,20 Aromatase deficiency syndrome is caused by genetic mutations of CYP19A1, but the ensuing endocrinologic disturbance leads to AN.21 A modification of the existing classification is proposed in Table 1. 4
ACCEPTED MANUSCRIPT Limited classifications address the disease severity. One group has suggested a quantitative scale of AN severity from 0 to 4, based on the affected areas with no
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consideration of the degree of skin alterations in each region.22 Another group has
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evaluated AN skin texture, hyperpigmentation, and the body parts involved (neck, axillae, trunk, extremities, or mucous membranes).23 A third group has included five
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anatomic sites (neck, axilla, knuckles, elbows, and knees) and the skin texture in each affected area and found the scales correlated with fasting insulin and body mass index
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(BMI).24
Pathogenesis
AN is most commonly associated with obesity, hyperinsulinemia, and insulin
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resistance, in adults and children alike.5 Mutations in the insulin receptor gene,
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leading to insulin resistance, are known to cause extensive AN with early onset in childhood.25 Also, genetic mutations involving FGFR2 and FGFR3 gene,26,27
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phosphatase and tensin homolog (PTEN) gene,28 and V-Ha-RAS Harvey rat sarcoma
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viral oncogene homolog (HRAS) gene show severe AN phenotypically.29 Paraneoplastic AN, more appropriately termed than malignant AN, is often associated with gastrointestinal adenocarcinoma,30 followed by lung cancers, then such gynecologic malignancies as breast or ovarian. Drug-induced AN is rare, where hormone-dependent, especially insulin but also sexual hormones, and glucocorticoids are described. There are also many case reports of AN as a side effect of nicotinic acid in the treatment of dyslipidemia.31 Pathogenesis of AN is incompletely understood. The histopathology is characterized mainly by hyperkeratosis and epidermal papillomatosis with minimal or no acanthosis, and basal hyperpigmentation with mild melanosis or discreet melanocytosis. In correlation with the etiologies, it suggests that proliferation of 5
ACCEPTED MANUSCRIPT epidermal keratinocytes or probably more the dermal fibroblasts induced by certain growth factors is of central pathogenic role. Insulin and insulin-like growth factor
With insulin resistance and compensatory hyperinsulinemia,
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insulin receptors.
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(IGF) are best characterized, whereby insulin at low concentrations binds to classic
insulin binds to IGF-1 receptors,31 which have been demonstrated in keratinocytes and There is no direct evidence to indicate the activation of IGF-1
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fibroblasts.32
receptors in epidermal keratinocytes or dermal fibroblasts in the lesions of AN.
The
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interaction between insulin, IGF-1, androgens, and growth factors may further explain the association between AN and obesity, endocrinopathies, or hormonal treatment.33 As in paraneoplastic AN, transforming growth-factor (TGF)-α is supposed to act on
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the increased epidermal growth factor receptor (EGFR) expressed in the epidermis.34 FGFR, PTEN, and HRAS genes control and regulate the cell proliferation,
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differentiation, and apoptosis.
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Acanthosis nigricans and metabolic syndrome
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There is substantial evidence that patients with AN bear a higher risk for developing the metabolic syndrome (METS) and type 2 diabetes in different age groups, with a significant correlation between AN and BMI, waist circumference, elevated blood pressure, dyslipidemia, hyperinsulinemia, hyperglycemia, impaired glucose intolerance, and insulin resistance like HOMA-index. Clustering of these components can be significant.6,35-37 Pregnant women with and without AN were found to have ratio of gestational diabetes at 35.8% and 9.2%, respectively.38 Presence of acanthosis nigricans during pregnancy could increase the risk of conversion of gestational diabetes to Type 2 diabetes mellitus or prediabetes within five years postpartum (odds ratio 3.10, 95% CI 1.64-5.87).39 6
ACCEPTED MANUSCRIPT Very few studies have examined the accuracy of applying AN in the prediction of insulin resistance or type 2 diabetes and the correlation between extent/severity of
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AN and degree of obesity or insulin resistance. In a prospective cohort-study of 76
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obese Caucasian children, the sensitivity, specificity, positive and negative predictive values, and accuracy level for AN to detect insulin resistance were 73.5%, 50%,
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54.3%, 70%, and 49%, respectively, with a low correlation between insulin and fasting glucose levels in AN-negative or AN-positive patients.40 In obese children,
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reactive insulinemia was found to be more pronounced, triglycerides higher, HDL-cholesterol lower, and atherogenic dyslipidemia more frequent in those with AN than without AN.41 Further large-scale studies in consideration of age and ethnicity
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are required.
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Syndromic acanthosis nigricans associated with metabolic syndrome Among the syndromes associated with AN, the hyperhormonotrophic form is
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induced by overproduction of hormones, mainly glucocorticoid, androgen, insulin and
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growth hormone, either through functional disturbances due to enzyme abnormalities or tumorigenic origin such as neoplastic or paraneoplastic. Examples are Cushing syndrome, Addison disease, polycystic ovarian syndrome, gigantism/acromegaly, Prader-Willi syndrome, and primary hypogonadism. The common occurrence of Cushing syndrome, precocious puberty, pituitary tumor, and acromegaly in McCune-Albright syndrome but with rare manifestation of AN indicates that a certain promoting or suppressing factor is involved in its formation.42 Another group of syndromes are characterized by autosomal recessive inheritance, insulin resistance with early onset of hyperinsulinemia, and AN in a usually extensive way. Examples are Rabson-Mendenhall syndrome, Alström 7
ACCEPTED MANUSCRIPT syndrome, Bardet-Biedl syndrome, Donohue syndromes and Berardinelli-Seip congenital lipodystrophy syndrome type I and II.42 Hirsutism is a common
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manifestation. Mutations in the insulin receptor gene (INSR) are found in the
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Rabson-Mendenhall syndrome and Donohue syndrome, which can cause retarded posttranslational processing of the receptor, impaired transport of the receptor to the
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cell membrane, reducing numbers of receptors on the cell surface, and reduced
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affinity of the receptor for insulin.
Alström syndrome and Bardet-Biedl syndrome are associated with defective ciliogenesis, stunted cilium and ciliopathies, which induce dysfunction in intracellular and intercellular sensing and signaling. Alström syndrome is caused solely by
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mutations in the ALMS1 gene while more than 19 genes on different chromosomes have been identified in Bardet-Biedl syndrome. In spite of obesity to a similar
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frequency and extent, patients with Alström syndrome are more likely than those with
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Bardet-Biedl syndrome to develop childhood type 2 diabetes mellitus and AN.43 Berardinelli-Seip syndrome
type
1
is
caused
by
mutations
in
the
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1-acylglycerol-3-phosphate O-acyltransferase 2 gene (AGPAT2), also known as lysophosphatidic acid acyltransferase-beta (LPAAT-beta), which catalyzes the biosynthesis of glycerophospholipids and triacylglycerol.44 Overexperssion leads to increased enzyme activity in correlation with enhanced transcription and synthesis of IL-6 and TNF-alpha, indicating that AGPAT2 overexperssion may amplify the cellular response to cytokine stimulation. Berardinelli-Seip syndrome type 2 is caused by mutations in the BSCL gene/seipin gene, which is involved in ER function and the remodeling of actin cytoskeleton for adipocyte differentiation.
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ACCEPTED MANUSCRIPT Aromatase deficiency syndrome is caused by mutations in the CYP19A1 gene leading to the failure in the conversion of androgens to estrogens.21 Virilization occurs
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in pregnant mothers during the antenatal period and also displays in female fetuses at
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birth with pseudohermaphroditism. Affected subjects of either gender later manifest with features of estrogen deficiency and androgen excess. Concurrence of METS with
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obesity, diabetes due to insulin resistance, and hyperinsulinemia, as well as AN, is
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commonly observed in affected patients.
A laminopathy due to a heterozygous missense mutation in ZMPSTE24 has been described in a patient with severe METS including hypertriglyceridemia, early onset type 2 diabetes, central obesity but without subcutaneous lipoatrophy, as well as AN,
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liver steatosis, and dilated cardiomyopathy. Mutations in ZMPSTE24 involve the only metalloprotease, transforming prelamin into mature lamin A.45
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HAIR-AN syndrome is a well-known but ill-defined entity, especially regarding
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the diagnosis of hyperandrogenism.46 It may be a subtype of polycystic ovarian syndrome, but obesity and/or other endocrinopathies play a primary pathogenic role.
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The association between AN and cutaneous hyperandrogenism, such as acne, hirsutism, and androgenic alopecia in the presence or absence of obesity, should be clarified. A recent study showed that AN, especially axillary AN, together with hirsutism, are the most reliable cutaneous markers of polycystic ovarian syndrome.47 Whether it is secondary to the often coexisting METS remains to be clarified. Similarly, the frequent presentation of AN in adults with Down syndrome was attributed to the higher prevalence of obesity,48 but studies on the lipid profile, prevalence of insulin resistance, or METS between adults with Down syndrome and controls are inconclusive.49
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ACCEPTED MANUSCRIPT There are several syndromes associated with endocrinopathy or hyperglycemia, but the presentation of AN is unclear. In inherited ACTH resistance syndromes, such Triple
A
syndrome
(Achalasia-Addisonianism-Alacrima)
and
familial
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as
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glucocorticoid deficiency syndrome, diffuse skin hyperpigmentation is common.50 H-syndrome is characterized by hyperpigmentation, hypertrichosis, hyperglycemia
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(insulin-dependent DM) and hypergonadotropic hypogonadism, in addition to histiocytosis and lymphadenopathy in the head and neck region, bilateral inguinal phalangeal
contractures,
sensorineural
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lymphadenopathy,
hearing
loss,
and
hyperglobulinemia. The responsible gene mutations were identified in solute carrier family 29, member 3 (SLC29A3), encoding equilibrated nucleoside transporter 3
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(hENT3).51
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Treatment
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Treatment of AN is usually unsatisfactory or frustrating. Well-controlled comparative studies with long-term follow-up are scarce. Topical retinoids, including
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tretinoin, adapalene, and tazarotene, are partially effective. Oral retinoids, such as acitretin and isotretinoin, have been reported to be effective for extensive involvement. Single case reports on the efficacy of topical agents, like vitamin D analogs, ammonium lactate, trichloroacetic acid, triple-combination depigmentation cream, urea, podophyllin, and salicylic acid, remain to be confirmed.52 Dermabrasion or abrasive laser therapy can also be attempted, but the long-term benefits are unknown. Correction of the contributing factors, such as obesity, hyperinsulinemia, and insulin resistance related to the METS, lead to clinical improvement of AN,53 but usually in the early phase, and the improvement varies.
Paraneoplastic AN mostly
vanishes when the associated cancers are eliminated. Use of insulin sensitizers such as 10
ACCEPTED MANUSCRIPT metformin, thiazolidinediones (e.g. pioglitazone), and inositols (e.g. myo-inositol and d-chiro-inositol) to treat insulin resistance in the METS may show promising effect on
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AN, especially metformin.54 Octreotide, a synthetic analog of the hypothalamic
glucagon, growth hormone, and insulin release.55
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hormone somatostatin, was also found to work on AN presumably via inhibition of
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We recommend phase-oriented cocktail treatment for obesity associated AN. In the early phase with pigmentary change, it is to start with lifestyle modification and
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improvement of insulin resistance, and the use of keratolytic agents like alpha-hydroxy acids and salicylic acids, in combination with depigmenting agents like hydroquinone or azelaic acid. We add topical tretinoin when velvety skin change
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appears. It usually takes 3-6 months to see a significant improvement, while complete resolution is rare. Skin irritation is a major concern, especially for children and in the
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Conclusions
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axillary regions.
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AN has been demonstrated to be a useful screening marker for obesity and insulin resistance. Early onset and extensive involvement is observed in genetic mutations affecting insulin receptor gene, ciliopathies, or lipogenesis. AN can be secondary to the associated METS or/and the involved genes can directly induce AN. Research on the activation and interaction of insulin/IGF-1, EGF/EGFR and FGF/FGFR signaling pathways will improve the understanding of the pathogenesis and help develop novel targeted therapies.
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ACCEPTED MANUSCRIPT 50. Elias, LL, Clark, AL. The molecular basis of adrenocorticotrophin resistance syndrome. Prog Mol Biol Transl Sci. 2009;88:155-171.
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indurated,
hyperpigmented,
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2008;59:79-85.
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52. Ng, HY. Acanthosis nigricans in obese adolescents: prevalence, impact, and management challenges. Adolesc Health Med Ther. 2017;8:1-10.
53. Sinha, S, Schwartz, RA.: Juvenile acanthosis nigricans. J Am Acad Dermatol.
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2007;57:502-508.
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54. Gong, L, Goswami, S, Giacomini, KM, et al.: Metformin pathways:
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pharmacokinetics
and
pharmacodynamics.
Pharmacogenet
Genomics.
2012;22:820-827.
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55. Romo, A, Benavides,
S.: Treatment options in insulin resistance
obesity-related acanthosis nigricans. Ann Pharmacother. 2008;42:1090-1094.
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ACCEPTED MANUSCRIPT Legends Fig. 1: A 10-year-old Indonesian boy with body weight 70kg/body height 150 cm
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(BMI 31.1), and fasting blood glucose 120 mg/dL/ insulin 25 mIU/L (HOMA-IR
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index 7.4). Acanthosis nigricans was observed in the anterior neck, nape and bilateral axillae.
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Table 1: Classification of acanthosis nigricans proposed by Chen and Karadag
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ACCEPTED MANUSCRIPT Table 1 Classification of acanthosis nigricans proposed by Chen and Karadag Subtypes
Unilateral nevoid AN
Acral
Acral AN (by Schwarz RA)
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Unilateral Focal 1
Obestiy-associated
Diabetes mellitus, Cushing syndrome, Addison disease, gigantism/acromegaly
Monogenic3
Rabson-Mendenhall syndrome Donohue syndromes Berardinelli-Seip syndrome Alström syndrome Bardet-Biedl syndrome
Multigenic4 Paraneoplastic
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Endocrinologic2
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Generalized
Insulin injection-induced AN
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Localized
Examples
HAIR-AN syndrome, PCO syndrome Gastrointestinal adenocarcinoma Insulin, testosterone, estrogen, nicotinic acid
Indeterminate
The so-called benign AN, familial AN of unknown genetics or mixed form
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Drug-induced
1 Obesity but does not fulfill the diagnosis of diabetes mellitus 2 Endocrinopathy with well-established diagnosis
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3 Genetic mutations identified and published in OMIM 4 Syndromes based on clinical diagnosis with heterogenous etiologies, HAIR-AN: hyperandrogenism, insulin resistance, acanthosis nigricans, PCO syndrome: polycystic ovary syndrome
20
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Figure 1
21
S0738-081X(17)30163-3 doi: 10.1016/j.clindermatol.2017.09.008 CID 7186
To appear in:
Clinics in Dermatology
Please cite this article as: Karada˘g Ayse Serap, You Yi, Danarti Retno, Al-Khuzae Safaa, Chen WenChieh, Acanthosis nigricans and metabolic syndrome, Clinics in Dermatology (2017), doi: 10.1016/j.clindermatol.2017.09.008
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ACCEPTED MANUSCRIPT Acanthosis nigricans and metabolic syndrome Ayse Serap Karadağ, MDa, Yi You, MD, PhDb, Retno Danarti, MDc, Safaa
a
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Al-Khuzae, MDd, WenChieh Chen, MDe,f*
Department of Dermatology, Goztepe Research and Training Hospital, School of
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Medicine, Istanbul Medeniyet University, Fahrettin Kerim Gökay cad., 34722
b
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Goztepe, Kadıkoy, Istanbul, Turkey
Department of Dermatology, Southwest Hospital, The Third Military Medical
University, 30 Gaotanyan Street, Chongqing 400038, P.R. China c
Department of Dermatology and Venereology, Faculty of Medicine, Universitas
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Gadjah Mada/Dr. Sardjito Hospital, Jalan Farmako Sekip Utara, Yogyakarta 55281,
d
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Indonesia
Department of Dermatology, Rumaillah Hospital, Hamad Medical Cooperation, Al
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Rumaila, Off Al Istiolal Street, P.O. Box 3050, Doha, Qatar IZZ-Immunologie Zentrum Zürich, Walchestr. 11, CH 8006 Zurich, Switzerland
f
Department of Dermatology and Allergy, Technische Universität München,
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e
Biedersteinerstr. 29, D-80802 Munich, Germany *Corresponding author. Tel.: + 41 (0) 44 434 10 00 Email-address: [email protected] Karadağ AS and You Yi share the first authorship.
1
ACCEPTED MANUSCRIPT Abstract Acanthosis nigricans (AN) describes clinically a darkly pigmented thickening
skin,
which
demonstrates
epidermal/dermal
hyperplasia
with
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orthokeratotic hyperkeratosis and papillomatosis of stratum spinosum with basal layer
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hyperpigmentation, in the absence of actual acanthosis and melanocytosis in histology. It is a reactive cutaneous change closely associated with obesity/insulin endocrinopathy,
gastrointestinal adenocarcinoma.
malignancy
in
particular
The prevalence varies, and ethnicity seems an
Evidence shows that AN is a useful clinical marker to identify
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independent factor.
or
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resistance/hyperinsulinemia,
patients susceptible to insulin resistance, the metabolic syndrome, and type 2 diabetes.
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Whether AN can be regarded as one of the risk factors for the diagnosis of metabolic syndrome, like large waist circumference and elevated blood pressure, is unclear.
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Correlation between AN and degree of hyperglycemia, insulin resistance, impaired glucose tolerance and dyslipidemia remains to be confirmed. Classification of AN is
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inconsistent, and assessment of its severity is less studied. Several monogenic
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diseases are known to present extensive AN of early onset and can act as models for a better understanding of its pathogenesis.
Therapeutic options are limited and results
are unsatisfactory. Retinoids seem to be the most effective topical treatment, while insulin sensitizers, represented by metformin to target insulin resistance, are promising, but controlled studies are lacking. Change of lifestyle to diminish the manifestations of the metabolic syndrome is beneficial, but the influence remains unclarified. Spontaneous remission seems more complete in the paraneoplastic AN than in the form associated with obesity/insulin resistance.
2
ACCEPTED MANUSCRIPT Introduction The term acanthosis nigricans (AN) was first described by Sigmund Pollitzer
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(1859-1937), Victor Janowsky (1847-1925) and Paul Gerson Unna (1850-1929) from
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Hamburg Germany in Unna´s eminent International Atlas of Rare Skin Diseases published in 1890.1 It commonly manifests as symmetrical, hyperpigmented, dark,
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rough patches/plaques typically in the intertriginous areas, flexures, and the neck.2 Elbows and knees, dorsal joints of hands/fingers (knuckles), external genitalia, and
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occasionally face and eyelids can be involved.3 Lesions may develop over the areolae, umbilicus, anus, lips, and rarely the conjunctiva and oral mucosa, with delicate smooth furrows and verrucous changes.3 The skin lesions begin with brown in
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fair-skinned or grey pigmentation in dark-skinned people, accompanied by dryness and roughness, then become palpably thickened and covered with small
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papillomatous elevations with a velvety texture.4 The distribution and severity are not always symmetrical, while the sequence of involvement varies individually.
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Superimposed skin tags (acrochordon) are commonly seen in advanced lesions.
Epidemiology and prevalence The prevalence of AN varies significantly, depending on age, ethnicity, skin type, degree of obesity, and concomitant diseases especially endocrinopathy, which can reach up to 25% in general surveys and above 60% in studies of overweight/obese children (Figure 1). Individuals with dark skin display this sign more commonly,5 with native Americans and African Americans being most commonly affected, followed by Hispanics, Asians, and much less Caucasians.3,6 In overweight/obese children, the ethnic influence on the prevalence rates appears less obvious.7 Occurrence of AN increases with age and shows no gender difference, whereas some 3
ACCEPTED MANUSCRIPT studies reveal a higher prevalence in girls of school age and in women with obesity or diabetes.8,9
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In most epidemiologic surveys of AN, only the nape was examined, which very
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likely underestimate the prevalence and severity of the disease. This may be why some studies show the presence of AN to be less sensitive than body index percentile
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for identification of youth with insulin resistance.10
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Classification
Different classifications of AN have been proposed, mainly based on the etiologic factors.11-13 Helen Ollendorff Curth (1899-1982) classified AN as malignant,
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benign/true, pseudo (related to endocrinopathies), and drug-induced.11 Enrioue Hernandez-Perez proposed a simple AN unrelated to malignancy and paraneoplastic
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AN.12 Smeeta Sinha and Robert A Schwartz combined etiology and localization and divided AN into obesity-associated, benign, syndromic, malignant, unilateral, acral,
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drug-induced, and mixed type.13 Many of the proposed nomenclatures are overlapping,
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unclear and confusing (e.g. benign, pseudo/true, malignant, mixed), reflecting the complexity of the disease pathogenesis. We would suggest discarding the use of benign, pseudo/true, malignant to describe AN, because AN itself is a reactive skin change in its nature, and a malignant transformation has so far never been observed. Overlapping is also met in acral AN which can be idiopathic,14 drug- or malignancy associated.15 Repeated insulin injection is known to induce local AN.16 The term familial AN refers to diverse presentations caused by mutations in insulin receptor gene or fibroblast growth factor receptor (FGFR)3,17,18 idiopathic or indeterminate cases with unclarified genetics.19,20 Aromatase deficiency syndrome is caused by genetic mutations of CYP19A1, but the ensuing endocrinologic disturbance leads to AN.21 A modification of the existing classification is proposed in Table 1. 4
ACCEPTED MANUSCRIPT Limited classifications address the disease severity. One group has suggested a quantitative scale of AN severity from 0 to 4, based on the affected areas with no
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consideration of the degree of skin alterations in each region.22 Another group has
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evaluated AN skin texture, hyperpigmentation, and the body parts involved (neck, axillae, trunk, extremities, or mucous membranes).23 A third group has included five
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anatomic sites (neck, axilla, knuckles, elbows, and knees) and the skin texture in each affected area and found the scales correlated with fasting insulin and body mass index
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(BMI).24
Pathogenesis
AN is most commonly associated with obesity, hyperinsulinemia, and insulin
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resistance, in adults and children alike.5 Mutations in the insulin receptor gene,
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leading to insulin resistance, are known to cause extensive AN with early onset in childhood.25 Also, genetic mutations involving FGFR2 and FGFR3 gene,26,27
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phosphatase and tensin homolog (PTEN) gene,28 and V-Ha-RAS Harvey rat sarcoma
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viral oncogene homolog (HRAS) gene show severe AN phenotypically.29 Paraneoplastic AN, more appropriately termed than malignant AN, is often associated with gastrointestinal adenocarcinoma,30 followed by lung cancers, then such gynecologic malignancies as breast or ovarian. Drug-induced AN is rare, where hormone-dependent, especially insulin but also sexual hormones, and glucocorticoids are described. There are also many case reports of AN as a side effect of nicotinic acid in the treatment of dyslipidemia.31 Pathogenesis of AN is incompletely understood. The histopathology is characterized mainly by hyperkeratosis and epidermal papillomatosis with minimal or no acanthosis, and basal hyperpigmentation with mild melanosis or discreet melanocytosis. In correlation with the etiologies, it suggests that proliferation of 5
ACCEPTED MANUSCRIPT epidermal keratinocytes or probably more the dermal fibroblasts induced by certain growth factors is of central pathogenic role. Insulin and insulin-like growth factor
With insulin resistance and compensatory hyperinsulinemia,
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insulin receptors.
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(IGF) are best characterized, whereby insulin at low concentrations binds to classic
insulin binds to IGF-1 receptors,31 which have been demonstrated in keratinocytes and There is no direct evidence to indicate the activation of IGF-1
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fibroblasts.32
receptors in epidermal keratinocytes or dermal fibroblasts in the lesions of AN.
The
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interaction between insulin, IGF-1, androgens, and growth factors may further explain the association between AN and obesity, endocrinopathies, or hormonal treatment.33 As in paraneoplastic AN, transforming growth-factor (TGF)-α is supposed to act on
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the increased epidermal growth factor receptor (EGFR) expressed in the epidermis.34 FGFR, PTEN, and HRAS genes control and regulate the cell proliferation,
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differentiation, and apoptosis.
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Acanthosis nigricans and metabolic syndrome
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There is substantial evidence that patients with AN bear a higher risk for developing the metabolic syndrome (METS) and type 2 diabetes in different age groups, with a significant correlation between AN and BMI, waist circumference, elevated blood pressure, dyslipidemia, hyperinsulinemia, hyperglycemia, impaired glucose intolerance, and insulin resistance like HOMA-index. Clustering of these components can be significant.6,35-37 Pregnant women with and without AN were found to have ratio of gestational diabetes at 35.8% and 9.2%, respectively.38 Presence of acanthosis nigricans during pregnancy could increase the risk of conversion of gestational diabetes to Type 2 diabetes mellitus or prediabetes within five years postpartum (odds ratio 3.10, 95% CI 1.64-5.87).39 6
ACCEPTED MANUSCRIPT Very few studies have examined the accuracy of applying AN in the prediction of insulin resistance or type 2 diabetes and the correlation between extent/severity of
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AN and degree of obesity or insulin resistance. In a prospective cohort-study of 76
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obese Caucasian children, the sensitivity, specificity, positive and negative predictive values, and accuracy level for AN to detect insulin resistance were 73.5%, 50%,
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54.3%, 70%, and 49%, respectively, with a low correlation between insulin and fasting glucose levels in AN-negative or AN-positive patients.40 In obese children,
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reactive insulinemia was found to be more pronounced, triglycerides higher, HDL-cholesterol lower, and atherogenic dyslipidemia more frequent in those with AN than without AN.41 Further large-scale studies in consideration of age and ethnicity
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are required.
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Syndromic acanthosis nigricans associated with metabolic syndrome Among the syndromes associated with AN, the hyperhormonotrophic form is
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induced by overproduction of hormones, mainly glucocorticoid, androgen, insulin and
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growth hormone, either through functional disturbances due to enzyme abnormalities or tumorigenic origin such as neoplastic or paraneoplastic. Examples are Cushing syndrome, Addison disease, polycystic ovarian syndrome, gigantism/acromegaly, Prader-Willi syndrome, and primary hypogonadism. The common occurrence of Cushing syndrome, precocious puberty, pituitary tumor, and acromegaly in McCune-Albright syndrome but with rare manifestation of AN indicates that a certain promoting or suppressing factor is involved in its formation.42 Another group of syndromes are characterized by autosomal recessive inheritance, insulin resistance with early onset of hyperinsulinemia, and AN in a usually extensive way. Examples are Rabson-Mendenhall syndrome, Alström 7
ACCEPTED MANUSCRIPT syndrome, Bardet-Biedl syndrome, Donohue syndromes and Berardinelli-Seip congenital lipodystrophy syndrome type I and II.42 Hirsutism is a common
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manifestation. Mutations in the insulin receptor gene (INSR) are found in the
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Rabson-Mendenhall syndrome and Donohue syndrome, which can cause retarded posttranslational processing of the receptor, impaired transport of the receptor to the
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cell membrane, reducing numbers of receptors on the cell surface, and reduced
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affinity of the receptor for insulin.
Alström syndrome and Bardet-Biedl syndrome are associated with defective ciliogenesis, stunted cilium and ciliopathies, which induce dysfunction in intracellular and intercellular sensing and signaling. Alström syndrome is caused solely by
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mutations in the ALMS1 gene while more than 19 genes on different chromosomes have been identified in Bardet-Biedl syndrome. In spite of obesity to a similar
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frequency and extent, patients with Alström syndrome are more likely than those with
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Bardet-Biedl syndrome to develop childhood type 2 diabetes mellitus and AN.43 Berardinelli-Seip syndrome
type
1
is
caused
by
mutations
in
the
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1-acylglycerol-3-phosphate O-acyltransferase 2 gene (AGPAT2), also known as lysophosphatidic acid acyltransferase-beta (LPAAT-beta), which catalyzes the biosynthesis of glycerophospholipids and triacylglycerol.44 Overexperssion leads to increased enzyme activity in correlation with enhanced transcription and synthesis of IL-6 and TNF-alpha, indicating that AGPAT2 overexperssion may amplify the cellular response to cytokine stimulation. Berardinelli-Seip syndrome type 2 is caused by mutations in the BSCL gene/seipin gene, which is involved in ER function and the remodeling of actin cytoskeleton for adipocyte differentiation.
8
ACCEPTED MANUSCRIPT Aromatase deficiency syndrome is caused by mutations in the CYP19A1 gene leading to the failure in the conversion of androgens to estrogens.21 Virilization occurs
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in pregnant mothers during the antenatal period and also displays in female fetuses at
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birth with pseudohermaphroditism. Affected subjects of either gender later manifest with features of estrogen deficiency and androgen excess. Concurrence of METS with
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obesity, diabetes due to insulin resistance, and hyperinsulinemia, as well as AN, is
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commonly observed in affected patients.
A laminopathy due to a heterozygous missense mutation in ZMPSTE24 has been described in a patient with severe METS including hypertriglyceridemia, early onset type 2 diabetes, central obesity but without subcutaneous lipoatrophy, as well as AN,
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liver steatosis, and dilated cardiomyopathy. Mutations in ZMPSTE24 involve the only metalloprotease, transforming prelamin into mature lamin A.45
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HAIR-AN syndrome is a well-known but ill-defined entity, especially regarding
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the diagnosis of hyperandrogenism.46 It may be a subtype of polycystic ovarian syndrome, but obesity and/or other endocrinopathies play a primary pathogenic role.
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The association between AN and cutaneous hyperandrogenism, such as acne, hirsutism, and androgenic alopecia in the presence or absence of obesity, should be clarified. A recent study showed that AN, especially axillary AN, together with hirsutism, are the most reliable cutaneous markers of polycystic ovarian syndrome.47 Whether it is secondary to the often coexisting METS remains to be clarified. Similarly, the frequent presentation of AN in adults with Down syndrome was attributed to the higher prevalence of obesity,48 but studies on the lipid profile, prevalence of insulin resistance, or METS between adults with Down syndrome and controls are inconclusive.49
9
ACCEPTED MANUSCRIPT There are several syndromes associated with endocrinopathy or hyperglycemia, but the presentation of AN is unclear. In inherited ACTH resistance syndromes, such Triple
A
syndrome
(Achalasia-Addisonianism-Alacrima)
and
familial
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as
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glucocorticoid deficiency syndrome, diffuse skin hyperpigmentation is common.50 H-syndrome is characterized by hyperpigmentation, hypertrichosis, hyperglycemia
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(insulin-dependent DM) and hypergonadotropic hypogonadism, in addition to histiocytosis and lymphadenopathy in the head and neck region, bilateral inguinal phalangeal
contractures,
sensorineural
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lymphadenopathy,
hearing
loss,
and
hyperglobulinemia. The responsible gene mutations were identified in solute carrier family 29, member 3 (SLC29A3), encoding equilibrated nucleoside transporter 3
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(hENT3).51
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Treatment
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Treatment of AN is usually unsatisfactory or frustrating. Well-controlled comparative studies with long-term follow-up are scarce. Topical retinoids, including
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tretinoin, adapalene, and tazarotene, are partially effective. Oral retinoids, such as acitretin and isotretinoin, have been reported to be effective for extensive involvement. Single case reports on the efficacy of topical agents, like vitamin D analogs, ammonium lactate, trichloroacetic acid, triple-combination depigmentation cream, urea, podophyllin, and salicylic acid, remain to be confirmed.52 Dermabrasion or abrasive laser therapy can also be attempted, but the long-term benefits are unknown. Correction of the contributing factors, such as obesity, hyperinsulinemia, and insulin resistance related to the METS, lead to clinical improvement of AN,53 but usually in the early phase, and the improvement varies.
Paraneoplastic AN mostly
vanishes when the associated cancers are eliminated. Use of insulin sensitizers such as 10
ACCEPTED MANUSCRIPT metformin, thiazolidinediones (e.g. pioglitazone), and inositols (e.g. myo-inositol and d-chiro-inositol) to treat insulin resistance in the METS may show promising effect on
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AN, especially metformin.54 Octreotide, a synthetic analog of the hypothalamic
glucagon, growth hormone, and insulin release.55
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hormone somatostatin, was also found to work on AN presumably via inhibition of
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We recommend phase-oriented cocktail treatment for obesity associated AN. In the early phase with pigmentary change, it is to start with lifestyle modification and
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improvement of insulin resistance, and the use of keratolytic agents like alpha-hydroxy acids and salicylic acids, in combination with depigmenting agents like hydroquinone or azelaic acid. We add topical tretinoin when velvety skin change
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appears. It usually takes 3-6 months to see a significant improvement, while complete resolution is rare. Skin irritation is a major concern, especially for children and in the
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Conclusions
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axillary regions.
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AN has been demonstrated to be a useful screening marker for obesity and insulin resistance. Early onset and extensive involvement is observed in genetic mutations affecting insulin receptor gene, ciliopathies, or lipogenesis. AN can be secondary to the associated METS or/and the involved genes can directly induce AN. Research on the activation and interaction of insulin/IGF-1, EGF/EGFR and FGF/FGFR signaling pathways will improve the understanding of the pathogenesis and help develop novel targeted therapies.
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26. Fonseca, R, Costa-Lima, MA, Cosentino, V, et al.: Second case of Beare-Stevenson syndrome with an FGFR2 Ser372Cys mutation. Am J Med Genet A. 2008;146:658-660. 14
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28. Shah, KR, Boland, CR, Patel, M, et al.: Cutaneous manifestations of gastrointestinal disease: part I. J Am Acad Dermatol. 2013;68:189.e1-21.
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niacin therapy. Dermatol Online J. 2011;17:11.
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binding protein-3 (IGFBP-3) localizes to and modulates proliferative epidermal keratinocytes in vivo. Br J Dermatol. 2005;152:225-230.
33. Melnik BC.: Permanent impairment of insulin resistance from pregnancy to adulthood: the primary basic risk factor of chronic Western diseases. Med Hypotheses. 2009;73:670-681.
34. Moreno-Artero, E, Querol, E, Ivars, M, et al.: Assessment of EGF receptor ligand expression in gastric carcinoma and in lesional skin of paraneoplastic acanthosis nigricans: a case report. J Eur Acad Dermatol Venereol. 2016 Dec 17. doi: 10.1111/jdv.14087. 15
ACCEPTED MANUSCRIPT 35. Kong, AS, Vanderbloemen, L, Skipper, B, et al.: Acanthosis nigricans predicts the clustering of metabolic syndrome components in Hispanic elementary
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school-aged children. J Pediatr Endocrinol Metab. 2012;25:1095-1102.
36. Abraham, C, Rozmus, CL.: Is acanthosis nigricans a reliable indicator for risk
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Sch Nurs. 2012;28:195-205.
37. Ayaz, T, Baydur Şahin, S, Şahin, OZ.: Relation of Acanthosis nigricans to metabolic syndrome in overweight and obese women. Metab Syndr Relat Disord. 2014;12:320-323.
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38. Yılmaz, E, Kelekci, KH, Kelekci, S.: Skin tag and acanthosis nigricans: do
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they have a predictive value for gestational diabetes mellitus? Exp Clin
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Endocrinol Diabetes. 2011;119:419-422.
39. Gupta, Y, Kapoor, D, Desai, A, et al.: Conversion of gestational diabetes
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mellitus to future type 2 diabetes mellitus and the predictive value of HbA1c in an Indian cohort. Diabet Med. 2017;34:37-43.
40. Aswani, R, Lochow, A, Dementieva, Y, et al.: Acanthosis nigricans as a clinical marker to detect insulin resistance in Caucasian children from West Virginia. Clin Pediatr (Phila). 2011;50:1057-1061.
41. Felszeghy, E, Káposzta, R, Juhász, E, et al.: Alterations of carbohydrate and lipoprotein metabolism in childhood obesity--impact of insulin resistance and acanthosis nigricans. J Pediatr Endocrinol Metab. 2009;22:1117-1126. 16
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43. Girard, D, Petrovsky, N.: Alström syndrome: insights into the pathogenesis of
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ACCEPTED MANUSCRIPT 50. Elias, LL, Clark, AL. The molecular basis of adrenocorticotrophin resistance syndrome. Prog Mol Biol Transl Sci. 2009;88:155-171.
characterized
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indurated,
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genodermatosis
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52. Ng, HY. Acanthosis nigricans in obese adolescents: prevalence, impact, and management challenges. Adolesc Health Med Ther. 2017;8:1-10.
53. Sinha, S, Schwartz, RA.: Juvenile acanthosis nigricans. J Am Acad Dermatol.
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Table 1: Classification of acanthosis nigricans proposed by Chen and Karadag
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ACCEPTED MANUSCRIPT Table 1 Classification of acanthosis nigricans proposed by Chen and Karadag Subtypes
Unilateral nevoid AN
Acral
Acral AN (by Schwarz RA)
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Unilateral Focal 1
Obestiy-associated
Diabetes mellitus, Cushing syndrome, Addison disease, gigantism/acromegaly
Monogenic3
Rabson-Mendenhall syndrome Donohue syndromes Berardinelli-Seip syndrome Alström syndrome Bardet-Biedl syndrome
Multigenic4 Paraneoplastic
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Endocrinologic2
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Generalized
Insulin injection-induced AN
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Localized
Examples
HAIR-AN syndrome, PCO syndrome Gastrointestinal adenocarcinoma Insulin, testosterone, estrogen, nicotinic acid
Indeterminate
The so-called benign AN, familial AN of unknown genetics or mixed form
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Drug-induced
1 Obesity but does not fulfill the diagnosis of diabetes mellitus 2 Endocrinopathy with well-established diagnosis
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3 Genetic mutations identified and published in OMIM 4 Syndromes based on clinical diagnosis with heterogenous etiologies, HAIR-AN: hyperandrogenism, insulin resistance, acanthosis nigricans, PCO syndrome: polycystic ovary syndrome
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Figure 1
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