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 Table of Contents  
REVIEW ARTICLE
Year : 2019  |  Volume : 20  |  Issue : 3  |  Page : 199-204

Childhood acanthosis nigricans


1 Department of Dermatology, KPC Medical College and Hospital, Kolkata, West Bengal, India
2 Department of Dermatology, Burdwan Medical College and Hospital, Burdwan, West Bengal, India

Date of Web Publication28-Jun-2019

Correspondence Address:
Dr. Anupam Das
“Prerana” 19, Phoolbagan, Kolkata - 700 086, West Bengal
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijpd.IJPD_34_18

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  Abstract 


Acanthosis nigricans (AN) is a frequently encountered dermatological condition seen commonly in middle aged or elderly, but in the recent times, there has been an increase in the childhood cases, especially in the adolescent age group. AN clinically manifested as dark, velvety, and thickened skin, symmetrically distributed over the neck, axillae, other flexural regions of the body and face. Facial AN, a somewhat recent entity that has been described and significant association with obesity, hyperinsulinemia, and metabolic syndrome, has been established. AN was once considered a rare paraneoplastic dermatosis but is now frequently observed in obese adolescents. Obesity in adolescence is a public health priority because it usually tracks into adulthood, resulting in enormous medical and social costs. This underscores the importance of early identification and intervention. The purpose of this narrative review is to provide a comprehensive overview of AN in childhood, including history, definition, classification, its clinical significance, management challenges, and the direction of future research.

Keywords: Acanthosis nigricans, childhood, obesity


How to cite this article:
Das A, Misra P, Panda S. Childhood acanthosis nigricans. Indian J Paediatr Dermatol 2019;20:199-204

How to cite this URL:
Das A, Misra P, Panda S. Childhood acanthosis nigricans. Indian J Paediatr Dermatol [serial online] 2019 [cited 2019 Oct 20];20:199-204. Available from: http://www.ijpd.in/text.asp?2019/20/3/199/261877




  Definition Top


Acanthosis nigricans (AN) is characterized by dark, rough, and thickened skin with a velvety feel, being symmetrically distributed on the neck, axillae, antecubital and popliteal fossae, groin folds, and face; histopathologically characterized by papillomatosis and hyperkeratosis of the skin.[1]


  History Top


At the international  Atlas More Details for rare skin diseases more than hundred years ago, the term AN was proposed for the first time by Dr. Paul Gerson Unna from Hamburg and the case report was published in 1891 by Dr. Sigmund Pollitzer. A similar case was described by Dr. Vitezslav Janovsky from Prague in the same issue.[2],[3]

The association of AN and obesity was first noted by Robinson and Tasker in 1947 who reported a case of AN juvenilis associated with obesity in a 17-year-old boy. They also presented a compilation of 10 cases from the medical literature.[4] As a consequence of the ongoing pandemic of obesity, AN associated with obesity is the most common cause of AN, which is true even for the pediatric population.[5]


  Classification Top


Curth classified AN into malignant, benign, and syndromic or pseudo-AN. Hernandez-Perez proposed more simplified classification: simple AN not related to malignancy and paraneoplastic AN. The most commonly used classification was given by Schwartz, who categorized the entity into the following eight types: benign, malignant, associated with obesity, syndromic, unilateral, drug induced, mixed, and acral. According to a recent classification in a textbook, unilateral nevoid has been grouped together with “syndromic AN” and “acral acanthotic anomaly” under the heading “other” causes of AN.[6]


  Epidemiology Top


The problem of pediatric obesity in US children and adolescents is quite evident from the fact that its prevalence has increased significantly during the past decade. Recent estimates are 10.4% in 2–5 years olds, 15.3% in 6–11 years olds, and 15.5% in 12–19 years olds.[7] This problem is generally underdiagnosed and less aggressively treated as parents tend to consider their “overweight” children as “healthy.” AN was seen in approximately 66% in adolescents with gross overweight, that is, weighing >200% of ideal. Of 139 US children who were overweight, 25% had AN, 50% of these children were of African lineage, and 8.2% were Caucasians.[8],[9]

In a study of 234 Israeli children and adolescents who were obese, 81% were given the diagnosis of insulin resistance and 56.6% manifested AN.[10]

The prevalence of AN in New Mexico was 49.2% in obese adolescents compared with 7.7% in those who were not obese.[11] There is no known sex predilection for AN. An Indian study showed that 77.8% were female and 22.2% were male, but since this was a hospital-based study, the result could be due to increased cosmetic concern and greater likelihood for seeking medical help in females.[12]

In an Indian study conducted among 100 obese children the most common cutaneous manifestation was AN seen in 42%.[13],[14]


  Pathogenesis Top


When the serum insulin level is within normal limits, it crosses the dermoepidermal junction, binds to the classical insulin receptors, and brings about a change in carbohydrate, lipid, and protein metabolism, but it does not increase the proliferation of keratinocytes. However, at higher concentrations, it can bind to the insulin-like growth factor 1 receptors (IGF-1Rs) stimulate proliferation of keratinocytes and fibroblasts, leading to AN. IGF-binding proteins (IGFBPs) bind to IGF-1 and thereby regulate the levels of metabolically active “free” IGF-1. In obese patients with hyperinsulinemia, IGFBP-1 and IGFBP-2 are decreased which increases the plasma concentrations of free IGF-1, promoting cell growth, and differentiation of keratinocytes leading to AN.[15]

Cyclosporine has been successfully used in some cases of AN which has lead to the belief that there could be some autoimmune factors responsible for the development of AN.[16]

Insulin and IGF levels are altered in hepatitis C infection which seems like a plausible explanation of development of acrochordon and AN in some cases of hepatitis C.[17]

Malignancy-associated AN might be explained by elevated levels of transforming growth factor-α (TGF-α), exerting effects on epidermal tissue through epidermal growth factor (EGF) receptor. The malignant cells produce TGF-α which is structurally almost similar to EGF-α and thus can bind to its receptor on the basal keratinocytes and lead to increase proliferation of normal keratinocytes causing AN.[18]


  Clinical Features Top


AN is generally diagnosed clinically without much difficulty. It presents as symmetric, velvety, brownish-black, hypertrophic, verrucous patches or plaques involving the axillae, posterior neck fold, flexor surfaces of the upper and lower extremities, umbilicus, groin, inframammary folds, face, and perioral and perianal surfaces [Figure 1]a and [Figure 1]b.[3],[6] Malignancy-associated and obesity-associated AN may involve periorbital and maxillary areas as well. In children, AN generally starts from the axillae or back neck fold, with hyperpigmentation as the first change observed. Involvement of the mucosal surfaces of the conjunctivae, lips, oral cavity, and vulva may occur, often with a papillomatous appearance more prominent than hyperpigmentation.[19]
Figure 1: (a) Clinical photograph showing classical features of acanthosis nigricans involving the neck in a 9-year-old obese girl (lateral view), family history of obesity and acanthosis nigricans absent and (b) Clinical photograph showing classical features of acanthosis nigricans involving the neck in a 9-year-old obese girl (posterior view), family history of obesity and acanthosis nigricans absent

Click here to view


AN may occasionally coexist with other disorders such as Becker's nevi.[20]


  Benign Acanthosis Nigricans Top


This type of AN usually appears at birth or during childhood or adolescence as an autosomal dominant trait with variable penetrance. Initially, there is unilateral involvement, but the palms and soles are usually spared. Progressive involvement tends to occur until puberty. Rarely, there may be generalized involvement. Whether insulin resistance has a role to play in this type of AN is still unknown, but it is advisable to undergo a complete evaluation.[3],[21],[22],[23],[24],[25],[26]


  Obesity-Associated Acanthosis Nigricans Top


Previously known as pseudo-AN, this is the most common type in both children and adults worldwide. In prepubertal children, the usual manifestations are obesity and hyperinsulinemia. Following puberty, the cutaneous manifestation of AN becomes evident. In a study comparing obese children with AN with normal nonobese children revealed higher insulin resistance and pancreatic beta-cell dysfunction in the former group. Hence, we can consider AN as a sign of high risk of type 2 diabetes mellitus (T2DM).[27]

In a Chinese study on 19 obese children with benign AN, all of them showed apparent insulin resistance. One of them was diagnosed as T2DM and ten of them showed impaired oral glucose tolerance. From this study, we can conclude that childhood benign AN is closely associated with obesity, hyperinsulinemia, insulin resistance, and T2DM and may be used as an index of insulin resistance.[28]

Adolescence is a time for developing autonomy from parents. Adolescents have the liberty to access to food of their own choice, especially when with peers at the same time, they are less able than adults to self-regulate caloric intake. This is particularly risky for excessive weight gain in light of hormonal and physical changes associated with puberty. Fortunately, there is a lot of scope for intervention during this adolescence making it a high-reward stage for obesity prevention.[29]


  Syndromic Acanthosis Nigricans Top


AN is associated with numerous syndromic conditions. The type A insulin resistance syndrome is also known as hyperandrogenism insulin resistance (HAIR)-AN syndrome, a constellation of HAIR, and AN.[30]

It is associated with polycystic ovarian disease and shows signs of virilization. Young girls and middle-aged women are mostly affected. The Type B insulin resistance syndrome is seen in women in their fourth decade.[3] HA and periocular AN are prominent features in this syndrome.[31] Type B insulin resistance is generally associated with other autoimmune diseases such as systemic lupus erythematosus, Hashimoto's thyroiditis, and autoimmune thrombocytopenia. Some of the other syndromes associated with AN are Berardinelli–Seip (congenital) and Lawrence (acquired) syndromes of generalized lipodystrophy, Hirschowitz's syndrome, polycystic ovarian syndrome, Donohue's syndrome (leprechaunism), Rabson–Mendenhall syndrome, Alstro¨m syndrome, familial partial lipodystrophy (Dunnigan type), and Crouzon's, Bloom's, and Prader–Willi syndrome.[32],[33],[34],[35],[36],[37],[38],[39],[40]


  Malignant Acanthosis Nigricans Top


It is very rare in pediatric age group and only 10 cases have been reported till date out of which gastric carcinoma is the most common association seen in three cases. There were two cases each of Wilm's tumor and osteosarcoma. The rest were adrenal carcinoma, papillary carcinoma thyroid, and malignant deciduoma.[5]


  Acral Acanthosis Nigricans Top


In acral AN, also called as acral acanthotic anomaly, the lesions are localized to the knee, ankle, phalangeal joints, and tarsophalangeal joints[3] [Figure 2]a and [Figure 2]b. It is apparently more common in persons with a dark complexion and affects acral areas without prominent affection of axilla and other flexures.[41] The clinical significance of acral AN is ambiguous and more studies are needed to settle this issue. According to Schwartz, this type of AN essentially occurs in healthy people with dark complexion and does not, on its own, call for a vigilant workup of those afflicted; for the possible presence of an internal malignancy. However, recently it has been reported in association with dermatofibrosarcoma protuberans, nonhodgkin's lymphoma, and gastric adenocarcinoma.[42]
Figure 2: (a) Typical case of acral acanthosis nigricans (over the dorsum of hands) in a 6-year-old boy and (b) classical lesions of acral acanthosis nigricans over the dorsum of feet in the same patient

Click here to view



  Unilateral Nevoid Acanthosis Nigricans Top


Unilateral nevoid AN (UNAN) has a morphology similar to classical AN, but the distribution is unilateral or localized and it is clinically manifested during childhood or later. There is no systemic, endocrine, or syndromic association. Familial involvement in UNAN is not present. The first description was given by Krishnaram in 1991 and following that report, very few cases have been reported.[43] Schwartz was the first to include this entity in the classification of AN in 1994. Das et al. reported a similar case of a 25-year-old male, the onset of the lesions being at the age of 17 years.[44]

Most of the cases respected the midline with the distribution being essentially unilateral. Petit et al. reported three cases of a rash with mixed clinical features of both epidermal nevus and AN, but since the pathophysiology of this rash was unclear, they proposed to name it “rounded and velvety epidermal nevus.”[45]


  Drug-Induced Acanthosis Nigricans Top


The induction of AN by pharmacologic agents is a well-known phenomenon and is not commonly diagnosed in children. Most widely recognized is the association between nicotinic acid and AN,[46],[47] which typically develops on the abdomen and flexor surfaces of the skin and resolves within 4–10 weeks of stopping the medication. Patients with insulin-requiring diabetes may acquire AN as a result of repeated injection of the same sites.[48]

Other medications known to result in the development of AN include oral contraceptives, diethylstilbestrol, heroin, corticosteroids, methyltestosterone, fusidic acid, and hydantoin-like derivatives.

Mixed-Type Acanthosis Nigricans

The presence of more than one type of above lesion in the same patient is defined as mixed type of AN. It generally occurs when a patient with one type of AN develops another type of AN lesion of a different type. An example would be a patient with obesity-associated AN who subsequently develops malignancy-associated AN.


  Facial Acanthosis Nigricans Top


Facial AN (FAN) is a fairly common entity nowadays and a recent multicentric study on Indian population has revealed male patients with elevated homeostasis model assessment (HOMA) 2-IR level, increased waist–hip ratio, impaired oral glucose tolerance test, and increased body mass index have a significantly higher probability of developing FAN. A protective role of smoking against the development of FAN was found in the study, but further studies are required to validate this finding. Thus, a patient of FAN should be thoroughly evaluated for underlying systemic illness, even if there are no signs and symptoms of cardiovascular disease and metabolic syndrome.[49]


  Investigations Top


Diagnosing a case of AN is quite forward clinically, but histopathology may be required to confirm the diagnosis. Biopsy characteristically demonstrates epidermal hyperkeratosis and minimal to mild acanthosis,[33],[50] and an upward projection of the dermal papillae into a thinned overlying epidermis with keratinaceous material filling up the regions between the ridges. Hyperpigmentation is generally the result of epidermal hyperkeratosis, but increased number of melanosomes in the stratum corneum is also seen in some patients.[5],[51]

The dermis characteristically lacks an inflammatory infiltrate.

Obesity can be determined by calculating the waist–hip ratio or body mass index.

Insulin resistance can be assessed by various methods:[1]

  1. HOMA – This provides an equations for estimating IR (HOMA-IR) and β-cell function from simultaneous fasting measures of insulin and glucose levels and is an excellent epidemiological and clinical assessment tool for IR. HOMA-IR = Fasting glucose (mmol) × Fasting insulin (uU/mL)/22.5. IR is diagnosed when the result is >2.71. Study shows obese children with AN show higher HOMA-IR levels However, the values are not standarised for the Indian population and more so not standarised for children
  2. Fasting insulin level – Simplest method but gives high false-positive results due to lack of standardization
  3. Glucose/insulin – This ratio has been used in studies as an index of IR. It is a highly sensitive and specific measurement of insulin sensitivity. In adults, a ratio of <4.5 is abnormal, whereas in prepubertal children <7 is abnormal
  4. Quantitative insulin sensitivity check index (QUICKI) – QUICKI provides a consistent and precise index of insulin sensitivity with better positive predictive power. It is calculated as: QUICKI = 1/(log [Insulin μU/mL] + log [Glucosemg/dL]). Patients with QUICKI index below 0.357 tend to have a higher risk of IR or frequently present with manifestations typical of metabolic syndrome
  5. Glucose insulin product – Product of plasma glucose and insulin concentrations has been considered an index of whole-body insulin sensitivity and it provides better index of insulin sensitivity.


Several novel markers such as IGFBP-1, hs-C-reactive protein, adiponectin, ferritin, hemoglobin A1c, C3 complement, tumor necrosis factor alpha, and soluble CD36 are now surfacing as surrogate markers of IR.[52] Other investigations for IR are fasting glucose and lipoprotein profile, hemoglobin A1c (HbA1c), body weight, blood pressure, and an alanine transferase test for evaluation of fatty liver.[53]


  Treatment Top


Eliminating the cause of AN is the first and foremost step in the treatment of AN. Weight reduction in case of obesity-induced AN leads to clinical improvement. Obesity prevention is rather a more decisive approach that can be started right away early in life. Behavioral weight management comprises diet, exercise, and behavior modification to encourage sustained lifestyle changes and can be initiated from childhood. Among dietary modification, avoiding sugary soft drinks, reducing the portion size but increasing the frequency to 5–6 small meals daily, and avoiding snacking in between meals such as consumption of chips and fried fast food are of primary importance.[54]

The only Food and Drug Administration (FDA)-approved drug for use in adolescents aged 12–16 years is orlistat (Xenical). It has been in the market since 1990 and has been available in the US as a nonprescription drug since 2007.[55] The mechanism of action of orlistat, a lipase inhibitor, is fat malabsorption. Fat-soluble vitamin supplements are therefore recommended.[56] The side effects of flatulence and steatorrhea may be distressing for the patients. Metformin (Glucophage), a biguanide derivative, has FDA approval for use in childhood T2DM, but not in childhood obesity. It has a good safety track record, and the only common side effects are mild nausea and vomiting. Most studies in children and adolescents have shown modest reductions in body weight. AN malignancy resolves following treatment of the underlying malignancy but may recur with the recurrence of the tumor. Stoppage of the incriminating drug may resolve the dermatosis. Treating patients with the HAIR-AN syndrome using oral contraceptives improves cosmesis and reduces hyperpigmentation and androgenic traits by lowering the concentration of free circulating androgens.[5]

Dietary fish oil treatment has been suggested in patients with lipodystrophic diabetes mellitus and generalized AN and may result in significant improvement in the AN despite the continuation of niacin treatment.[57]

In congenital lipodystrophy-associated AN, recombinant leptin has shown good response.[35]

In an Indian study, topical adapalene gel was found to be quite effective in reducing the skin pigmentation with minimal irritation.[58] Topical tretinoin or oral isotretinoin may reduce and even eliminate AN.[59]

Combination therapy with 0.05% topical tretinoin and 12% ammonium lactate has shown efficacy in treating obesity-associated AN.[60] Besides, hyperkeratosis of the nipple associated with acanthosis nigricans has shown good response to topical calcipotriol.[61]

Other topical agents that may be used include podophyllin, urea, and salicylic acid. A newer treatment modality that has shown promise in treating idiopathic AN is long-pulsed alexandrite laser treatment.[62]

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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  In this article
Abstract
History
Classification
Epidemiology
Pathogenesis
Clinical Features
Benign Acanthosi...
Obesity-Associat...
Syndromic Acanth...
Malignant Acanth...
Acral Acanthosis...
Unilateral Nevoi...
Drug-Induced Aca...
Facial Acanthosi...
Investigations
Treatment
Definition
References
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