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ACANTHOSIS NIGRICANS ASSOCIATED WITH LONG-TERM

GLUCOCORTICOID TREATMENT

Akira Prayudijanto, Alpha Fardah, Muhammad Faizi, Netty EP

Endocrinology DivisionDepartment of Child Health Faculty of Medicine

Airlangga University - Dr. Soetomo Hospital Surabaya

ABSTRACT

Acanthosis nigricans is characterized by symmetrical, hyperpigmented,

velvety plaques that may occur in almost any location. The posterior neck is

the most commonly affected site in children. The exact incidence of

acanthosis nigricans is unknown.

MA, a 10-year-4-month-old boy was referred to Pediatric Endocrinology

Outpatient Clinic of Dr. Soetomo Hospital with the main complaint of

hyperpigmented skin on the face, axillaries and posterior neck areas with the

history of took glucocorticoid treatment for 2 years.

Based on history, physical, laboratory and histopathology examinations, the

diagnosis of Acanthosis nigricans with Atopy dermatitis, Obese and Short

Stature was established.

The treatments of glucorticoid was stopped, chlortrimeton (CTM), and allergen

avoidance were continued with observation on side effects of previous steroid

administration.

Follow up visits at Outpatient Clinic showed improvements.

ABSTRAK

Acanthosis nigricans adalah suatu lesi hiperpigmentasi di kulit seperti beludru

dan simetris. Dapat terjadi pada beberapa lokasi tetapi yang tersering adalah

di daerah ketiak, selangkangan dan tengkuk. Angka kejadian acanthosis

nigricans belum diketahui secara pasti.

MA, seorang anak laki-laki berumur 10 tahun 4 bulan dirujuk ke unit rawat

jalan endokrin anak dengan keluhan kulit kehitaman pada daerah muka,ketiak

dan leher bagian belakang setelah mendapatkan pengobatan glukokortikoid

selama 2 tahun.

Berdasarkan riwayat sakit, pemeriksaan fisik, laboratorium dan histopatologi

ditegakkan diagnosa Acanthosis nigricans, dermatitis atopi, obesitas dan

perawakan pendek.

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Terapi glukortikoid dihentikan, terapi chlortrimeton (CTM) diteruskan dengan

nasehat menghindari penyebab alergi dan dipantau kemungkinan efek

samping dari pemberian glukokortikoid terdahulu.

Pemantauan lebih lanjut menunjukkan perbaikan pada kasus ini.

INTRODUCTION

Acanthosis nigricans was first documented in 1889, and by 1909 this

dermatosis was suspected to be associated with internal malignancy. In 1976,

Kahn et al published their landmark study that described the association

between acanthosis nigricans and insulin resistance. Acanthosis nigricans is

characterized by symmetrical, hyperpigmented, velvety plaques that may

occur in almost any location but most commonly appear on the intertriginousareas of the axilla, groin, and posterior neck. The posterior neck is the most

commonly affected site in children. 1-5

In the United States, the exact incidence of acanthosis nigricans is

unknown. In an unselected population of 1,412 children, the changes of

acanthosis nigricans were present in 7.1%. Obesity is closely associated with

acanthosis nigricans. The malignant form of acanthosis nigricans is far less

common and no racial propensity noted. Acanthosis nigricans is much morecommon in people with darker skin pigmentation with highest prevalence in

African Americans (13.3%) when compared to Caucasians (

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CASE REPORT

MA, a 10-year-4-month-old boy was referred from Dermatology and

Venereal Disease Department to Pediatric Endocrinology Outpatient Clinic of

Dr. Soetomo Hospital with the main complaint of hyper-pigmented skin on the

face, axillaries and posterior neck areas.

The history of the disease was initiated with recurrent itch for three

months with suspicion of food allergy (chicken). His parents sent him to the

general practitioner and then diagnosed with allergic condition. He was

treated with green pill (possibly prednisone) and amoxicillin tablet three times

daily for a week. His condition was getting better but still relapsed every

month. He routinely took the same medication advised by general practitioner

for recurrent condition.

His parents then brought him to another general practitioner. The

general practitioner gave him amoxicillin capsule and dexamethasone tablet.

After six months of routine medication, the skin showed hyper-pigmentation

on the face and then followed with axillaries and posterior neck areas. This

condition was followed by fatigue, weight gain (about 10 kg in a year) and

increasing appetite ever since he took green pill. No complaints of headache,

shortness of breath, blurred vision or abdominal pain reported.

After 2 years of treatment, his parents stopped dexamethasone by

themselves and looked for second opinions to Outpatient Clinic of

Dermatology and Venereal Disease Department of Dr. Soetomo Hospital.

This patient was admitted in the Dermatology and Venereal ward by indication

of further diagnostic examinations for 3 days.

Laboratory examination of complete blood count showed normal result

Serum sodium level, potassium level and chloride level were within normal

limit. Liver function tests were within normal limit. Renal function tests were

within normal limit. Urinalysis showed normal result.

Based on history, physical, and laboratory examination, the diagnosis

of Atopy dermatitis with suspicion of Cushing syndrome was established by

the Dermatology and Venereal Disease Department. The patient was treated

with chlortrimeton (CTM), hydrocortisone 1% ointment followed by keratolytic

ointment, allergen avoidance and then referred to Pediatric EndocrinologyOutpatient Clinic for further examinations including the signs of adrenal crisis.

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Work up in Pediatric Endocrinology Outpatient Clinic that revealed

normal history of birth. His father had an allergy of urticaria with cold exposure

and his mother suffered from diabetes mellitus.

Anthropometry examination revealed an alert boy, body weight 34 kg

and body height 118.5 cm ( P < 3rd

). Body mass index ( BMI ) was 24.5 ( P >95th , classified as obese). His waist circumference was 115 cm and his hip

circumference was 95 cm. His waist to hip ratio was 1.2 which was

appropriate for central obesity. His fathers height was 140 cm, his mothers

height was 155 cm. Midparental height was 154 cm, and the target height was

154 8.5 cm.

Physical examination showed normal vital signs. Symmetric hyper-

pigmented and velvet plaques were found on intertriginous areas of cheek,axillaries, feet and neck posterior areas. Moon face and facial plethora was

found without any purple striae, supraclavicular fat pads, or buffalo hump.

Heart and lung examinations were within normal limit. The abdomen was flat,

no enlargement of the liver and spleen was found. His extremities were warm

without any edema. The external genitalia were normal. Proximal muscle

weakness, hirsutism or easy bruising was not found.

We planned the examinations of oral glucose tolerance test, basal and

night cortisol levels, C-peptide, thyroid function tests, bone age, adrenal

ultrasound, and skin biopsy as supportive measures to establish the exact

diagnosis.

Laboratory examination revealed fasting glucose level of 85 mg/dl ( 70-

110 mg/dL ), oral fasting glucose tolerance test level of 94 mg/dl ( 70-110

mg/dL ). Oral postprandial glucose tolerance level was 81 mg/dL (

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orthokeratosis basket weave in stratum corneum, irregular acanthosis

epidermis with fingerlike projection and benign basal cells. Pigmented cells

and normal pilosebaceous unit were found in the dermis. The result was

appropriate for acanthosis nigricans.

Based on history, physical, laboratory and histopathologyexaminations, the diagnosis of Acanthosis nigricans with Atopy dermatitis,

Obese and Short Stature was established. No signs of adrenal crisis were

found.

The treatments of hydrocortisone 1% ointment was stopped,

chlortrimeton ( CTM ), and allergen avoidance were continued with

observation on side effects of the past steroid administration.

Follow up visits at Outpatient Clinic showed improvements withdecreasing skin hyperpigmentation and reduced body weight ( 4 kg reduction

in 4 months ).

Acanthosis nigricans

Figure 1: Clinical photograph of Acanthosis nigricans showinghyperpigmented skin (at admission)

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Figure 2: Clinical photograph showing central obesity in a child

Figure 3: BMI > P 95th

, and Height for age < P 3rd

.

DISCUSSION

The patient came with the main complaint of hyperpigmented skin on

the face, axillaries and posterior neck areas. The history of glucocorticoid

treatment for 2 years prior to admission and physical examination and

supported by histopathology examination concluded the diagnosis of

Acanthosis nigricans induced by long-term glucocorticoid treatment.

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Waist to Hip Ratio(WHR)

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Acanthosis nigricans is characterized by symmetrical, hyperpigmented,

velvety plaques that may occur in almost any location but most commonly

appear on the intertriginous areas of the axilla, groin, and posterior neck. The

posterior neck is the most commonly affected site in children. 1-8

In our case, the clinical manifestation of symmetrical, hyperpigmented,velvety plaques appeared on the intertriginous areas of the axilla, groins, and

posterior neck was in accordance to the features of acanthosis nigricans.

Moon facies, facial plethora and obese were found in this patient which were

appropriate with side effect of long-term glucocorticoid treatment. Weight gain

was also found, but no hypertension and impaired immune function were

noted in the patient.

The differential diagnosis of skin hyperpigmentation includes Addisondisease. Addison disease most commonly results from nonspecific

autoimmune destruction of adrenal gland that leads to adrenal insufficiency.

The clinical manifestations of Addison disease include prominent

hyperpigmentation in areas of the skin that are subject to increased pressure,

such as over the knuckles or skin creases and buccal mucosa; weakness and

weight loss, nausea, vomiting and diffuse abdominal pain and mood

disturbances.15-19

In this case, skin hyperpigmentation occurred in intertriginous areas of

posterior neck, axilla and groin accompanied by velvety plaques that were not

commonly found in patients with Addison disease. No hyperpigmentation in

the knuckles or buccal mucosa and other symptoms of Addison disease found

which excluded the possibility of Addison disease in this patient.

Skin biopsy from hand by the Dermatology and Venereal Disease

Department was done with histopathology examination revealed slight

hyperkeratosis, orthokeratosis basket weave in stratum corneum, irregular

acanthosis epidermis with fingerlike projection and benign basal cells.

Pigmented cells and normal pilosebaceous unit were found in the dermis. The

result was appropriate with acanthosis nigricans.

Acanthosis nigricans most likely is caused by factors that stimulate

epidermal keratinocyte and dermal fibroblast proliferation. In the benign form

of acanthosis nigricans, the factor is probably insulin or an insulinlike growth

factor that incites the epidermal cell propagation. In malignant acanthosis

nigricans, the stimulating factor is hypothesized to be a substance secreted

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either by the tumor or in response to the tumor. Transforming growth factor

is structurally similar to epidermal growth factor and is a likely candidate.

Exogenous medications also have been implicated as etiologic factors.1-5

The definitive cause for acanthosis nigricans has not yet been

ascertained, although several possibilities have been suggested. Eight types

of acanthosis nigricans have been described. 1-8

Obesity-associated acanthosis nigricans.

Drug-induced acanthosis nigricans.

Syndromic acanthosis nigricans.

Acral acanthosis nigricans (acral acanthotic anomaly).

Unilateral acanthosis nigricans.

Familial acanthosis nigricans. Malignant acanthosis nigricans.

Mixed-type acanthosis nigricans.

Laboratory examinations for patients with adult onset of acanthosis

nigricans need a basic workup for underlying malignancy. Screen for diabetes

with a glycosylated hemoglobin level or glucose tolerance test. Screen for

insulin resistance will show high values in those with insulin resistance as the

most sensitive test to detect a metabolic abnormality of this kind because

many younger patients do not yet have overt diabetes mellitus and an

abnormal glycosylated hemoglobin level, but they do have a high plasma

insulin level.5-14

In our case, the acanthosis nigricans was classified as drug-induced

acanthosis nigricans due to long-term glucocorticoid treatment. It was based

on history of long-term glucocorticoid treatment and supported by histology

examination from skin biopsy that was appropriate for acanthosis nigricans

and laboratory examination that revealed no hyperinsulinemia condition

(normal fasting and postprandial blood glucose levels, normal oral glucose

tolerance test without increased level of serum C-peptide) as the sign for

insulin resistance that acts as the most common etiology of acanthosis

nigricans. Diabetes screening by fasting and postprandial blood glucose

levels and glucose tolerance test showed normal results that made the

possibility of diabetes in this patient highly unlikely, although glycosilated

hemoglobin and plasma insulin level examinations were not done yet due to

financial problem.

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Physical examination of a child treated with long-term high-dose

glucocorticoids should look for treatment-associated complications;

examination should aim to identify specific features that may indicate the

complications, such as: 20-23

Obesity: obesity is almost always present. Abnormality of pubertal development.

Increasing of blood pressure.

Abdominal examination: Obesity makes abdominal examination

difficult. Hepatomegaly may occur in patients with insulin resistance

who has fatty liver infiltration.

Abnormality of musculoskeletal system.

Skin examination: particularly in long-term use of potent topicalglucocorticoids shows telangiectasia, facial fullness and plethora,

fungal infections in skin folds, and thinning of skin. Signs of insulin

resistance can include acanthosis nigricans and skin tags.

Infections: high glucocorticoid levels increase the risk of bacterial and

fungal infections.

In our case, the manifestations of complication caused by long-term

glucocorticoid treatment by a general practitioner due to recurrent pruritus

were found. The patient developed moon facies, facial plethora, acanthosis

nigricans and central obesity. No pubertal developmental abnormality,

musculoskeletal abnormality, infection or elevated blood pressure was found

in the patient.

Short stature and delayed bone age study for his age (delayed for 88

months) in the patient were not caused by long-term steroid treatment. The

epiphyseal lines in this patient were not closed yet so that no early closure of

epiphyseal lines was found as the common manifestation of steroid-induced

short stature. Further examination were done to explore the possibility of other

underlying diseases, such as hypothyroid or growth hormone deficiency.

Normal thyroid function tests excluded the possibility of hypothyroid.

Unfortunately, growth hormone level could not be examined due to financial

problem.

Exogenous steroids suppress the hypothalamic-pituitary-adrenal axis,

with full recovery taking up to 1 year after cessation of glucocorticoid

administration. More than 90-95% of patients have their hypothalamic-

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pituitary-adrenal axis recovered by 12 months after stopping treatment, with

more than 50% of the remainder recovering in the following 6-12 months.

Thus, patients who are taking or who have taken steroids are at risk for

developing an adrenal insufficiency and potentially make adrenal crisis.10-14

Permanent adrenal insufficiency has been described, although it is rare. Earlyrecognition and prompt treatment of the early signs of adrenal insufficiency is

essential because this may be life threatening if not managed appropriately. 14,

20-23

In this case, no signs of adrenal crisis were found. Basal cortisol level

was decreased because of the hypothalamic-pituitary-adrenal axis

suppression and disturbance of diurnal cycle. In the normal condition, the

diurnal or circadian cycle of cortisol shows the highest level in basal state ( inthe morning ). The diurnal cycle in this patient was abnormal and suppressed

of hypotalamic-pituitary-adrenal axis was caused by long-term glucocorticoid

treatment. These conditions can be proven by examination of Synacthen test

or adrenocorticotrophin hormon level. Unfortunately had not been done yet

caused by technical and financial problem. The patient had stable vital signs

without any other complaints of adrenal crisis. However, further observation

has been done in order to monitor the early signs of adrenal crisis to be

managed appropriately.

The goal therapy of acanthosis nigricans is to correct the underlying

disease process. Treatment of the lesions of acanthosis nigricans is for

cosmetic reasons only. No treatment of choice exists for acanthosis nigricans.

Topical medications that have been effective in some cases include

keratolytics ( e.g. topical tretinoin ). Oral agents that have shown some benefit

include etretinate and dietary fish oils.1

Actually in this case, the main treatment is to reduce glucocorticoid

medication that should be done gradually to avoid adrenal crisis associated

with decreasing cortisol level abruptly. Antihistamine was given for the allergy

condition and topical steroid medication for inflammatory condition was

stopped with intensive observation for the side effect that might arise. The

patient has been improving up to now with decreasing hyper-pigmentation

and reducing body weight.

In this case, the prognosis is good. The lesions have been regressing

showed by decreasing hyper-pigmentation. No psychological effects of the

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skin hyper-pigmentation were found in this patient. No other side effects have

been found up to now. Decreasing of body weight and fatigue are also

considered as positive signs in the course of disease.

SUMMARY

A case of acanthosis nigricans in a child associated with long-term

glucocorticoid treatment was reported.

A 10-year-4-month-old boy came with main complaint of

hyperpigmented skin in the intertriginous areas after 2 years of corticosteroid

treatment due to his allergy condition of recurrent itch. He also suffered from

moon facies, facial plethora, growth failure and central obesity as

complications of steroid administration. Physical examination which was

supported by laboratory, radiology and histopathology examinations

concluded the diagnosis of acanthosis nigricans associated with long-term

glucocorticoid treatment.

Cessation of steroid accompanied by antihistamine, were given in this

case. Further intensive observation is still needed to monitor early signs of

adrenal crisis that could be life-threatening.

Safe and effective use of corticosteroid requires clinical judgment,knowledge of their physiological and pharmacological properties and should

be monitored carefully because of its side effects.22

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