ACANTHOSIS NIGRICANS ASSOCIATED WITH LONG-TERM
GLUCOCORTICOID TREATMENT
Akira Prayudijanto, Alpha Fardah, Muhammad Faizi, Netty EP
Endocrinology Division
Department 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”.
1
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 intertriginous
areas 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 more
common in people with darker skin pigmentation with highest prevalence in
African Americans (13.3%) when compared to Caucasians (<1%) and
Hispanics (5.5%). The incidence of acanthosis nigricans is equal for men and
women. 5-14
The definitive cause for acanthosis nigricans has not yet been
ascertained. One kind of types is drug-induced acanthosis nigricans, although
uncommon, may be induced by several medications, including nicotinic acid,
insulin, pituitary extract, systemic corticosteroids, and diethylstilbestrol. The
lesions of acanthosis nigricans may regress following the discontinuation of
the offending medication.9-11
The purpose of this paper is to report a case of Acanthosis nigricans in
a child associated with long-term glucocorticoid treatment.
2
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 Endocrinology
Outpatient Clinic for further examinations including the signs of adrenal crisis.
3
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 father’s height was 140 cm, his mother’s
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 hyperpigmented 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 ( 70110 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 ( <140
mg/dL ). C-peptide was 0.83 ng/dL ( 1.1-5 ng/dL ). Basal cortisol level was < 1
µg/dL ( 5-25 µg/dL ). Sodium level was 142 mEql/L ( 132-145 mEql/L ).
Potassium level was 3.2 mEql/L ( 3.1-5.1 mEql/L ). Thyroid function tests
showed normal results with serum free T4 of 1 ng/dL ( 0.65-6.3 ng/dL ) and
serum TSHs of 2.33 g/mL ( 0.36-5.4 g/mL ).
Bone age examination according to Pyle index was appropriate for 36month-old ( delayed bone age for 88 months ). Abdominal and adrenal
ultrasound revealed normal results.
Skin biopsy from hand by the Dermatology and Venereal Department
and
the
histopathology
examination
revealed
slight
hyperkeratosis,
4
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
histopathology
examinations, 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 with
decreasing skin hyperpigmentation and reduced body weight ( 4 kg reduction
in 4 months ).
Acanthosis nigricans
Figure 1: Clinical photograph of Acanthosis nigricans showing
hyperpigmented skin (at admission)
5
Waist to Hip Ratio
(WHR)
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”.
6
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 Addison
disease.
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
7
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.
8
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 topical
glucocorticoids 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 hypothalamic9
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. Early
recognition 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 ( in
the 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
10
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
11
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