Acanthosis Nigricans, Congenital Adrenal Hyperplasia
MAKALE #1667 © Yazan Prof.Dr.Mehmet Emre ATABEK | Yayın Ekim 2008 | 3,508 Okuyucu
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The Turkish Journal of Pediatrics 2005; 47: 183-187 Case
Acanthosis nigricans in association with congenital adrenal
hyperplasia: resolution after treatment
Case report
Selim Kurtoðlu
1, M. Emre Atabek1, Mehmet Keskin1, Özlem Canöz2
Departments of
1Pediatric Endocrinology and 2Pathology, Erciyes University Faculty of Medicine, Kayseri, Turkey
SUMMARY: Kurtoðlu S, Atabek ME, Keskin M, Canöz Ö. Acanthosis nigricans
in association with congenital adrenal hyperplasia: resolution after treatment.
Turk J Pediatr 2005; 47: 183-187.
A case is described of a three-day-old female with salt wasting type of
21-hydroxylase deficient congenital adrenal hyperplasia who presented with
acanthosis nigricans of both axillae. Following corticosteroid and
mineralocorticoid therapy for disease, the acanthosis nigricans resolved. It is
believed that this is the first reported case of acanthosis nigricans occurring
in association with congenital adrenal hyperplasia, a phenomenon that resolved
after treatment. We speculate that the acanthosis nigricans resulted from
hyperandrogenemia or other unknown factors in our patient.
Key words: acanthosis nigricans, congenital adrenal hyperplasia, newborn.
Acanthosis nigricans (AN) is characterized by
hyperpigmented, velvety, hyperkeratotic plaques
that are most often localized to the neck, axillae,
inframmary areas, groin, inner thighs, and
anogenital region. The histologic changes are
those of papillomatosis and hyperkeratosis
rather than acanthosis or excessive pigment
formation. AN has classically been associated
with obesity; drugs such as nicotinic acid;
endocrinopathies, including diabetes mellitus,
Addison disease, Cushing’s syndrome,
acromegaly, hypo- and hyperthyroidism, Stein-
Leventhal syndrome, and hyperandrogenic or
hypogonadal syndromes; and many other
genetic syndromes such as Bloom’s Crouzon’s
or Rud’s syndromes. Occasionally, it may be
familial with autosomal dominant inheritance.
AN was present in 71% of the 1,412 children
in an unselected population. It is rarely found
in the neonatal period, but has been reported
in this period in association with some
syndromes such as Beare-Stevenson syndrome,
congenital lipodystrophies, bone dysplasia and
Leprechaunism
1-4. However, AN has not been
reported in patients with congenital adrenal
hyperplasia (CAH).
A case of AN associated with salt wasting type
of 21-hydroxylase (21-OH) deficienct CAH is
presented. To our knowledge this is the first
such association reported in the literature.
Case Report
This case was referred to the Endocrinology
Service at three days of age because of
ambiguous genitalia. The child’s weight at birth
was 3300 g and length was 51 cm after an
uneventful pregnancy followed by a spontaneous
vaginal delivery at term. It was the sixth
pregnancy of a 24-year-old healthy mother. There
was first-degree consanguinity between mother
and father. There was no history of disease and
no use of drugs before or during pregnancy. The
fifth child is a healthy three-year-old boy.
However, the first four boy infants died at birth,
two months of age, four months of age and one
month of age, respectively; no diagnosis had been
made in any of the cases. In our patient, physical
examination showed ambiguous genitalia. The
genital tubercle measured 2x1 cm, the urethral
opening was at the perineum, and two gonads
were not palpable within a bifid scrotal structure
(Fig. 1). The genitalia, areola and axilla were
markedly hypergimented, and there were
hyperkeratotic plaques. In particular, the axillary
skin had a velvet texture and a grayish-brown
pigmentation with marked grayish-red
papillomatous vegetations (Fig. 2a). Bone age
was 38 weeks by knee X-ray. The infant’s blood
pressure was 60/45 mmHg. Blood was drawn
for electrolytes, androgen levels, and karyotype.
Serum sodium concentration was decreased
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(109 mEq/L) and serum potassium concentration
was elevated at 8.7 mEq/L. Metabolic acidosis
(serum bicarbonate concentration was 8.5 mmol/
L) was also present. The therapy for salt wasting
was started. Serum concentrarions of adrenal
steroids and their precursors before the first dose
of hydrocortisone were abnormal. 17-
hydroxyprogesterone (17 OHP) was 150 ng/ml
(normal: 0.4-2 ng/ml), 11-deoxycortisol was
11.56 ng/ml (normal: 0.1-1.5 ng/ml),
dehydroepiandrosterone sulfate (DHEA-S) was
2938 ng/ml (normal: 50-110 ng/ml), androstenedione
was 34.76 ng/ml (normal: 0.06-
0.68 ng/ml), total testosterone was 1859 ng/dl
(normal: 75-400 ng/dl), free testosterone was
74.68 pg/ml (normal: 1.5-31 pg/ml),
adrenocorticotropic hormone (ACTH) was
114 pg/ml (normal: 0-60 pg/ml), and cortisol was
6.52
μg/dl (normal: 2.8-23 μg/dl). Ureterogram
showed a normal uterus. Echocardiographic study
showed patent foramen ovale with a diameter of
3 mm. Ultrasonography revealed bilateral adrenal
hyperplasia. The karyotype was 46,XX. The
Fig. 1.
Patient showing ambiguous genitalia.
Fig. 2.
a) Acanthosis nigricans involving the axilla region prior to treatment.
b) Six months after treatment, the acanthosis nigricans is markedly diminished.
patient had presented with a combination of
aldosterone and cortisol deficiency and androgen
excess. Thus, she was diagnosed as salt wasting
type of 21-OH-deficient CAH. CAH due to 21-OH
deficiency was diagnosed according to published
criteria
5. Diagnosis was based on elevation of 17-
OHP, supported by clinical presentation and serum
electrolyte abnormalities, and by genital ambiguity.
After the acute manifestations were under control,
the patient required chronic replacement therapy
for her aldosterone and cortisol deficiencies.
Glucocorticoid (hydrocortisone: 20 mg/m
2) and
mineralocorticoid (Florinef 0.1 mg daily) were
given perorally. The androgens and 17-OHP were
suppressed after one-month of treatment. Because
the skin changes were unusual, AN was suspected.
A diagnosis of AN was made after skin biopsy
(Fig. 3). Fasting insulin, leptin, and glucose were
measured. The glucose/insulin ratio calculated as
a measure of insulin resistance was 6.2
(normal value,
≥6) and leptin level was normal.
Following treatment for CAH, the skin
pigmentation and AN resolved (Fig. 2b).
(a) (b)
184
Kurtoðlu S, et al The Turkish Journal of Pediatrics • April - June 2005
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Fig. 3.
Histopathologic changes consistent with acanthosis nigricans: the epithelium shows papillomatosis,
hyperkeratosis, acanthosis and keratin plaques. There is an orthohyperkeratotic stratum corneum overlying a
mammillated hyperplastic epidermis. There is no significant inflammatory infiltrate.
Discussion
Congenital adrenal hyperplasia due to 21-OH
deficiency is an autosomal recessive condition in
which deletions or mutations of the cytochrome
P450 21-hydroxylase gene result in glucocorticoid
and/or mineralocorticoid deficiency or excess,
respectively. This leads to increased secretion of
ACTH, adrenal hyperplasia, and increased
production of androgens and steroid precursors
before the enzymatic defect. Current treatment
is to provide adequate glucocorticoid and, when
necessary, mineralocorticoid substitution to
prevent adrenal crises and to suppress the
abnormal secretion of androgens and steroid
precursors from the adrenal cortex
6-8. In our
patient with ambiguous genitalia, clinical and
endocrinologic evaluation at presentation revealed
that she had the salt-wasting type of classic 21-
OH deficiency. The patient with CAH presented
with a darkening of the skin of the axilla and
areola and of the oral and genital mucosa. Her
axillary skin was especially marked in particular
was by a grayish-brown pigmentation. Because it
was characterized by the appearance of
papillomatosis with hyperpigmented and
hyperkeratotic plaques with a velvet texture and
a grayish-brown coloration, AN was suspected in
the patient with CAH. The underlying usual
diseases could not be determined at the initial
screening, and diagnosis was confirmed with
biopsy. Acanthosis nigricans appears to be a
dermatological manifestation of the severe
hyperinsullinemia and hyperandogenism
9.
Although the factors that induce acanthosis
nigricans development have not been fully
elucidated, insulin, insulin-like growth factor
(IGF)-I, epidermal growth factor, and testosterone
have been implicated. Thus, Cruz and Hud
10
recently categorized AN into two types: (1) AN
associated with increased insulin binding to IGF
receptors, and (2) AN due to other causes. It can
be speculated that elevated androgens and/or
perhaps their precursors might contribute to the
development of AN in the patient.
Increased pigmentation of the skin should
always alert the clinician to the possibility of
adrenocortical insufficiency. This manifestation
occurs in those conditions in which there are
a deficiency of cortisol and excessive secretion
of corticotropin, as in primary adrenal
hypoplasia, familial glucocorticoid deficiency,
adrenoleukodystrophy, and Addison disease.
When adrenal disease is severe, as in CAH due
to cortisol synthetic enzyme defects, adrenal
hemorrhage, or congenital absence of the
adrenals, disturbances in serum electrolytes
with hyponatremia and hyperkalemia or
ambiguous genitalia may provide diagnostic
clues. Hyperpigmentation may also provide the
clue to CAH with increased ACTH levels.
Pigmentation may be first apparent on the face
and hands and is most intense around the
genitalia, umbilicus, axillae, nipples, and joints.
Scars and freckles may be especially
pigmented
11,12. The interesting points of our
case were presentation with AN and response
to treatment. Significant improvement in skin
of the axilla was noted after corticosteroid and
mineralocorticoid therapy. This further enforces
the correlation between the adrenal hyperplasia
process and the skin changes in the patient.
This finding is consistent with knowledge in
Volume 47 • Number 2 Acanthosis Nigricans in Congenital Adrenal Hyperplasia
185
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the literature where skin changes regressed or
disappeared following treatment of hyperandrogenemia,
as was observed in HAIR-AN syndrome
and polycystic ovary syndrome
13,14. However, the
presence of AN in these conditions is a significant
clue that indicated insulin resistance. Therefore,
elevated androgen levels may have contributed to
the development of acanthosis in our patient. The
mechanism of this correlation and indeed the
mechanism of CAH-induced AN are not clear. We
suggest that AN is probably caused by excess of
adrenal androgens that may stimulate
keratinocytes and dermal fibroblasts at the cell
receptor level.
Previous researchers have reported that
hyperandrogenism caused by an inborn error of
adrenal steroidogenesis could produce insulin
resistance in females with 21-hydroxylase
deficiency
15. Furthermore, a recent study report
that children with classic CAH have significantly
higher serum leptin and insulin concentrations
and increased insulin resistance index, compared
with their healthy counterparts
16. The skin
lesions appear to be a manifestation of insulin
resistance. The clinical severity and
histopathologic features of AN correlate
positively with the degree of hyperinsulinism. It
has been hypothesized that insulin resistance,
with compensatory hyperinsulinism, leads to
insulin binding to and activation of IGF
receptors, promoting epidermal growth
17-21. An
association between AN and CAH could be
coincidental, although the fact that
hyperandrogenism regressed together with AN
after the CAH treatment would suggest some
relationship between these diseases. After the
treatment, endocrinological abnormalities and
cutaneous manifestations of AN markedly
improved in the patient. Perhaps in the
intrauterine period, both elevated leptin and
insulin concentrations played a role in the
development of AN. We could not document
insulin resistance and increased leptin at the
time of diagnosis, but in an effort to identify the
pathogenetic mechanisms of AN in these
patients, insulin resistance might be documented
in the prenatal period. In addition, we speculate
that small amounts of tissue insulin (despite
normoinsulinemia) may transducer proliferative
effects in skin cells, leading to AN.
In conclusion, while the underlying pathophysiologic
mechanism remains unknown, AN can
be associated with CAH as identified in our
patient. To our knowledge, there is no report in
the literature of AN associated with CAH.
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