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Children with classical
common variants of congenital adrenal
hyperplasia (CAH) usually present with genital
ambiguity in girls and sexual precocity in boys
with or without salt losing crisis (rarer types
like 17
α-hydroxylase
and 3
β-
hydroxysteroid dehydrogenase deficiencies cause
undervirilization in the male). The consequences
of delayed diagnosis and/or undertreatment in
patients with CAH are short stature, sexual
precocity, menstrual disturbances, infertility,
adrenal myelolipoma, and not uncommonly,
testicular adrenal rest tumors.
Testicular adrenal rest
tumors (TART) are the ectopic adrenal rest cells
which show functional features of ACTH dependent
adrenocortical tissue [1]. The prevalence of
TART ranges between 0 and 94% depending upon the
modality of tumor detection [2,3]. Ectopic
adrenal rests have also been described in
spermatic cords, ovaries and rarely even in
celiac plexus, spinal cords and liver in normal
individuals [4]. We report a case of CAH with
TART who presented with bilateral macroorchidism
and responded well to treatment with
dexamethasone.
Case Report
A 14-year-old boy, product of
non-consanguineous marriage presented with short
stature, bilaterally enlarged testes and
acneiform lesions over the trunk. The parents
noticed enlargement of testes at the age of 3
years along with appearance of facial and body
hair. He also experienced rapid height gain in
early childhood. He had no history of
hypoglycemic episodes, dehydration, failure to
thrive, jaundice or seizures in neonatal period.
Developmental milestones were normal. He had no
complaints of headache, gelastic episodes,visual
abnormalities, constipation, delayed eruption of
teeth or abdominal pain. No history of sibling
death was present.
On examination, his weight
was 41 kg, height 144 cm, upper to lower segment
ratio of 1.18:1 (78cm:66cm), target height of
172 cm, predicted adult height of 159 cm, height
age of 11.1 years and bone age of 16 years (Greulich
and Pyle’s charts). His blood pressure was
166/120 mm Hg in supine position (>99
percentile). Tanner’s sexual maturity rating was
genitalia stage V, pubic hair stage V, axillary
hair were present. Both testes measured greater
than 25 mL and stretched penile length was 9 cm.
He had no gynecomastia. No facial dysmorphism or
any skeletal defects were apparent. Rest of the
systemic examination was normal.
On investigations, hemoglobin
was 9.8 g/dL, total leukocyte count 6600/mm3
with normal differential and platelet counts.
Biochemistry revealed serum sodium 144 mEq/L,
potassium 3.1 mEq/L, creatinine 1.22 mg/dL and
urea 53.1 mg/dL. Arterial blood pH was 7.36 and
HCO3,
20.9 mmol/L. The hormonal work-up showed serum
LH <0.1 mIU/L (1.7-8.6), FSH 0.3 mIU/L
(1.5-12.4), testosterone 17.4 nmol/L (9.9-27.8),
estradiol 26.8pg/mL (7.6-42.6), ACTH 244.2 pg/mL
(5-60), cortisol 223.2nmol/L (171-536),
prolactin 17.4ng/mL (4-19), T3
0.8 ng/mL (0.8-2.0), T4
5.2 µg/dL (4.8-12.7), free T4
1.3ng/dL (0.7-1.7 ng/dL) and TSH 3.0 mIU/mL
(0.3-4.2 mIU/mL). Basal 17 OH-progesterone was
20.5 ng/mL and 60 minutes after 250 µg
cosyntropin, it did not increase further (21.6
ng/mL).
Ultrasonography of the testes
revealed diffusely enlarged bilateral testes,
[right testes measured 4.2× 7.9×4.5 cms (volume
105 cc) and left 5.1× 2.8× 7.9 cms (volume 80
cc)], heteroechoic with thickened epididymis.
MRI testes confirmed these observations. CT Scan
showed normal right adrenal but bulky medial
limb of left adrenal, and normal kidneys. MRI
sella was normal.
Testicular biopsy showed
diffuse sheets and lobules of large, polygonal
cells with abundant eosinophilic cytoplasm. The
cells had ill defined borders separated by thick
fibrous septa and and focally some cells
contained brown lipofuschin pigment. Normal
sertoli cells and Leydig cells were also seen.
However, no germ cells, seminiferous tubules or
Reinke crystals could be appreciated. There was
no evidence of any infiltrative disorder. Based
on these features a diagnosis of TART was
considered.
The patient was advised oral
potassium supplementation, dexamethasone 0.5 mg
twice a day and ramipril 5 mg daily.
Discussion
We describe a patient of CAH
with testicular adrenal rest tumor based on
isosexual precocious puberty, short stature,
hypertension, hypokalemia, bilateral
orchidomegaly and elevated 17 OH-progesterone.
The possibility of 11
β-hydroxylase
deficiency is most likely as patient had
hypertension, hypokalemia without any genital
ambiguity. The increase in 17OH-progesterone in
patients with 11 β-
hydroxylase deficiency is modest as this enzyme
converts 11-deoxy cortisol to cortisol, while
17OH-progesterone is upstream in the steroid
biosynthetic pathway.
TART have not been
demonstrated in non classical 21α-hydroxylase
or 11 β-hydroxylase
deficient variant of CAH [6]. This can be
possibly be explained because of milder enzyme
deficiency in the non classical CAH while in 11
β-hydroxylase
deficiency, 11 deoxy cortisol has cortisol like
activity, thereby some degree of hypothalamo-pituitary-adrenal
axis feedback is maintained resulting in modest
rise in ACTH. The possible reason for having
TART in the present case may be due to
longstanding, untreated CAH. There are
conflicting reports of functioning status of
these tumors as some authors have described a
steroid gradient between gonadal vein and
peripheral vein sampling, while others could not
demonstrate such findings [1-6].
Consequences of TART include
discomfort due to massive orchidomegaly and
infertility. Infertility is attributed to
compression of the surrounding seminiferous
tubules by the tumor tissue [6], ongoing
ischemia and fibrosis and suppression of
gonadotropins due to weaker adrenal androgens,
consequently resulting in atrophy of the tubules
[7,8]. The present case had absence of germ
cells on testicular biopsy and azoospermia on
semen analysis, suggesting irreversible damage
to seminiferous tubules.
Glucocorticoid treatment in
patients of CAH with TART results in regression
of testicular size and restoration of fertility
[9]. In the present case, steroid therapy led to
decrease in the testicular size after a follow
up visit at 6 months; however, spermatogenesis
was not restored because of fibrotic changes in
testes.
References
1. Claahsen-van der Grinten
HL, Otten BJ, Sweep FC, Span PN, Ross HA,
Meuleman EJ, et al. Testicular tumours in
patients with congenital adrenal hyperplasia due
to 2l-hydroxylase deficiency show functional
features of adrenocortical tissue. J Clin
Endocrinol Metab. 2007; 92: 3674-80.
2. Avila NA, Premkumar A,
Merke DP. Testicular adrenal rest tissue in
congenital adrenal hyperplasia: comparison of MR
imaging and sonographic findings. Am J
Roentgenol. 1999;172:1003-6.
3. Claahsen-van der Grinten
HL, Sweep FCGJ, Blickman JG, Hermus A RMM, Otten
BJ. Prevalence of testicular adrenal rest tumors
in male children with congenital adrenal
hyperplasia due to 21-hydroxylase deficiency.
Eur J Endocrinol. 2007;157:339-44.
4. Souverijns G, Peene P,
Keuleers H, Vanbockrijck M. Ectopic localization
of adrenal cortex. Eur Radiol. 2000;10:1165-8.
5. Reisch N, Scherr M, Flade
L, Bidlingmaier M, Schwarz HP, Müller-Lisse U,
et al. Total adrenal volume but not
testicular adrenal volume is associated with
normal control in patients with 21-hydroxylase
deficiency. J Clin Endocrinol Metabol.
2010;95:2065-72.
6. Claahsen-van der Grinten
HL, Otten BJ, Stickelbroeck MML, Sweep FCGJ,
Hermus ARMM. Testicular adrenal rest tumours in
congenital adrenal hyperplasia. Best Pract Res
Clin Endocrinol Metabol. 2009;23: 209-20.
7. Claahsen-van der Grinten
HL, Otten BJ, Hermus AR, Sweep FC, Hulsbergen-van
de Kaa CA. Testicular adrenal rest tumours in
patients with congenital adrenal hyperplasia can
cause severe testicular damage. Fertil Steril.
2008;89:597-601.
8. Bercovici JP, Fiet J,
Gibault L,Volant A, Abalain JH, Floch HH, et
al. Testicular adrenal rest tumours in salt
wasting congenital adrenal hyperplasia (in vivo
and in vitro studies). J Steroid Biochem Mol
Biols. 2005;93:67-72.
9. White CP, Carter JN.
Adrenal and testicular tumors and azoospermia in
congenital adrenal hyperplasia. Aust New Zeal J
Med. 1993;29:410.
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