Two adults with adrenal myelolipoma and 21-hydroxylase deficiency.

Abstract

We present incidentally discovered adrenal myelolipomas in two adult males with untreated congenital adrenal hyperplasia (CAH). The patients had simple virilizing form of CAH due to mutations in the CYP21 gene coding for 21-hydroxylase; one was heterozygous for the I172N mutation and the other compound heterozygous for the I172N and I2splice mutations. The masses were not removed since myelolipomas are considered benign tumors, and the tumor size did not increase during four- and nine-year observation periods. An adrenal myelolipoma is an important exception to the rule that large tumours should be removed. Untreated CAH with prolonged excessive ACTH stimulation might contribute to the growth of adrenal masses. CAH should be considered as a differential diagnosis of patients with adrenal masses or adrenal myelolipomas.

Full text

Page 1

Hindawi Publishing Corporation
Case Reports in Medicine
Volume 2009, Article ID 916891, 4 pages
doi:10.1155/2009/916891
Case Report
TwoAdults withAdrenalMyelolipomaand
21-Hydroxylase Deficiency
Ingrid Nermoen,1,2Ivar Følling,1,2Kjetil Vegge,3Arne Larmo,3Bjørn Gunnar Nedrebø,4
EysteinSverreHusebye,4,5andKristianLøv˚ as4,5
1Department of Endocrinology, Akershus University Hospital, 1478 Lørenskog, Norway
2Institute of Medicine, Faculty Division Akershus University Hospital, University of Oslo, 1478 Lørenskog, Norway
3Department of Radiology, Akershus University Hospital, 1478 Lørenskog, Norway
4Department of Medicine, Haukeland University Hospital, 5021 Bergen, Norway
5Institute of Medicine, University of Bergen, 5021 Bergen, Norway
Correspondence should be addressed to Ingrid Nermoen, ingrid.nermoen@ahus.no
Received 21 April 2009; Accepted 20 July 2009
Recommended by Paul Kaplowitz
We present incidentally discovered adrenal myelolipomas in two adult males with untreated congenital adrenal hyperplasia
(CAH). The patients had simple virilizing form of CAH due to mutations in the CYP21 gene coding for 21-hydroxylase; one was
heterozygous for the I172N mutation and the other compound heterozygous for the I172N and I2splice mutations. The masses
were not removed since myelolipomas are considered benign tumors, and the tumor size did not increase during four- and nine-
year observation periods. An adrenal myelolipoma is an important exception to the rule that large tumours should be removed.
Untreated CAH with prolonged excessive ACTH stimulation might contribute to the growth of adrenal masses. CAH should be
considered as a differential diagnosis of patients with adrenal masses or adrenal myelolipomas.
Copyright © 2009 Ingrid Nermoen et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.
1.Introduction
Adrenal incidentalomas are common; the challenge is to rule
out malignancy or excess hormone secretion [1]. Myelolipo-
mas are benign endocrine inactive tumors composed of
adrenal, adipose, and myeloid tissue, representing 1.5%–9%
of adrenal incidentalomas; the radiological characteristic is
round, sharp-demarcated lesion with negative attenuation
values because of its high fat content [2–5]. Large adrenal
massesshouldusuallyberemoved,butmyelolipomasusually
do not need resection. However, many of the reported cases
were diagnosed after adrenalectomy. Rarely, myelolipomas
have been associated with hormone excess syndromes,
such as congenital adrenal hyperplasia (CAH) [6–10]. We
here report two cases, which illustrate that large adrenal
myelolipomas need not to be surgically removed and that
CAH must be considered in patients with adrenal inciden-
talomas.
2.CaseReport 1
In 1999 a 50-year-old man presented with a right adrenal
mass 5.7 × 5.1 × 1.9cm. Medical history revealed precocius
puberty at age 4, and he was diagnosed with “Morbus Glan-
dulae Suprarenalis” when he was 9. Urinary 17-ketosteroids
were found elevated, but suppressible with dexamethasone.
He was treated with cortisone acetate 12.5mg thrice daily
from age 9, but at 18 he stopped the medication, after which
he felt that his general wellbeing is improving. After this time
he was lost to follow-up. At the age of 37 he underwent
radioiodine treatment for thyrotoxicosis. He was otherwise
healthy, working full time, and was the father of one child.
In spite of radioiodine treatment he felt he had persistent
goitre, and his general practitioner referred him to a cervical
CT, which due to his short stature included the upper
abdomen. Pronounced bilateral adrenal hyperplasia and a
5.7cm in diameter tumor described as a typical adrenal

Page 2

2Case Reports in Medicine
R
10 cm
(a)
(b)
(c)
Figure 1: Computed tomography of the adrenals in Patient 1.
(a) Arrows show a 5.7 centimetre large, expansive process in the
right adrenal with a heterogeneous stroma, fat, calcifications, and
in addition, pronounced bilateral adrenal hyperplasia. Magnetic
resonanceimagesoftheadrenaltumor,T1WeightedImaging,with
hyperintense fat (b) showing signal loss in fat suppressed image (c).
myelolipoma (capsule, heterogeneous stroma, and fat in the
adrenal mass) was found (Figure 1).
Further investigation revealed height 164cm, weight
76kg, and blood pressure 120/80mmHg. On palpation the
Table 1: Myelolipoma: baseline measurements and endocrinologi-
cal test results.
Patient 1
Patient 2 Normal
Baseline
ACTH, pmol/L6–32.8∗
10.9–94.2(2–13)
Cortisol, nmol/L 210
387 (250–750)
17 OH-progesterone,
nmol/L
DHEAS, µmol/L
>605
445(<6)
14.4
1.8 (6–12)
Androstendione, nmol/L 43.8
10.9(<5.6)
Testosterone, nmol/L
ACTH stimulation∗∗
Cortisol 30 minutes,
nmol/L
Cortisol 60 minutes,
nmol/L
17 OH-progesterone 30
minutes, nmol/L
17 OH-progesterone 60
minutes, nmol/L
Dexamethasone
suppression∗∗∗
Cortisol, nmol/L
11.7
10.1(10–40)
211
409
231
412(>550)
>605
445
>605
560(<30)
22
45(<50)
17 OH-progesterone,
nmol/L
∗Most values in the higher range.∗∗Corticotropin (250ug i.v.).∗∗∗1mg
overnight test in Patient 2 and 0.5mg × 4 for 2 days in Patient 1.
14.3
18.8
patient had no enlargement of the thyroid gland. Genital
examination showed normal penile size and subnormal tes-
ticularvolumeof12mLbilaterally.Biochemicalinvestigation
revealed low basal cortisol, which did not increase after
ACTH stimulation (Table 1). He had a high basal level of
17-OH-progesterone, typical of 21-hydroxylase deficiency,
which was suppressed after a conventional dexamethasone
test (Table 1). DNA sequencing of the CYP21 (steroid 21-
hydroxylase) gene revealed the c. 515T > A point mutation,
which results in the predicted amino acid change I172N.
The mutation was present in hemi- or homozygous form
(i.e., the genotype was I 172N/deletion or I172N/I172N).
The adrenal mass caused no symptoms and was considered
highly likely benign and therefore left untreated. The tumor
and hyperplasia did not change radiologically over a nine-
year subsequent observation period. The patient continues
to do well without steroid medication, but is instructed to
take steroids during stress.
3.CaseReport 2
A previously healthy 68-year-old man, father of one child,
presented in 1994 with fatigue and nausea. For many
years he had suffered arthralgic pain and had been treated
with antiflogistics. The last months he had experienced
problems with nocturia and impotence. He was referred

Page 3

Case Reports in Medicine3
to ultrasonography of the abdomen, on which a tumor
in the right adrenal was detected. An adrenal CT scan
showed a 4 ×4 ×2.5cm tumor in the right adrenal with
high fat content, which was radiologically considered to be
a myelolipoma. The left adrenal was evaluated as normal.
Further clinical investigation showed height 165cm,
blood pressure 140/80mmHg, and normal male genitalia
with testicular tenderness bilaterally. Biochemical investiga-
tion showed high basal level of 17-OH-progesterone, which
was suppressible with dexamethasone, and an impaired
cortisol response to ACTH stimulation (Table 1). Adrenal
iodomethyl-19-norcholesterol scintigraphy showed high
uptake in the right adrenal, which however was suppressed
by dexamethasone; uptake was normal or low in the left
adrenal. DNA sequencing of CYP21 revealed compound
heterozygozity for the I172N mutation (c. 515T > A) and the
I2 splice mutation (g.655A/C > G, I172N/I2splice).
The myelolipoma was not removed and the tumor size
did not increase during a four-year observation period. The
patient was started on treatment with 5mg prednisolone
daily for one year, later cortisone acetate 12.5mg twice a
day whereupon his condition improved. The patient died
suddenly, 73 years old, in his home; the cause of death
remains unknown.
4.Discussion
We here report two male patients who presented late in life
with large adrenal myelolipomas. One was previously treated
for CAH, whereas one was diagnosed with 21-hydroxylase
deficiency after being diagnosed with the adrenal tumor at
68 years of age. Both tumors were left untreated and did not
grow over five- and nine-year observation periods.
An adrenal mass normally requires surgical removal if
the largest diameter exceeds 3cm [1]. Undiagnosed CAH
must always be considered as a differential diagnosis to
tumor, particularly with bilateral adrenal masses. Adrenal
myelolipomas are benign and usually asymptomatic tumors
that usually need not to be resected [2, 6, 7, 11]. Many
of the cases that have been reported in literature were
diagnosed after adrenalectomy [2, 6, 7, 11]. The imaging
characteristics of myelolipomas usually allow presumptive
diagnosis, but which may be confirmed by percutaneous
needle biopsy in cases of extra-adrenal myelolipomas
[5].
However, large myelolipomas could be dangerous if
they start bleeding and give symptoms with pain, nausea,
vomiting, and hypotension [2]. Because of mass effects and
the risk of haemorrhage, elective removal of myelolipomas
that exceed 10cm in diameter might be considered.
Increased prevalence of adrenal tumors has been
reported in CAH patients and in heterozygote mutation
carriers, possibly due to increased levels of ACTH which
acts as a growth factor [12–15]. It has been suggested
that inadequate glucocorticoid coverage in early life or
frequent episodes of infection, both resulting in chronic
ACTH increase, contribute to the development of adrenal
tumors later in life [15, 16]. The aetiology is unknown, but
several theories have been proposed, such as development
from residual embryonic mesenchymal tissue in the adrenal
glands, or metaplasia of reticuloendothelial cells as a result of
chronic stress [2].
It was postulated early in the 1950s that ACTH ele-
vation might induce transformation of adrenal tissue into
myeloid tissue [17], and myelolipomas could thus be par-
ticularly associated with CAH. Hagiwara et al. investigated
ACTH receptors and androgen receptor in a resected giant
myelolipooma in a woman with CAH. They did not
find that the receptors were overexpressed and suggest a
limited direct role for these hormones in the develop-
ment of the myelolipoma [18]. However this conclusion is
debatable.
Toourknowledgelessthan20casesofadrenalmyelolipo-
mas have been reported in patients with CAH to date [7–
10, 16, 18–20]. Jaresch et al. found adrenal masses in 83% of
CAHpatientsand45%ofheterozygousCYP21mutationcar-
riers, which is high compared to the general population [13].
However, their study included only 22 homozygous CAH
patients and 20 heterozygous siblings. Conversely, series of
adrenal incidentalomas have been tested for germline CYP21
mutations, showing inconsistent results which could be due
to small samples [12, 13, 15]. Consequently, it appears that
adrenal masses are common in CAH, but that CAH is not a
common cause of adrenal masses.
The diagnosis of CAH in a patient with an incidental
adrenal mass is important as the patient is at risk of adrenal
crises [21]. Such patients may benefit from glucocorticoid
therapy and should at least be equipped with emergency
medication and a medical alert card. Patient 1 had a
blunted cortisol response to ACTH stimulation, but he had
managed well for 30 years without steroids, working full-
time and did not want to take steroids because of the
psychological side effects he experienced during adolescence.
He was nonetheless advised to take steroids under stressful
situations. Patient 2 had higher basal level of cortisol,
but suboptimal cortisol response to ACTH stimulation. He
had symptoms of cortisol deficiency, and his condition
improved considerably after treatment with prednisolone
was commenced. He had a low normal testosterone level
and tenderness of the testicles. This could be the result
of testicular adrenal rest tumors but was not investigated
further. Whether glucocorticoid suppression therapy in
adult age halts further growth of the tumor is uncertain.
In our patients the tumors did not grow over four to
nine year observation periods despite high ACTH levels.
Conversely, Rajput et al. described progressive evolution of
an adrenal myelolipoma in a woman with CAH who was
treated with prednisolone, although taken irregularly, ren-
dering the level of 17-OH-progesterone persistently elevated
[19].
In conclusion, congenital adrenal hyperplasia, per se,
should be included in the differential diagnosis of adrenal
masses. If suspected clinically, assay of cortisol, ACTH, and
17OH-progesterone should be performed. Adrenal tumors
are common in CAH and might require surgical removal,
but myelolipomas are benign tumors that usually can be left
untreated. Whether, treatment of CAH halts myelolipoma
growth is uncertain.

Page 4

4Case Reports in Medicine
References
[1] W. F. Young Jr., “The incidentally discovered adrenal mass,”
The New England Journal of Medicine, vol. 356, no. 6, pp. 601–
610, 2007.
[2] P. J. Kenney, B. J. Wagner, P. Rao, and C. S. Heffess,
“Myelolipoma: CT and pathologic features,” Radiology, vol.
208, no. 1, pp. 87–95, 1998.
[3] E. Lezoche, M. Guerrieri, F. Crosta, et al., “Perioperative
results of 214 laparoscopic adrenalectomies by anterior
transperitoneal approach,” Surgical Endoscopy, vol. 22, no. 2,
pp. 522–526, 2008.
[4] G. Mansmann, J. Lau, E. Balk, M. Rothberg, Y. Miyachi, and S.
R. Bornstein, “The clinically inapparent adrenal mass: update
in diagnosis and management,” Endocrine Reviews, vol. 25, no.
2, pp. 309–340, 2004.
[5] P. Rao, P. J. Kenney, B. J. Wagner, and A. J. Davidson, “Imaging
and pathologic features of myelolipoma,” Radiographics, vol.
17, no. 6, pp. 1373–1385, 1997.
[6] H. Hisamatsu, H. Sakai, S. Tsuda, K. Shigematsu, and H.
Kanetake, “Combined adrenal adenoma and myelolipoma in
a patient with Cushing’s syndrome: case report and review of
the literature,” International Journal of Urology, vol. 11, no. 6,
pp. 416–418, 2004.
[7] R. Ravichandran, F. Lafferty, M. J. McGinniss, and H. C.
Taylor, “Congenital adrenal hyperplasia presenting as massive
adrenal incidentalomas in the sixth decade of life: report of
two patients with 21-hydroxylase deficiency,” The Journal of
Clinical Endocrinology & Metabolism, vol. 81, no. 5, pp. 1776–
1779, 1996.
[8] M. Sakaki, H. Izaki, T. Fukumori, R. Taue, T. Kishimoto, and
H.-O. Kanayama, “Bilateral adrenal myelolipoma associated
with adrenogenital syndrome,” International Journal of Urol-
ogy, vol. 13, no. 6, pp. 801–802, 2006.
[9] M. B. Umpierrez, S. Fackler, G. E. Umpierrez, and J. Rubin,
“Adrenal myelolipoma associated with endocrine dysfunction:
review of the literature,” American Journal of the Medical
Sciences, vol. 314, no. 5, pp. 338–341, 1997.
[10] K. H. Allison, G. N. Mann, T. H. Norwood, and B. P. Rubin,
“An unusual case of multiple giant myelolipomas: clinical and
pathogeneticimplications,”EndocrinePathology,vol.14,no.1,
pp. 93–100, 2003.
[11] A. Oliva, B. Duarte, R. Hammadeh, L. Ghosh, and R. J. Baker,
“Myelolipoma and endocrine dysfunction,” Surgery, vol. 103,
no. 6, pp. 711–715, 1988.
[12] S. M. Baumgartner-Parzer, S. Pauschenwein, W. Waldh¨ ausl, K.
P¨ olzler, P. Nowotny, and H. Vierhapper, “Increased prevalence
of heterozygous 21-OH germline mutations in patients with
adrenal incidentalomas,” Clinical Endocrinology, vol. 56, no. 6,
pp. 811–816, 2002.
[13] S. Jaresch, E. Kornely, H.-K. Kley, and R. Schlaghecke,
“Adrenal incidentaloma and patients with homozygous or
heterozygous congenital adrenal hyperplasia,” The Journal of
Clinical Endocrinology & Metabolism, vol. 74, no. 3, pp. 685–
689, 1992.
[14] M. Kjellman, M. Holst, M. Backdahl, C. Larsson, L.-O.
Farnebo, and A. Wedell, “No overrepresentation of congenital
adrenal hyperplasia in patients with adrenocortical tumours,”
Clinical Endocrinology, vol. 50, no. 3, pp. 343–346, 1999.
[15] A. Patocs, M. Toth, and C. Barta, “Hormonal evaluation and
mutation screening for steroid 21-hydroxylase deficiency in
patients with unilateral and bilateral adrenal incidentalomas,”
European Journal of Endocrinology, vol. 147, no. 3, pp. 349–
355, 2002.
[16] S.Pang,D.Becker,J.Cotelingam,etal.,“Adrenocorticaltumor
in a patient with congenital adrenal hyperplasia due to 21-
hydroxylase deficiency,” Pediatrics, vol. 68, no. 2, pp. 242–246,
1981.
[17] H. Selye and H. Stone, “Hormonally induced transformation
of adrenal into myeloid tissue,” American Journal of Pathology,
vol. 26, pp. 211–233, 1950.
[18] H. Hagiwara, T. Usui, T. Kimura, et al., “Lack of ACTH and
androgen receptor expression in a giant adrenal myelolipoma
associated with 21-hydroxylase deficiency,” Endocrine Pathol-
ogy, vol. 19, no. 2, pp. 122–127, 2008.
[19] R. M. Rajput, A. M. Bhansali, N. M. Khandelwal, and B. D.
Radotra, “Evolution of adrenal myelolipoma in a patient with
congenital adrenal hyperplasia,” Endocrinologist, vol. 17, no. 4,
pp. 200–201, 2007.
[20] R. Dell’Avanzato, F. Gastaldi, C. Giovanni, et al., “Giant
symptomatic myelolipoma of the right adrenal gland: a case
report,” Chirurgia Italiana, vol. 61, no. 2, pp. 231–236, 2009.
[21] D. P. Merke, “Approach to the adult with congenital adrenal
hyperplasia due to 21-hydroxylase deficiency,” The Journal of
Clinical Endocrinology & Metabolism, vol. 93, no. 3, pp. 653–
660, 2008.