Abbreviations: CAH – congenital adrenal hyperplasia, OART – ovarian adrenal rest tumour, CT – computer tomography, MRI – magnetic resonance imaging
Congenital adrenal hyperplasia, or CAH, is a group of autosomal recessive disorders resulting in the deficiency of one of the enzymes required to synthesize cortisol (1). Ninety to ninety-five percent of cases of CAH are due to a deficiency in the 21-hydroxylase enzyme. A result of this deficiency is increased production of corticotropin-releasing hormone and ACTH, and chronically high levels of ACTH which leads to adrenal hyperplasia and production of excess adrenal androgens. Aldosterone deficiency may or may not be involved in CAH, depending on the severity of the 21-hydroxylase deficiency .
Adrenal rest tumours (ART) are extra-adrenal manifestations of adrenal tissue and 50% of neonates with CAH have ART. ART gradually undergo involution with the subsequent prevalence falling to 1% by adulthood(2) . For men with CAH, testicular adrenal rest tumours (TART) are common with a prevalence as high as 95% in some reports and detection can occur as early as childhood (3). TART is a benign tumour that most often presents bilaterally in patients and is located in the rete testis(4). When TART is not detected and treated, infertility may result as a result of compression of the seminiferous tubules leading to obstructive azoospermia (4). If steroid therapy does not improve TART, fertility-sparing surgical procedures are available (5).
Ovarian adrenal rest tumours (OART) are another, albeit less common, form of an extra adrenal tissue that can occur in females with CAH. To date, only eleven cases of OART have been described in the English-speaking literature(6) making it difficult to choose an optimal treatment approach for affected patients. Here we add an additional case of a young woman with CAH including OART who presented with a contralateral adrenal mass and a 17 year history of non-compliance with adrenal hormone replacement therapy.
A 23 year old Hispanic female presented to the emergency room with a three day complaint of vague abdominal pain, nausea, vomiting, and dizziness. Medical history revealed intermittent gross haematuria, dysuria, and bilateral flank pain. Although initially diagnosed with CAH due to 21-hydroxylase deficiency and treated medically and surgically, the patient stopped her hormone replacement therapy at age 6 due to financial issues. Past surgical history was notable for a clitoroplasty at age 3 in Mexico. Per the patient’s recount, she appeared phenotypically female until age 14 when she began to develop masculine secondary sex characteristics. Physical examination demonstrated male pattern baldness (Figure 1A) a male distribution of body hair on the face, stomach and chest (Figure 2), and pubic hair consistent with a male Tanner 5 stage. Visit thehealthmania.com/
to learn more about treatments.
Figure 1A. Upon initial admission to the hospital, the patient had a noticeable male pattern baldness
Figure 2. Body hair pattern , consistent with a male Tanner V pattern.
In addition, the patient had no breast development and has not undergone menarche.
In the emergency room, laboratory values demonstrated hypokalaemia and hypochloraemia with an anion gap. The cause of her symptoms was delineated as pyelonephritis and she was acutely admitted to the intensive care unit for suspected urosepsis and volume depletion. She was placed on intravenous antibiotics and fluid replacement. On initial admission, the patient had a CT scan as part of her workup, which showed a 12 cm left adrenal mass, concerning for malignancy based on its size (Figure 3).
Figure 3. MR imaging of the patient’s adrenal mass
Moreover, a cystic right ovarian mass was seen, concerning for desmoid tumour per the radiology report. Endocrinologic laboratory studies showed DHEA levels of 3871 ng/dL (normal 162-995), testosterone level of 876 ng/dL (normal 65-119), and oestrogen levels of 9605 pg/mL (normal < 800). An initial measure of 17-hydroxyprogesterone was 3260 ng/dL (normal 20-290) upon the patient’s presentation to the hospital.
The patient subsequently underwent laparoscopic right salpingo-oophorectomy and left adrenalectomy to remove the ovarian mass and the adrenal area concerning for adrenal hyperplasia (Figure 4A and 4B).
Figure 4A. Gross pathology of the adrenal tumour
Figure 4B. Gross pathology of the ovarian tumor. The ovary was bivalved showing the gross tumour.
After an uncomplicated post operative course, the patient was discharged to home on glucocorticoid and mineralocorticoid replacement. Pathology demonstrated adrenal hyperplasia in the adrenal gland associated with myelolipoma. Ovarian histology displays ectopic adrenal tissue compatible with CAH – establishing the diagnosis of OART.
Currently, the patient is compliant with her medical regimen in our specialized disorders of sex development (DSD) clinic. Her testosterone and 17-hydroxyprogesterone levels are now in the normal range for an adult female. Reversal of the patient’s virilization and increased estrogenization has become noticeable as her male pattern baldness is less apparent (Figures 1B and 1C) and breast bud formation has begun.
Figure 1B. The patient’s hair pattern 10 weeks post operatively with treatment of CAH. Return of hair is appreciated.
Figure 1C. The patient’s hair pattern 6 months post operatively with continued return of hair.
The patient’s overall skin tone is also lighter, further indicating compliance with mineralocorticoid replacement. However, the patient continues to have significant facial hair, which will likely require electrolysis for amelioration.
OART is a rare manifestation of CAH due to 21-hydroxylase deficiency in female patients, with the first case reported in the literature in 1957(7). A systematic review of the English-speaking literature by Tiosano et. al reveals only 11 confirmed cases to date (6). These patients range in age from 2 to 41 years of age and all exhibited elevated ACTH levels.
For the clinician, the severity of the OART must not be underestimated as misdiagnosis can be deadly(8). However, prompt diagnosis of OART can be elusive. This raises the concern of the lack of defined criteria for a radiologic diagnosis of OART (9). Using ultrasonography and MRI, Stikkelbroeck et al. attempted to establish radiologic criteria for establishing a diagnosis of OART in 13 females with CAH. However, there were no cases of OART, a testament to the low prevalence of the tumour. This is in contrast to TART where MRI and ultrasound, the preferred diagnostic modalities, readily diagnose the disease, even tumours several millimeters in diameter (3).
Optimal treatment of the ovaries with adrenal rests remains unclear as multiple approaches have been utilized. In our case, as a result of concern for desmoid tumour on MRI, a surgical approach of laparoscopic oopherectomy was elected. Other approaches have included laparoscopy with biopsy of both ovaries and subsequent steroid treatment(10). However, a majority of the patients with OART eventually had one or both ovaries surgically removed(6) (11). While unfamiliarity with the diagnosis of OART may lead to surgical treatment that may not be necessary, the large size of the tumour coupled with lack of outcome data may justify removal in some instances. With the advancement in our understanding of how OART present and the natural history of these benign tumours, the possibility arises that organ-sparing protocols can be developed, similar to the treatment of TART.(5) (12)
In conclusion, surgical treatment for OART remains unclear due to the rarity of these tumours. For girls and women with CAH for whom medical treatment is unavailable or who are noncompliant with their therapy, OART should be considered when ovarian masses are detected. If an OART is detected early enough and glucocorticoid therapy is received, it is possible that the OART will decrease in size following suppression of ACTH levels.
IRB and patient approval were obtained for the figures used.
1. Speiser PW, White PC. Congenital Adrenal Hyperplasia. N Engl J Med 2003;349(8):776-88.
2. Ambroziak U Bednarczuk T, Ginalska-Malinowska M, et. al. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency – management in adults. Polish Journal of Endocrinology. 2010;61:142-55.
3. Mouritsen A, Jorgensen N, Main KM, Schwartz M, Juul A. Testicular adrenal rest tumours in boys, adolescents and adult men with congenital adrenal hyperplasia may be associated with the CYP21A2 mutation. International Journal of Andrology. 2010;33(3):521-7.
4. Claahsen-van der Grinten HL, Otten BJ, Stikkelbroeck MM, Sweep FC, Hermus AR. Testicular adrenal rest tumours in congenital adrenal hyperplasia. Best Pract Res Clin Endocrinol Metab. 2009 Apr;23(2):209-20.
5. Stikkelbroeck NM Otten BJ, Pasic A, et. al. High Prevalence of Testicular Adrenal Rest Tumors, Impaired Spermatogenesis, and Leydig Cell Failure. Journal of Clinical Endocrinology and Metabolism. 2001;86(12):5721-8.
6. Tiosano D, Vlodavsky E, Filmar S, Weiner Z, Goldsher D, Bar-Shalom R. Ovarian adrenal rest tumor in a congenital adrenal hyperplasia patient with adrenocorticotropin hypersecretion following adrenalectomy. Horm Res Paediatr. 2010;74(3):223-8.
7. Epstein JA, Levinson C, Kupperman HS. Ovarian adrenal rest tumor (masculinovoblastoma) stimulating adrenal virilism: report of a case with hormone studies. Am J Obstet Gynecol. 1957;74(5):982-8.
8. Claahsen-van der Grinten HL, Hulsbergen-van de Kaa CA, Otten BJ. Ovarian adrenal rest tissue in congenital adrenal hyperplasia–a patient report. J Pediatr Endocrinol Metab. 2006 Feb;19(2):177-82.
9. Stikkelbroeck NM, HermusA, Schouten D, et. al. Prevalence of ovarian adrenal rest tumours and polycystic ovaries in females with congenital adrenal hyperplasia: results of ultrasonography and MR imaging. Eur Radiol. 2004;14:1802-6.
10. Russo G, Paesano P, Taccagni G, Del Maschio A, Chiumello G. Ovarian Adrenal-like Tissue in Congenital Adrenal Hyperplasia. New England Journal of Medicine. 1998;339(12):853-4.
11. Al-Ahmadie H, Stanek J, Liu J, Mangu P, Niemann T, Young RH. Ovarian `Tumor’ of the Adrenogenital Syndrome: The First Reported Case. The American Journal of Surgical Pathology. 2001;25(11):1443-50.
12. Nagamine WH, Mehta SV, Vade A. Testicular adrenal rest tumors in a patient with congenital adrenal hyperplasia: sonographic and magnetic resonance imaging findings. J Ultrasound Med. 2005;24(12):1717-20.
Date added to bjui.org: 27/07/2011