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 Table of Contents  
Year : 2023  |  Volume : 3  |  Issue : 3  |  Page : 174-178

Early-onset virilization may rarely be due to an adrenocortical neoplasm

Department of Endocrinology, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India

Date of Submission21-Apr-2023
Date of Decision17-Jun-2023
Date of Acceptance30-Jun-2023
Date of Web Publication14-Aug-2023

Correspondence Address:
Dr. Kalyani Sridharan
Department of Endocrinology, All India Institute of Medical Sciences, Veerbhadra Marg, Rishikesh - 249 203, Uttarakhand
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ipcares.ipcares_90_23

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Background: Adrenocortical tumors are rare neoplasms of childhood; most of which are functional in childhood, producing excess hormones. Virilization, precocious puberty, and Cushing's syndrome are common presenting features. Clinical Description: A 6-year-8-month-old girl presented with features of virilization, which started appearing at 2 ½ years of age. The mother gave a history of progressive enlargement of the clitoris with the development of pubic, axillary, and facial hair over the years. There was no history of perinatal complications, features of adrenal insufficiency, atypical external genitalia at birth, or family history of malignancy. On examination, she had features of heterosexual peripheral precocious puberty. The hormonal investigation was suggestive of cortisol and androgen excess. Radiologically, she had an adrenal tumor appearing like adrenocortical carcinoma (ACC)-large size, high noncontrast Hounsfield units, and poor washout. Management and Outcome: As virilization was not present since birth and there was no evidence of adrenal insufficiency, therefore, the possibility of congenital adrenal hyperplasia was unlikely. Investigations revealed that the testosterone levels were much higher than other adrenal androgen precursors like dehydroepiandrosterone sulfate. This was a clinical clue to the well-differentiated and benign nature of the tumor although radiologically it appeared like ACC. The child underwent en bloc resection of the mass, and histopathology was suggestive of a benign adrenocortical adenoma. Seven days after surgery, the serum testosterone had dropped substantially. Conclusion: This case creates awareness about the possibility of an adrenocortical neoplasm in a child with early-onset virilization, which can be diagnosed correctly by following a step-wise, logical sequence of investigations.

Keywords: Adrenocortical carcinoma, congenital adrenal hyperplasia, Wieneke criteria

How to cite this article:
Nanda N, Kaur K, Kadian K, Sridharan K. Early-onset virilization may rarely be due to an adrenocortical neoplasm. Indian Pediatr Case Rep 2023;3:174-8

How to cite this URL:
Nanda N, Kaur K, Kadian K, Sridharan K. Early-onset virilization may rarely be due to an adrenocortical neoplasm. Indian Pediatr Case Rep [serial online] 2023 [cited 2023 Sep 26];3:174-8. Available from:

Adrenocortical tumors (ACTs), including adrenocortical adenomas and adrenocortical carcinomas (ACCs), are rare neoplasms of childhood, with a reported incidence of 0.2–0.3 per 1 million children, per year, together accounting for only 6% of all adrenal tumors in children.[1] Unlike in adults, nearly 95% of pediatric ACTs are functional–producing hormones.[2] Virilization and precocious puberty are the most common presentations of ACTs.[2] Cushing's syndrome without virilization is less frequent.[3] Differentiating adrenocortical adenoma from carcinoma can be difficult clinically. We report a child with early onset and progressive virilizing features, diagnosed with an ACT only after 6 years of age.

  Clinical Description Top

A 6-year-8-month-old girl presented to us with features of progressive virilization, noticed by the mother post infancy. Earlier, the family had tried multiple indigenous medications with no response, before showing to a local pediatrician. The pediatrician suspected congenital adrenal hyperplasia (CAH) and referred her to our center.

At our institute, we revisited the child's history. The patient had steadily progressive enlargement of the clitoris with the development of pubic, axillary, and facial hair over the chin since 2.5 years of age. The patient came to us after 4 years of onset of symptoms. Furthermore, the mother complained of the development of acne over the face and a change in voice. She was growing taller compared to her peers, and all these symptoms had worsened over the past 6 months. There was no history of bleeding per vaginum, easy fatigability, weight loss, salt craving, and dehydration episodes. There was no usage of any topical hormone creams, ointments, or any other form of androgens.

She was born at term, out of nonconsanguineous marriage, by a normal vaginal delivery. Her birth weight was 2.5 kg, and the mother confirmed that at the time of birth, she had typical female external genitalia without any signs of virilization. The patient was breastfed for 6 months and then shifted to feeds from the home pot. She was immunized for her age and achieved development milestones at the normal age. The patient had two live and healthy siblings without any history of sibling death. There was no family history of malignancy.

On examination, her weight was 30 kg (+3 SDS), and height was 125.5 cm (+1.5 SDS; between the 75th and 90th centile; midparental height being 3rd–10th centile). She had no pallor, icterus, clubbing, lymphadenopathy, or pedal edema. She was afebrile, with normal volume pulses of 80/min, blood pressure of 108/60 mmHg (<90th centile), and respiratory rate of 17/min. She had masculine body habitus with signs of virilization in the form of pustular acne, deepening of the voice, hirsutism (Modified Ferriman-Gallwey score 33/36), clitoromegaly (clitoral index 5.25 cm2) (Prader stage 1 of virilization: isolated clitoromegaly without posterior labial fusion), axillary hair, and discordant secondary sexual characters (Tanner stage: breast stage 1, pubic hair stage 4) [Figure 1]. There were no neurocutaneous markers, hyperpigmentation of the skin, inguinal masses, and no signs of Cushing's syndrome. There was neither organomegaly nor any palpable lump per abdomen. The rest of the systemic examination was unremarkable.
Figure 1: Clinical images of the patient showing (a) temporal balding, (b) facial hirsutism, and (c) Tanner stage 4 pubic hair growth with clitoromegaly

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Based on history and examination, a diagnosis of classic CAH was unlikely, as virilization started sometime after birth, and there were no symptoms/signs of adrenal insufficiency. Although symptoms of adrenal insufficiency may be absent in simple virilizing CAH, the virilization should still be evident at birth. These points make an adrenocortical tumor a likely diagnosis. The time of appearance of virilizing features, as well as the progressive nature of the virilization favored an ACT.

  Management and Outcome Top

The child underwent investigations on the lines of ACT. Routine investigations revealed hemoglobin 15 g/dL, total leukocyte count 5000/mm3, and platelets 300 × 109/L, with a bilirubin of 0.1 mg/dl, alanine aminotransferase 12 U/L, aspartate aminotransferase 16U/L, blood urea of 11 mg/dl (5–20), 0.8 mg/dL (0.5–1), serum sodium 143 mmol/L, potassium 4.9 mmol/L, and chloride 98 mmol/L. Her bone age was 15 years with fused epiphyses (as per Greulich–Pyle atlas) [Figure 2].
Figure 2: Bone age was 15 years

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On hormonal evaluation [Table 1], it was found that 8 am testosterone was 78 nmol/L (0.1–0.5), and after dexamethasone suppression, serum testosterone was 122 nmol/l (0.1–0.5), which was, thus, diagnosed as nonsuppressible. Further, on overnight dexamethasone test and low-dose dexamethasone suppression test, serum cortisol was 290 nmol/L (<50) and 228 nmol/L (<50), respectively, which were also nonsuppressible. Late-night salivary and midnight serum cortisol values were 19 nmol/L (<5.5) and 162 nmol/L (<200), respectively. The adrenocorticotropic hormone was not done due to affordability issues. The serum level of 17 hydroxyprogesterone was 17 nmol/L (<6), which was mildly elevated. Karyotyping revealed 46XX.
Table 1: Biochemical and hormonal parameters of the child before surgery

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Ultrasonography of the abdomen and pelvis showed a left suprarenal mass of size 6 cm × 6 cm × 6.5 cm, likely adrenal in origin, with bilateral normal ovaries, normal liver, kidneys, and spleen with no para-aortic or mesenteric lymphadenopathy. The magnetic resonance imaging (MRI) of the pelvis showed normal ovaries, and the uterus could not be visualized. MRI of the pelvis was performed in the initial workup to look for the Mullerian structures. Later, the USG of the abdomen showed an adrenal lesion, for which contrast-enhanced computed tomography (CECT) of the abdomen was done. The CECT of the abdomen showed a hetero-echoic left suprarenal mass measuring 6 cm × 6 cm × 6.5 cm with indistinct fat planes with the body and tail of the pancreas anteriorly with multiple foci of the calcific and necrotic areas with no lymphadenopathy. The mass had a baseline Hounsfield unit of 39 with an absolute washout of 55% and relative washout of 40% – features suggestive of an ACC [Figure 3]. The visualized right adrenal gland was normal. Contrast-enhanced computed tomography of the chest was done as part of a metastatic workup, which was normal. As CECT of the chest and abdomen as well as MRI of the pelvis were negative for metastasis, further functional imaging like positron emission tomography scan was not done.
Figure 3: Axial sections of contrast enhanced computed tomography images showing a 6 cm × 6 cm × 6.5 cm heterogeneous left adrenal mass with necrotic areas in the arterial phase in (a) and intense contrast enhancement in the venous phase in (b)

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At this point, based on history and radiological imaging findings, the child was diagnosed with childhood-onset virilization due to ACC of stage 2 (T2N0M0) associated with increased cortisol levels, without overt features of Cushing's syndrome.

As the child was not having any features of overt Cushing's syndrome, the patient was not started on any medical management before surgery. The child underwent exploratory laparotomy under perioperative intravenous hydrocortisone cover, and en bloc resection of the mass was done. Postsurgery, the patient was put on intravenous hydrocortisone 50 mg 6 hourly.

The grossly resected adrenal lesion was globular, measuring 7.5 cm × 5.5 cm × 4.5 cm in size, weighed 104 g, and was reddish in color, with a smooth surface without any hemorrhage, with cut surface showing multinodular growth with multiple cystic spaces and a single focus of calcification. Histopathology showed that the tumor cells were round to oval with large nucleoli, irregular nuclear membrane with occasional mitotic figures (score 1), no necrosis, or atypia. There was no extension into the periadrenal soft tissues and no evidence of venous invasion or capsular invasion. Overall, the Wieneke score was 1 (>4 is considered malignant) [Figure 4]. As per the Wieneke criteria, our case did not fulfill the requirements for malignancy [Box 1]. Hence, although the radiological picture was suggestive of ACC, the histopathology confirmed a diagnosis of benign adrenocortical adenoma.
Figure 4: Surgical resected specimen of the adrenocortical tumor (a) and histopathology images (in hematoxylin and eosin stain) in low power (b) and high power (c) showing tumor cells with large nucleoli, abundant eosinophilic granular cytoplasm with occasional mitotic figures, but no areas of necrosis, capsular invasion, or significant atypia

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Postsurgery, the patient was hemodynamically stable. The patient was shifted from IV hydrocortisone to oral hydrocortisone. Serum testosterone repeated on the 7th day after surgery had dropped to 0.65 nmol/L (0.1–0.5). The child was discharged after 8 days postsurgery, on a maintenance dose (8 mg/m2) of oral hydrocortisone. The plan was to stop hydrocortisone in the next visit after 15 days and to repeat the serum cortisol. However, unfortunately, the patient was lost to follow up.

The case described above depicts a child with early childhood-onset virilization, who was mistakenly diagnosed as CAH, thereby delaying the true diagnosis of a functioning adrenocortical adenoma. Further, this case also depicts difficulty in differentiating between adrenocortical adenoma and carcinoma.

ACTs may have a variable presentation. While some have an indolent course, others tend to be highly malignant tumors with an aggressive course and a relatively poor prognosis, especially in those with distant metastasis.[4] The condition is more common in females, with nearly half of the children with ACC presenting before the age of 4 years.[5] Our case also developed virilizing features of the disease, quite early, by 2.5 years of age; however, due to a lack of seeking proper medical advice and appropriate investigations, the diagnosis was made after 6 years of age. On the other hand, the eight children with ACC, reported by Li et al., had a median age of onset of 6 years, with only 37.5.% below 5 years of age.[6]

Depending on the ability to produce hormones, ACC can be divided into two categories – functional ACC, which mainly produces cortisol, aldosterone, and sex hormones. Nonfunctional ACC does not secrete hormones, and thus, affected individuals usually present with local symptoms caused by the volume of the tumor, like low back or abdominal pain, or an abdominal mass, with some systemic symptoms such as loss of appetite, weight loss, anemia, low-grade fever, and bone pain. Such nonfunctional ACC is often diagnosed in the late stages.[6]

Most of the ACC tumors in children are functional, with virilization and Cushing's syndrome being the most common presenting features of this condition.[2] The clinical presentation of ACT depends on the predominant hormonal secretory pattern. While isolated Cushing's syndrome in ACC is seen in children in only about 5%, isolated virilizing ACC is more common (seen in 55%) of children with ACC.[7] Our patient manifested features of only heterosexual precocious puberty, but no signs of Cushing's syndrome, which can be explained by the anabolic effect of increased androgen levels in the body. In two previous large reports on 209 and 254 pediatric and adolescent cases, the most common presentation was virilization, followed by a mixed picture of virilization and Cushing's syndrome.[2],[8] In our patient, the level of testosterone was much higher than the other adrenal androgen precursors like Dehydroepiandrosterone sulfate. Although this cannot be called a pure testosterone-secreting adrenal tumor as there was subclinical cortisol excess, it is interesting to note that the tumor cells produced much greater amounts of the finished end product like testosterone with much lesser amounts of the androgen precursors and cortisol. This could be a clinical clue to the well-differentiated and benign nature of the tumor, although radiologically it appeared like ACC. Gundgurthi et al. described a 2-year-old with ACC, who had features of both androgen and glucocorticoid excess, but despite having androgen excess, showed poor growth.[7]

Children with a functioning ACT are subject to growth disturbances.[9] Premature exposure to excess androgen and estrogen may result in an increased growth rate and premature epiphyseal closure. In many instances, the increased somatic growth of these children, their generally healthy appearance, and the lack of a palpable abdominal mass diverted pediatricians from the possibility of a malignancy, resulting in a delay in diagnosis;[10] a situation, quite similar to our case.

ACCs in children may be sporadic; however, a strong genetic association with the tumor has also been described in children, characterized by copy-neutral loss of heterozygosity of chromosomes 11 and 17, involving anomalies of genes such as TP53, insulin-like growth factor 2 (IGF2) overexpression, IGF1R, ZNRF3, CTNNB1, multiple endocrine neoplasia type 1, PRKAR1A, and 11p15.5. Mutations in epidermal growth factor receptors have also been reported.[11] Genetic anomalies ideally need to be evaluated before surgery. However, due to financial constraints, genetic analysis could not be done in our case.

In individuals with 46XX, virilization can result from severe androgen excess due to overproduction or enzymatic defects of adrenal and gonadal steroid biosynthesis.[12] Very rarely, it is caused by drug abuse and environmental toxins.[12] The most common genetic cause of virilization before and at puberty is CAH caused by 21-hydroxylase deficiency, causing variable glucocorticoid deficiency with adrenal androgen excess leading to signs of virilization.[12] Our patient presented with virilization starting at around 2.5 years of age, which was severe and progressive and was not associated with clinical or biochemical evidence of cortisol deficiency. Hence, classic CAH was unlikely in our case. Rarely, simple virilizing CAH with ovarian adrenal rest tumors can explain progressive virilization in a child with CAH.[13] However, this was also less likely as virilization was not present at birth, and biochemically, there was evidence of cortisol excess. This suggested a tumor as the source of androgen production, very likely ACT, which was co-secreting both adrenal androgens and cortisol.

It is difficult to differentiate adrenocortical adenoma from carcinoma clinically, radiologically, as well as histologically. In our case, radiologically characteristics were in favor of ACC. However, histologically, the low score on the Wieneke scoring confirmed benign adrenocortical adenoma. Although the Weiss scoring is used in adults for ACC diagnosis and prediction, the Wieneke scoring system has been validated for pediatric ACTs, and it performs well in tumor prognostication.[14] The Wienke criteria for malignancy and their scoring in our case are shown in Box 1.

In our patient, a step-wise clinical, hormonal, radiological, and histological evaluation revealed a left benign functioning adrenocortical adenoma that co-secreted cortisol and androgens. It is unfortunate that the definitive management was delayed due to the delay in seeking medical opinion, thereby resulting in a loss in final adult height and untoward psychological trauma to the growing child.

Surgical treatment is a primary modality of treatment with a preferably open approach to avoid the risk of rupture or peritoneal carcinomatosis. Mitotane, which is commonly used in adult ACC, has been shown to improve outcomes in pediatric ACC. However, it is not widely used due to poor tolerability. Systemic chemotherapy with cisplatin, etoposide, and doxorubicin is also another option in residual disease or stages 3 and 4. Newer drugs such as pembrolizumab and cabozantinib are under trial and have shown partial response in pediatric ACC.[4]

The prognosis is highly variable and not predictable. Risk factors for poor outcomes include older age, high mitotic rate, large tumor size, and a large percentage of necrosis.[15]

Complete resection of the tumor is usually favorable. The patient should be followed up at 3 months with repeat hormonal workups and imaging. The residual disease can be managed with repeat surgery, adjuvant systemic treatment (mitotane for chemotherapy), or rarely radiation therapy.[4] Unfortunately, we could not follow up the child and are, thus, not able to convey the outcome of our intervention. However, serum testosterone repeated on day 7 of surgery was 0.65 nmol/L (0.1–0.5).

To conclude, by reporting this child with ACT, an entity not commonly seen by pediatricians, we intend to create awareness about this condition and reiterate the fact that early-onset virilization is not always due to CAH. All attempts must be made to follow a step-wise, logical sequence of investigations, including the histological evaluation and appropriate scoring, so as to correctly ascertain the exact etiology.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil (Clinical images).

Conflicts of interest

There are no conflicts of interest.

  References Top

Klein JD, Turner CG, Gray FL, et al. Adrenal cortical tumors in children: Factors associated with poor outcome. J Pediatr Surg 2011;46:1201-7.  Back to cited text no. 1
Michalkiewicz E, Sandrini R, Figueiredo B, et al. Clinical and outcome characteristics of children with adrenocortical tumors: A report from the international pediatric adrenocortical tumor registry. J Clin Oncol 2004;22:838-45.  Back to cited text no. 2
Miele E, Di Giannatale A, Crocoli A, et al. Clinical, genetic, and prognostic features of adrenocortical tumors in children: A 10-year single-center experience. Front Oncol 2020;10:554388.  Back to cited text no. 3
Ilanchezhian M, Varghese DG, Glod JW, et al. Pediatric adrenocortical carcinoma. Front Endocrinol (Lausanne) 2022;13:961650.  Back to cited text no. 4
McAteer JP, Huaco JA, Gow KW. Predictors of survival in pediatric adrenocortical carcinoma: A surveillance, epidemiology, and end results (SEER) program study. J Pediatr Surg 2013;48:1025-31.  Back to cited text no. 5
Li J, Zhang W, Hu H, et al. Adrenocortical carcinoma in eight children: A report and literature review. Cancer Manag Res 2021;13:1307-14.  Back to cited text no. 6
Gundgurthi A, Kharb S, Dutta MK, et al. Childhood adrenocortical carcinoma: Case report and review. Indian J Endocrinol Metab 2012;16:431-5.  Back to cited text no. 7
Neblett WW, Frexes-Steed M, Scott HW Jr. Experience with adrenocortical neoplasms in childhood. Am Surg 1987;53:117-25.  Back to cited text no. 8
Hauffa BP, Roll C, Mühlenberg R, et al. Growth in children with adrenocortical tumors. Klin Padiatr 1991;203:83-7.  Back to cited text no. 9
Sandrini R, Ribeiro RC, DeLacerda L. Childhood adrenocortical tumors. J Clin Endocrinol Metab 1997;82:2027-31.  Back to cited text no. 10
Kamilaris CD, Hannah-Shmouni F, Stratakis CA. Adrenocortical tumorigenesis: Lessons from genetics. Best Pract Res Clin Endocrinol Metab 2020;34:101428.  Back to cited text no. 11
Santi M, Graf S, Zeino M, et al. Approach to the virilizing girl at puberty. J Clin Endocrinol Metab 2021;106:1530-9.  Back to cited text no. 12
Chen HD, Huang LE, Zhong ZH, et al. Ovarian adrenal rest tumors undetected by imaging studies and identified at surgery in three females with congenital adrenal hyperplasia unresponsive to increased hormone therapy dosage. Endocr Pathol 2017;28:146-51.  Back to cited text no. 13
Jehangir S, Nanjundaiah P, Sigamani E, et al. Pathological prognostication of paediatric adrenocortical tumours: Is a gold standard emerging? Pediatr Blood Cancer 2019;66:e27567.  Back to cited text no. 14
Sandru F, Petca RC, Carsote M, et al. Adrenocortical carcinoma: Pediatric aspects (Review). Exp Ther Med 2022;23:287.  Back to cited text no. 15


  [Figure 1], [Figure 2], [Figure 3], [Figure 4]

  [Table 1]


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