By Laurence M. Demers, PhD, and Andrew Behnke, MD
An 11-year-old Caucasian female presented to her family doctor with complaints of excessive facial hair and a deepening of her voice. At the age of 8 it was noted that she had a rather early appearance of pubic hair growth, showed evidence of acne on her forehead, had increased amounts of apocrine sweat gland activity and yet had little evidence of breast development or signs of menarche. As part of her mildly presenting symptoms of androgen excess, she had a DHEA-S blood level drawn at the time that was 600 ng/ml. She was in the 90th percentile for height and weight. The diagnostic impression at this time was precocious adrenarche. This was based on a mildly elevated DHEA-S level, normal serum estradiol and a bone age of 10 1/2 years. Over the next three years, this young girl experienced progression of her facial acne and began to show increasing evidence of facial hair growth. Her acne manifestation prompted a dermatologic consultation that resulted in treatment with Retin-A and tetracycline. She also started to experience significant weight loss that reached 15 pounds by the time she was 11. This was partially attributed to an intense ballet program and her desire to lose weight at the suggestion of her ballet teacher. Her family physician however became concerned with her overt manifestations of virilism and ordered lab work to justify her suspicion.
On physical examination, she presented as a thin, white female with virilizing features including excessive facial hair, a deep voice and considerable cystic acne. Her evaluation included an MRI of the adrenals and ovaries and an ACTH stimulation test. A diagnosis of delayed onset congenital adrenal hyperplasia was considered but hormone analysis revealed a normal baseline cortisol, 17 hydroxyprogesterone and 11 deoxycortisol levels. The cortisol level however did not stimulate beyond the baseline level following cortrosyn stimulation. She also had markedly elevated levels of DHEA-S for age at 3,000 ng/ml, and an elevated testosterone at 218 ng/dl. Her bone age was 13 with a chronological age of 11. An MRI scan revealed a right adrenal mass with a normal left adrenal suggesting a right adrenal tumor. At this time she was referred to the endocrine service at a university hospital for further evaluation and work-up.
The endocrine consult at the university hospital revealed a young girl with considerable clinical evidence of androgen excess. She had moderately severe facial hirsutism and severe facial acne along with acne form eruptions on her back. She showed small amounts of hair around her nipples and adult amounts of pubic hair. Her voice was deep-timbered although she did not exhibit much of an increase in muscle mass considering her hyper-androgen state. The patient’s height was at the 85th percentile with weight at the 50th percentile. She had less than 1 cm of breast tissue on either breasts and examination of her genitalia revealed no evidence of in utero virilization. Her clitoris was enlarged however yet she had no evidence of estrogen exposure as judged by examination of her vaginal mucosa. The DHEA-S was repeated and was found to be 2,600 ng/ml. Her testosterone level was also determined by radioimmunoassay following partial purification of the sample by celite chromatography and was elevated at 150 ng/ml. With the laboratory and radiographic studies, the diagnosis of a possible adrenal tumor was confirmed. The patient subsequently underwent an excision of her right adrenal mass. Her post-operative course was uneventful and her elevated androgen levels began to return to normal for her age and pubertal status.
Virilizing tumors of the adrenal gland are relatively rare entities not commonly seen in clinical practice. The estimated incidence is 1 per 1.7 million. The presentation of precocious virilization however, is not uncommon in children and can present from birth up through puberty.
The most common cause of androgen excess in children is cogenital adrenal hyperplasia (CAH) that results from an enzymatic block at the 21 hydroxylase enzyme step in the cortisol biosynthetic pathway. This enzyme block results in cortisol deficiency that leads to a compensatory rise in pituitary ACTH secretion. The increase in ACTH produces a redirection of steroid substrate through the adrenal androgen pathway which is not dependent on the 21 hydroxylase enzyme. The result is excess availability of the major adrenal androgen, dehydroepiandrosterone (DHA) which is converted to testosterone and produces the metabolic response associated with excess androgens.
A similar clinical picture can present in patients with an 11 hydroxylase enzyme deficiency of the adrenal. This enzyme step is immediately proximal to the formation of cortisol. The incidence of CAH from an 11 hydroxylase deficiency however is much rarer and is usually accompanied by hypertension. Laboratory measurements of DHEA in its sulfated form is often used to exclude or include the adrenal as the reason for the clinical manifestation of virilizing symptoms.
Because DHEA-S has a significant age dependent reference range, normal levels for a young adult can be quite abnormal when present in a pre-adolescent child.
In the case of this patient, the presenting level of 600 ng/ml at the age of 8 is well within the normal range for a 14 year old but is clearly elevated for an 8 year old. Thus age related norms must be considered when interpreting the level of DHEA in the face of a suggested overactive adrenal androgen metabolic pathway.
DHEA-S measurements are also considered to be an important marker for adrenal tumors. As with this patient, other adrenal steroids including aldosterone and cortisol are sometimes found normal in patients with tumors of the adrenal. The discriminating steroid to measure when suspecting an adrenal tumor is DHEA-S which is usually markedly raised in patients with an adrenal carcinoma.
Although hirsutism alone can be the initial presenting symptom, patients with an adrenal tumor usually present with other symptoms of virilization as well. Although more commonly observed in adults, the virilization usually manifest itself as excess facial and body hair, severe acne in the face and back areas, male pattern baldness, increased muscle mass and cliteromegaly. Reproductive age women will cease their menstrual periods as well. Symptoms of androgen excess however are not restricted to an adrenal tumor. Hyperandrogenism can present in patients with congenital adrenal hyperplasia and polycystic ovarian disease as well. Although rare, there is a bimodal peak in the age of incidence of virilizing adrenal tumors in the first and fourth decades of life.
The presentation of an adrenal tumor in a pre-pubertal child is quite rare. It is easy to see how the initial complains of excessive pubic hair growth in an 8 year old may simply have signaled the early onset of adrenarche, the period when the adrenal androgen pathway starts to become active.
The fact that this young girl continued to show continued and progressive hirsutism without evidence of an estrogenic response to normal puberty should have pointed the family practitioner towards an endocrine consult earlier.
Adrenal function testing is an important part of identifying the cause of excessive manifestations of virilism. Since congenital enzyme blocks are not that uncommon, the use of provocative adrenal function testing like the cortrosyn stimulation test is usual practice in working up a patient who presents with signs and symptoms of androgen excess.
The normal baseline levels of cortisol, 11deoxycortisol and 17 hydroxy progesterone and response to exogenous ACTH tended to rule out an exzymatic block as the cause of excess androgen production.
The key to the diagnosis was the DHEA-S level. At the age of 8 the level was already 600 ng/ml. Although this level is within the limit usually thought of as suggestive of non-neoplastic disease, for the patient’s age, it was nevertheless, significantly elevated.
By the time the patient presented with overt androgen symptoms of excessive facial hair and a deepening voice, the level was close to 3,000 ng/ml, a value markedly elevated in an 11 year old who had yet to show apparent signs of normal puberty.
Within two days following surgical removal of the adrenal mass, the level of DHEA-S had dropped to 708 ng/ml. Within two weeks after surgery the DHEA-S level had fallen to an appropriate 88 ng/ml for pubertal status with normal levels of testosterone, cortisol and 11 deoxycortisol.
Surgery was the only logical treatment choice for treating this isolated adrenal mass. Once the adrenal tumor was removed, the adrenal steroid pattern reverted to normal. It is expected that this young girl will experience normal puberty once the elevated androgen levels become normalized in her system.
- Wooten, MD, King, DK. Cancer 72:3145-3152, 1993, Adrenal Cortical Carcinoma: Epidemiology and Treatment.
- McKenna, TJ, Cunningham, SK and Loughlin, T. Clin Endcrinol. Metab. 14:997-1020, 1985, The adrenal Cortex and virilization.
This case study was provided by Laurence M. Demers, PhD, Professor Emeritus of Medicine and Pathology at Penn State College of Medicine, 500 University Drive, Hershey, PA 17033, and Andrew Behnke, MD, Instructor, Department of Medicine, Penn State College of Medicine. This material may not be reproduced without the permission of the authors.