Precocious Puberty: An Infant With a Virilizing Ovarian Tumor
A 6-month-old girl presented to the clinic for her routine health maintenance visit. Her mother had noted a clear to whitish vaginal discharge that had started 2 weeks prior to the visit.
The infant was developmentally appropriate for her age. Her mother was pleased with the rapid growth of her daughter, whose height and weight had both reached the 90th percentile after having been in the 50th and 25th percentile, respectively.
The pregnancy, labor, and delivery had been unremarkable. Family history was significant for thyroid cancer in the girl’s maternal grandmother. The infant was not on any medication and had no history of exposure to any product with estrogenic or androgenic constituents.
The baby was alert, active, and appeared healthy during the physical examination. Breast development consistent with a Tanner stage II was noted. Fine, curly, dark hair was present in the axillae (Figure 1), and sparse growth of thin, black hair was present around the mons pubis and labia majora (Figure 2). A small amount of transparent, white, mucoid discharge was evident at the fourchette. Her labia minora and clitoris were mildly hypertrophied. Her abdomen was soft and nontender, and no masses were palpable.
Results of initial laboratory evaluations are summarized in the accompanying Table. Abdominopelvic ultrasonography revealed a large, complex, 7 × 10-cm pelvic mass near the right ovary. The mass contained both solid and cystic components and extended from the region of the right kidney to the pelvis, displacing the right kidney and bowel loops. The adrenal glands, liver, and spleen appeared unremarkable. Computed tomography scanning confirmed these findings and showed no evidence of metastatic spread. There were no calcifications within the mass. The right kidney was extrinsically compressed but otherwise appeared normal.
The baby was taken for surgical removal of the abdominal mass. At laparotomy, a right ovarian mass was found and excised (Figure 3). The cut surface of the mass was composed of yellowish granular tissue within a stroma of edematous, gelatinous material (Figure 4). The left ovary and fallopian tube were grossly normal.
Both adrenal glands, the cul-de-sac, and peritoneum were carefully inspected for implants but none were detected. Postoperative recovery was rapid and uneventful.
Histologic and immunohistochemical features of the mass were consistent with a sex cord-stromal neoplasm. The histopathologic diagnosis was that of a gonadal stromal tumor of indeterminate type. It did not show differentiate along granulosa or Sertoli lines.
During a follow-up visit 3 months after surgery, the girl’s levels of inhibin A (< 10 pg/mL) and dehydroepiandrosterone (DHEA, < 15 ng/dL) had dropped to negligible values. At the 1-year follow-up visit, the child was developmentally appropriate for her age. Her rapid growth velocity had ceased, and she had dropped to the 53rd percentile for weight and the 66th percentile for height. The breast tissue enlargement had resolved, with a minimal excess of skin around the nipple area. Scanty pubic hair was observed on the lower portion of the mons pubis. No axillary hair was present. Results of abdominal ultrasonography were normal.
Precocious puberty in infants may be the result of a central or peripheral cause. The most common mechanism is central, with early activation of pulsatile secretion of gonadotropin-releasing hormone. In out patient, however, the presence of both virilizing and feminizing characteristics without elevation of her gonadotropin levels suggested an underlying pathologic peripheral cause of her precocity.
Virilizing features such as pubic hair growth result from the effects of androgens that may result from the early maturation of the adrenal glands (adrenarche), exogenous androgens, and congenital adrenal hyperplasia,1 or from virilizing androgenic lesions of the ovaries.2
Ovarian tumors are rare in pediatric patients, with a prevalence of less than 3 cases per 100,000 girls.2 Ovarian tumors are classified according to their most probable tissue of origin: surface epithelial tissues, germ cells, sex cord-stromal tissues of the ovary, secondary or metastatic ovarian tumors, and a group that contains elements of multiple tissues and thus defies classification.3
Sex cord tumors account for less than 10% of ovarian tumors.2 Ovarian sex cord-stromal tumors traditionally are classified according to histologic type as androgen-producing tumors (Sertoli cell and Leydig cell tumors) or estrogen-producing tumors (granulosa cell and theca cell tumors).3 Ovarian sex cord-stromal tumors in children do not always differentiate into these strict histologic categories. Undifferentiated tumors such as gonadoblastomas have been identified that contain mixed germ cell elements as well as stromal elements.3
Juvenile granulosa cell tumors are the most common childhood ovarian neoplasm with estrogenic manifestations and account for 1% to 10% of all ovarian tumors.2 They rarely are reported in infants less than 1 year old.4,5 These tumors almost always are unilateral.2 Plasma levels of estradiol and inhibin B typically are elevated.2,3 Some juvenile granulosa cell tumors are virilizing.2
Sertoli-Leydig cell tumors are rare sex cord-stromal neoplasms that represent less than 1% of ovarian tumors.6
Our patient had significant elevations of testosterone, DHEA, inhibin A and B, and estradiol levels. Elevated testosterone in a prepubertal girl with an ovarian mass would suggest a virilizing ovarian tumor such as arrhenoblastoma, gonadoblastoma, or Sertoli-Leydig cell tumor.6 Inhibin is a nonspecific marker of ovarian neoplasms; it often is secreted by granulosa cells and Sertoli cells of the ovary, and serum levels may be elevated in sex cord-stromal tumors.2,3
Markedly elevated DHEA levels can cause the signs and symptoms of hyperandrogenism in girls. Most mild elevations in DHEA levels are idiopathic but often are encountered in polycystic ovaries and may indicate increased androgen production from an ovarian or adrenal source.7-9 Our patient had no adrenal masses or cystic changes of the ovaries, and her DHEA levels decreased after excision of the tumor. The sulfated ester of dehydroepiandrosterone (DHEA-S) is predominantly of adrenal origin.7,9DHEA-S is measured more frequently than DHEA because of its stable plasma levels and longer half-life, but in most clinical situations the tests may be used interchangeably.8,10 Even though DHEA is produced mostly by the adrenal glands, very high levels of DHEA in prepubertal girls should prompt a search for an adrenal cause (such as a hormone-secreting adrenal tumor11 or congenital adrenal hyperplasia) or ovarian sources, because ovarian tumors also may produce elevated DHEA, as in our patient’s case.
Changes suggestive of precocious puberty in infants should alert to the possibility of underlying adrenal or ovarian tumors, despite their rarity. Evaluation of levels of hormones such as estrogen, testosterone, DHEA, and DHEA-S may confirm suspicions and differentiate between an adrenal or ovarian pathology, but clinicians should be aware that undifferentiated tumors of the ovaries do not always follow strict hormonal rules and may produce DHEA, as seen in our patient. Further studies are necessary to evaluate the usefulness of DHEA as tumor marker in the diagnosis of undifferentiated virilizing ovarian malignancies.
Andrew Faniku, MD, is a pediatrician at San Felipe Health Centers in Del Rio, Texas.
Osvaldo Regueira, MD, is an associate professor of pediatric hematology and oncology at Texas Tech University Health Sciences Center in Amarillo, Texas.
Michael Okogbo, MD, is a pediatrician at Scott & White Healthcare in Killeen, Texas.
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7. DHEAS. American Association for Clinical Chemistry Lab Tests Online. https://labtestsonline.org/understanding/analytes/dheas/tab/test. Updated February 24, 2015. Accessed August 6, 2015.
8. Dehydroepiandrosterone sulfate (DHEA-S), serum. Mayo Medical Laboratories. http://www.mayomedicallaboratories.com/test-catalog/Overview/8493. Accessed August 6, 2015.
9. Dehydroepiandrosterone and dehydroepiandrosterone sulfate. University of Rochester Medical Center Health Encyclopedia. https://www.urmc.rochester.edu/encyclopedia/content.aspx?ContentTypeID=167&ContentID=dhea. Accessed August 6, 2015.
10. DHEA-SO4: Siemens Immulite 2000. http://labmed.ucsf.edu/labmanual/db/resource/proc-DHEA-S_SeimensImmulite.pdf. Accessed August 6, 2015.
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