Virilization in a female infant born to a mother with an ovarian steroid cell tumor

Steroid cell tumors are rare ovarian neoplasms, accounting for <0.1% of all ovarian tumors. When they produce androgens, pregnant women may develop virilization due to hyperandrogenism.1 Reports also describe virilization in female fetuses when mothers have ovarian tumors with hyperandrogenism.2 We report a case of virilization in a female infant born to a mother with a steroid cell tumor. A female infant was delivered at 32 + 6 weeks, weighing 2106 g, by emergency cesarean section. During pregnancy, a 9-cm subserosal fibroid had been noted, but at delivery, the mass was found to be an ovarian tumor and was resected. The infant was born without asphyxia (Apgar scores 8/9) and admitted to the NICU with oxygen supplementation. She was appropriate for gestational age. At admission, clitoromegaly was noted without pigmentation, with no other external malformations (Figure 1). Ultrasonography revealed normal head and cardiac findings, confirmed the presence of the uterus and vagina, and showed no testis-like structures. Laboratory tests revealed no electrolyte or glucose abnormalities. The respiratory disorder was diagnosed as transient tachypnea of the newborn and resolved with supportive care. For evaluation of clitoromegaly, hormone levels were measured on day 1 of life, showing an ACTH level of 65.5 pg/mL. Hydrocortisone (2 mg/kg/day) was initiated for suspected congenital adrenal hyperplasia, but 17-hydroxyprogesterone was not elevated and ACTH decreased to 14.8 pg/mL by day 4. Hydrocortisone was tapered from day 9 and discontinued on day 16. Serum testosterone was elevated at 5.42 ng/mL on day 1 and declined to 0.41 ng/mL by day 5 (normal range in women: 0.15–0.46 ng/mL). Chromosomal G-banding on day 0 revealed a 46,XX karyotype. Based on these results and the clinical course, the patient was diagnosed as a female infant with virilization. Urinary steroid profile on day 0, obtained before steroid therapy, showed a 21-deoxycortisone metabolite of 0.01, excluding P450 oxidoreductase (POR) deficiency. Brain MRI at 42 days was normal. The infant was discharged on day 49 (corrected 39 + 6 weeks) at 3072 g, with follow-up for disorders of sex development arranged at a specialized institution. The maternal ovarian tumor resected at cesarean section was pathologically diagnosed as a steroid cell tumor. Maternal stored serum showed markedly elevated testosterone of 250 ng/mL the day before delivery (32 + 5 weeks), which decreased to 1.04 ng/mL immediately after. Postpartum interviews revealed increased facial, abdominal, and chest hair, worsening acne, and early pregnancy hoarseness, indicating maternal virilization during gestation. In this case, a female infant born to a mother with an ovarian steroid cell tumor exhibited signs of virilization. Although maternal ovarian steroid cell tumors causing fetal virilization have been reported,3 our case uniquely demonstrated a serial decrease in the infant's serum testosterone, providing direct evidence of transplacental testosterone transfer. As congenital adrenal hyperplasia was excluded, possible factors to be considered when both the mother and infant show virilization include fetal aromatase deficiency, POR deficiency, or maternal androgen excess.4 In the present case, POR deficiency was excluded based on the results of the urinary steroid profile. Regarding aromatase deficiency, which is a rare disorder, affected neonates with virilization typically present not only with external genital abnormalities but also with findings such as polycystic ovaries and decreased bone mineral density.5 However, none of these abnormalities were observed during the hospitalization at our institution in this case. With respect to maternal androgens, the clinical course suggested excessive testosterone production due to an ovarian steroid cell tumor, which was considered the most likely cause of virilization. Steroid cell tumors account for <0.1% of ovarian tumors; 56–77% of affected pregnant women show virilization.3 Normally, maternal testosterone is thought to have little effect on the fetus because it is converted to estrogen by placental aromatase. However, there have been reports of maternal ovarian tumors, such as steroid cell tumors and luteomas, associated with hyperandrogenism during pregnancy in which female fetuses developed virilization.2, 3 Excess androgens exceeding placental aromatase capacity may have crossed the placenta and affected the fetus. In the present case, it is possible that a similar mechanism led to the virilization of the female infant. Continued detailed evaluation of this patient may provide further insights into the mechanisms underlying fetal virilization. M.A. and K. F. drafted the manuscript and figures. M.A., Y.M., S.O., M.D., and K.F. provided patient care. M.D. and K.N. provided clinical advice. All authors critically reviewed the manuscript, approved the final manuscript for submission, and agreed to be accountable for all aspects of the report. During the preparation of this work, the authors used ChatGPT (OpenAI) in order to improve the English translation of the manuscript. After using this tool, the author(s) reviewed and edited the content as needed and took full responsibility for the content of the published article. The authors declare no conflict of interest. Informed consent was obtained from the parents for the publication. The data that support the findings of this study are available from the corresponding author upon reasonable request.