Diagnostic Conundrum of a Sertoli Cell Tumor in a 2-Year-Old Girl with Peripheral Precocious Puberty and a Café-au-Lait Macule: A Case Report

Abstract

Introduction

Ovarian Sertoli cell tumors represent a subset of sex cord stromal tumors and are exceedingly rare in prepubertal children. Here, we report a girl with vaginal bleeding due to a Sertoli cell tumor who was originally thought to have McCune-Albright syndrome (MAS).

Case Presentation

A previously healthy girl presented at age 2 years 6 months with breast development and vaginal bleeding. On exam, she had Tanner 4 breasts, Tanner 1 pubic hair, estrogenized vaginal mucosa, and a café-au-lait macule. Laboratory studies revealed an elevated estradiol with suppressed gonadotropins and negative tumor markers. Her bone age was advanced by more than 3 years. Pelvic ultrasound (US) revealed an enlarged uterus and a slightly larger left compared to right ovary. She was started on tamoxifen for presumed MAS. A repeat pelvic US 1 month later showed a heterogenous mass in the left ovary which was subsequently resected. Pathology revealed a Sertoli cell tumor, lipid-rich variant. Germline sequencing revealed a pathogenic STK11 variant, diagnostic for Peutz-Jeghers syndrome (PJS).

Conclusion

The findings in our patient were strikingly similar to those encountered in MAS. To our knowledge, our patient is the youngest ever reported to present with precocious puberty due to a Sertoli cell tumor in the setting of PJS.

Established Facts

• Peripheral precocious puberty is caused by excess exposure to sex steroids independent of gonadotropin stimulation.

• Girls with McCune-Albright syndrome develop recurrent unilateral ovarian cysts.

Novel Insights

• Sertoli cell ovarian tumors are exceedingly rare in prepubertal children.

• Serial ovarian imaging is essential to rule out ovarian tumors in prepubertal girls with vaginal bleeding for which the etiology is unclear.

Introduction

McCune-Albright syndrome (MAS) is a rare disorder with an estimated prevalence of 1 in 100,000–1,000,000 individuals [1, 2]. The diagnosis is based on clinical findings characterized by a classic triad of peripheral precocious puberty (PPP), café-au-lait macules, and fibrous dysplasia of bone [3]. However, some patients have an atypical or forme fruste variant in which not all the classic features are present [4]. In girls with MAS, vaginal bleeding is due to estrogen withdrawal from large unilateral ovarian cysts that can be mistaken for ovarian neoplasms on pelvic imaging [5]. Therapeutic options for the treatment of precocious puberty in girls with MAS include tamoxifen or the aromatase inhibitor letrozole [4, 6].

Ovarian tumors are extremely rare in premenarchal girls, with an estimated incidence of 2.6 cases per 100,000 per year [7]. These can present with PPP characterized by excess androgens or estrogen in addition to abdominal pain, a palpable mass, and gastrointestinal complaints [7]. Germ cell tumors are most common, followed by surface epithelial stromal tumors and sex cord stromal tumors such as a Sertoli cell tumor [7]. Interestingly, tumor markers are positive in only 54% of cases [7]. Thus, negative tumor markers with indeterminate imaging in the context of PPP create a diagnostic challenge.

Here, we report a girl with breast development and vaginal bleeding due to a Sertoli cell tumor in the setting of Peutz-Jeghers syndrome (PJS) who was originally thought to have MAS. This case illustrates the importance of serial pelvic ultrasounds (USs) when the etiology of PPP is unclear.

Case Presentation

A previously healthy girl was referred to our pediatric endocrinology clinic at age 2 years 6 months for evaluation of precocious puberty. Eight months prior, she developed breast buds followed by monthly vaginal bleeding for 3 months with associated breast tenderness, abdominal pain, rapid growth, and moodiness. Her physical exam (shown in Fig. 1) revealed Tanner 4 breasts, Tanner 1 pubic hair, and estrogenized vaginal mucosa. A café-au-lait macule with irregular borders was noted on her right scapula. She did not have acne or clitoromegaly. She had a paternal great grandmother with an unspecified pituitary tumor and hirsutism as well as several relatives with type 2 diabetes. There was no known family history of genetic syndromes or endocrine disorders in children.

Fig. 1.

Physical exam findings. Breast development (a), café-au-lait macule on the right scapula (b), and oral mucocutaneous lentigines on the bottom lip (c) of the patient.

As seen in Table 1, laboratory studies showed an elevated estradiol level of 520 pg/mL with suppressed gonadotropins, normal androgens, and negative tumor markers (lactate dehydrogenase, alpha fetoprotein, inhibin A and B, anti-mullerian hormone). Her bone age was advanced to 5 years 9 months with a bone age-to-chronologic age ratio of 2.2. A technetium bone scan was normal. Her initial pelvic US revealed an enlarged uterus measuring 5.7 cm with a thickened endometrial stripe of 20 mm and a slightly larger left ovary (3.0 cm) compared to the right (1.9 cm). A repeat pelvic US was notable for an enlarging yet homogenous 10 mL left ovary without a dominant cyst or discrete mass and small cysts on the right ovary. She was cautiously diagnosed with a forme fruste of MAS and started on tamoxifen 10 mg daily. Genetic testing for MAS was not undertaken.

Table 1.

Laboratory workup

Endocrine labs	Reference range	Tumor markers	Reference range
LH, 0.06 mIU/mL	0.02–0.3	LDH, 228 units/L	140–271
LH-ECL, 0.075 mIU/mL	0.02–0.3	AFP, 2.2 ng/mL	0.0–25.0
FSH, 0.066 mIU/mL	1.0–4.2	Beta-hCG <0.6 mU/L	≤4.9
Estradiol, 520 pg/mL	<20	Inhibin A, 7 pg/mL	<7–69*
Total testosterone, <10 ng/dL	<10	Inhibin B, 38 pg/mL	1–182
17-Hydroxyprogesterone, 20.8 ng/dL	≤256	AMH, 2.452 ng/mL	0.256–6.345

Abnormal values are shown in bold.

AFP, alpha fetoprotein; AMH, anti-mullerian hormone; FSH, follicle-stimulating hormone; ECL, electrochemiluminescence; hCG, human chorionic gonadotropin; LDH, lactate dehydrogenase; LH, luteinizing hormone.

*Reference range for Tanner stage 4 girls.

A pelvic US obtained 1 month later showed a 26-mm endometrial stripe and the left ovary now measuring 18 mL with a heterogenous mass juxtaposed to normal tissue. Her tamoxifen was discontinued. She underwent a diagnostic laparoscopy with ovary-sparing resection of the mass. Pathology revealed a 4.5 × 4.0 × 2.0-cm Sertoli cell tumor, lipid-rich variant classified as stage 1a and treated with surgical resection only (shown in Fig. 2). Genetic testing revealed a de novo heterozygous pathogenic variant in STK11 (c.540dup) as shown in Figure 3, a mutation only previously reported once and diagnostic of PJS. Subsequent estradiol levels were undetectable, pelvic US showed regression of her uterus and ovaries to prepubertal measurements, and a repeat bone age obtained 1 year later showed reduction in bone age-to-chronologic age ratio to 1.7. She developed oral mucocutaneous lentigines, characteristic of PJS, which were not seen on her initial exam 14 months prior (shown in Fig. 1c).

Fig. 2.

Surgical findings. Yellow lobulated Sertoli cell tumor (a) with the lipid-rich variant (b).

Fig. 3.

Sequence image of the pathogenic STK11 variant with purple “I” indicating the heterozygous c.540dup.

Discussion

PPP is caused by exposure to sex steroids independent of gonadotropin stimulation. Etiologies of PPP in girls include MAS, ovarian tumors, exogenous exposure to sex hormones, and adrenal pathology such as congenital adrenal hyperplasia. In our patient, there was no history of exogenous hormone exposure, and her findings clearly indicated a process involving excess estrogen.

The clinical and biochemical findings in our patient were strikingly similar to those seen in MAS including her enlarged uterus and ovarian asymmetry visualized on US. Ovarian cysts in MAS can be easily missed on imaging due to spontaneous resolution. Foster et al. [8] performed a study investigating ovarian function in 8 girls with MAS, half of whom had the classic triad. Six girls had ovarian cysts and five had asymmetric ovaries seen on pelvic US [8]. One girl previously had an oophorectomy due to a large cyst and later developed cysts in the remaining ovary [8]. Similarly, Nabhan et al. [5] reported 9 girls with vaginal bleeding due to MAS, of whom only 3 had the classic triad. Of the 6 who had pelvic USs performed, all had an enlarged uterus and 5 had a unilateral ovarian cystic mass [5]. Four girls had subsequent unilateral oophorectomies due to concerns for ovarian tumors, and all pathology reports showed benign cysts [5]. These case series highlight that findings on ovarian imaging are nonspecific and indicate the need for a period of US surveillance in girls with vaginal bleeding and asymmetric ovaries as the abnormalities will resolve if due to MAS. Establishing the correct diagnosis is essential as girls with MAS have normal fertility potential and thus oophorectomies are contraindicated [9].

There are many overlaps in presentation between MAS and ovarian neoplasms such as juvenile granulosa cell tumors [5]. As in our patient, both pathologies can present with PPP, elevated estradiol levels, normal tumor markers, and an advanced bone age [5]. Our patient had a café-au-lait macule and recurrent vaginal bleeding in favor of MAS, and while she did not have evidence of fibrous dysplasia, her young age did not make this surprising. Interestingly, there have been several reports of patients with MAS developing oral melanotic pigmentation mimicking those seen in PJS and Carney complex [9–12]. In our patient, her mucocutaneous lentigines were not present on her initial exam but only became apparent during follow-up.

While our patient’s imaging showed asymmetric ovaries, she did not develop an identifiable mass until her third pelvic US. Oliva et al. [13] reported a series of 54 ovarian Sertoli cell tumors measuring 0.8–30 cm in females aged 2–76 years. Of 6 cases found in girls that presented with estrogen-driven precocious puberty, half had developed vaginal bleeding prior to diagnosis [13]. Within the entire cohort, 6 patients were also found to have PJS – of whom three were prepubertal [13].

PJS is an autosomal dominant cancer predisposition syndrome characterized by hamartomatous gastrointestinal polyps and mucocutaneous pigmentation [14, 15]. PJS has an estimated prevalence of 1 in 50,000–200,000 individuals [14, 15]. The pigmented lesions, termed mucocutaneous lentigines, are most often the initial presenting symptom and nearly always present before age 5 years [14, 15]. The most common ovarian tumor associated with PJS is a sex cord tumor with annular tubules, and the literature suggests that it develops in the majority of women with PJS [15, 16]. While Sertoli cell tumors are known to be associated with PJS, the average age at diagnosis is 30 years [17]. Similar cases of lipid-rich Sertoli cell tumors have been reported in girls aged 4 and 4.5 years with breast development and PJS, both of whom had lower estradiol levels of 62.3 and 102 pg/mL respectively as compared to our patient [18, 19]. Only the latter of these two patients had oral mucocutaneous lentigines at initial presentation [19].

Ultimately, the diagnosis of an ovarian tumor was made in our patient due to persistent radiographic monitoring. While cystic lesions are much more suggestive of MAS, the solid ovarian mass noted in our patient pointed toward a neoplastic process. She is being followed by pediatric oncology with surveillance USs and has shown no signs of recurrence 1 year later. To our knowledge, our patient is the youngest ever reported to present with PPP due to a Sertoli cell tumor in the setting of PJS and illustrates the importance of serial pelvic USs when the diagnosis is unclear.

Statement of Ethics

Ethical approval is not required for this study in accordance with local or national guidelines. We state that the subject and her parents have given their written informed consent for the publication of the details of her medical case and any accompanying images.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

This study was not supported by any sponsor or funder.

Author Contributions

L.A.R. was the primary pediatric endocrinologist who coordinated care and wrote the manuscript. D.F.B. was the pediatric surgeon who performed the resection and edited the manuscript. M.J.F. was the pediatric oncologist who followed the patient and edited the manuscript. E.A.E. was consulted throughout the patient’s evaluation, provided supervision, and edited the manuscript.

Funding Statement

This study was not supported by any sponsor or funder.

Data Availability Statement

The data that support the findings of this study are not publicly available due to their containing information that could compromise the privacy of the research participant but are available from L.A.R. upon reasonable request.