Swyer Syndrome With Coexisting Germ Cell Neoplasia In Situ and Gonadoblastoma

CASE REPORT

A 15-year-old patient assigned female at birth presented to our outpatient department for evaluation of primary amenorrhea. She was born of a nonconsanguineous marriage. No genital ambiguity was noted at birth, and she had an uneventful childhood. The patient's mother noticed breast development during the prior year but perceived the development to be inadequate. The patient denied the use of exogenous sex steroids. She had no history of cyclical abdominal pain, inguinal or labial swellings, hernia, or pubertal virilization. Gender identity and social role were consistent with the female sex.

Examination revealed a young female with normal vital signs, height of 160.5 cm (+0.38 standard deviation score for females and –0.72 standard deviation score for males), weight of 57.1 kg, and body mass index of 22.2 kg/m². Mid-parental height was 163.5 cm for a female and 176.5 cm for a male child. The upper segment to lower segment ratio was 0.84, and the arm span was 168 cm. Sexual maturity rating revealed Tanner stage 3 breast and Tanner stage 3 pubic hair development, with scant axillary hair. The patient had a normal feminine voice and unambiguous female external genitalia. External masculinization score was 1/12, and Prader score corresponded to stage 0. Complete blood count, liver function tests, kidney function tests, and routine urine examination were normal. Hormonal investigations revealed hypergonadotropic hypogonadism (Table) and karyotype was 46,XY (Giemsa banding; 30 cells analyzed). Bone age corresponded to 13 years in a female child and 14 years in a male child, according to the Greulich and Pyle method.

Given primary amenorrhea in an unambiguous female with a 46,XY karyotype, we considered the following differentials: (1) complete gonadal dysgenesis, (2) complete androgen insensitivity syndrome, and (3) androgen biosynthetic defects such as Leydig cell hypoplasia. The pattern of gonadotropin elevation (follicle-stimulating hormone >> luteinizing hormone, with predominant luteinizing hormone elevation expected in complete androgen insensitivity syndrome and Leydig cell hypoplasia); low anti-Müllerian hormone levels (often normal or elevated in complete androgen insensitivity syndrome and Leydig cell hypoplasia); and female-range testosterone levels (elevation to male range in complete androgen insensitivity syndrome) clearly favored complete gonadal dysgenesis vs other etiologies. The patient's neuropsychological assessment, electrocardiography, echocardiography, and pure-tone audiometry (to evaluate for organ dysfunction associated with gonadal dysgenesis) were normal.

Magnetic resonance imaging (MRI) of the pelvis revealed a prepubertal uterus measuring 14 × 47 × 32 mm, maintained endometrial-myometrial differentiation, endometrium thickness of approximately 3 mm, and a corpus to cervix ratio <1. Bilateral streak gonads were noted in the region of the ovarian fossa (Figure 1). Clinical exome sequencing did not reveal any pathogenic variant in genes known to cause gonadal dysgenesis (eg, SRY, NR5A1/SF1, SOX9, MAP3K1, WT1, DHH, DMRT1, ATRX, GATA4). Fluorescence in situ hybridization performed to look for large SRY [Yp11.3] deletion revealed a 46,XY karyotype with the presence of the SRY gene. Thus, the genetic workup was negative for the common causes of complete gonadal dysgenesis.

• Download figure
• Open in new tab
• Download PowerPoint

Figure 1.

(A) T2 sagittal magnetic resonance image of the pelvis shows a small prepubertal uterus (corpus [red arrowhead], cervix [blue arrow]), a corpus to cervix ratio <1, and a vagina (green arrow). (B, C) T2 fat-suppressed axial views show bilateral streak gonads (green arrows).

The patient and her family were informed regarding the nature of the disorder and the need for bilateral gonadectomy. Future fertility options in the form of an ovum donation pregnancy were also discussed. The patient underwent laparoscopic gonadectomy, and the streak gonads were removed through the 10 mm central port in an endobag. Histopathology suggested germ cell neoplasia in situ in the left gonad (Figure 2) and gonadoblastoma in the right gonad (Figure 3).

• Download figure
• Open in new tab
• Download PowerPoint

Figure 2.

Photomicrographs of the left gonad with hematoxylin and eosin staining show germ cell neoplasia in situ (arrows) at (A) 20 × magnification and at (B) 50 × magnification. (C) Sex cord stromal cells show positive inhibin B staining (arrowhead).

• Download figure
• Open in new tab
• Download PowerPoint

Figure 3.

Photomicrographs of the right gonad with hematoxylin and eosin staining show gonadoblastoma at (A) 40× magnification and at (B) 200× magnification, with the tumor comprising well-defined calcified nests (black arrow) intermingled with round to angulated sex cord cells and germ cells (white arrow). Sex cord cells form a palisade at the periphery and are surrounded by a basement membrane deposit (Call–Exner bodies [arrowhead]). (C) Sex cord stromal cells show positive inhibin B staining. (D) Germ cells show positive Ki-67 staining.

The patient's postoperative course was uneventful, and at week 4, she began hormone replacement therapy with estradiol valerate (1 mg per day), with a plan to monitor pubertal progression, escalate to adult doses over a period of 1 to 2 years, and add progesterone once her breasts reach Tanner stage 5.