Abnormal fetal genitalia: two- and three-dimensional ultrasound assessment

Introduction

There have been several studies on prenatal three-dimensional (3D) ultrasound diagnosis of fetal abnormal external genitalia [1], [2], [3], [4], [5], [6], [7]. The incidence of external genital anomalies of the fetus is 0.6 %, with the degree of agreement between pre- and postnatal diagnoses of external genital anomalies being high (94.3 %) using two- (2D) or 3D dimensional ultrasound [8]. Fernandez et al. [9] reported that 3D ultrasound provides the best information to evaluate the external genitals and their anatomical relations. However, overall 2D sonography with 3D ultrasound showed a trend toward higher performance compared with 2D sonography alone for the prenatal diagnosis of hypospadias, although the difference was not significant [10]. Three-dimensional ultrasound is not a more effective modality to diagnose hypospadias, but it may provide additional information to explain the findings of hypospadias better to parents and neonatologists [11]. Therefore, the usefulness of 3D ultrasound to diagnose abnormal external fetal genitalia remains controversial. In the current investigation, we evaluated the incidence of abnormal external genitalia and discussed the accuracy of prenatal diagnosis using 2D and 3D ultrasound in second- and third-trimester fetal screenings.

Materials and methods

During the 24 months from February 2023 to January 2025, second- and third-trimester fetal screenings were performed by six JSUM (Japan Society of Ultrasonics in Medicine) Registered Medical Sonographers at 18–21+6 and 28–31+6 weeks of gestation, respectively, in 1,623 pregnant women. Second- and third-trimester fetal screenings were performed using 2D ultrasound according to ISUOG Guidelines [12], 13]. When abnormal external genitalia were suspected, fetal external genitalia were assessed by a Senior Fellow of JSUM (T.H.) using 2D and 3D ultrasound with HDlive or HDlive Studio (GE Healthcare, Voluson Expert22 BT22 or BT24, Zipf, Austria). Antenatal counselling was conducted by a pediatric expert (Y.N.). After birth, cross-examination was performed by a pediatric expert (Y.N.) to check the external genitalia. Genetic testing was not conducted antenatally and postnatally.

The study was conducted following approval by the Ethics Committee of Miyake Clinic, Okayama, Japan. All participants provided informed consent after a full explanation of the aim of the study.

Results

Twelve cases of abnormal genitalia (hypospadias: 3; hypospadias with penoscrotal web: 1; micropenis: 3; buried penis: 2; clitoromegaly: 2; genital tumor: 1) were suspected prenatally (0.74 %). All cases except for Case 6 (only 2D ultrasound was used in this case) were diagnosed with both 2D and 3D ultrasound. Clinical and birth characteristics are shown in Table 1. Three cases were diagnosed during second-trimester screening, and 9 were detected in third-trimester screening. The mean gestational age at confirmation of the diagnosis was 28.7 weeks (SD: 3.0). The mean maternal age was 29.6 y. o. (SD: ±5.6), median para was 0.5 (range: 0–2), mean birth age was 39.0 weeks (SD: ±1.3), and mean birth weight was 3,026.8 g (SD: ±392.6). Nine were male, and 3 were female. Apgar scores at 1 and 5 min were 8 (range: 6–9) and 9.5 (range: 9–10), respectively. The umbilical artery pH was 7.31 (SD: ±0.07). Nine involved vaginal delivery and 3 underwent cesarean section.

In 9 fetuses with suspected abnormal male genitalia, the penile length was below the lower 90th confidence interval [14] (Table 1). Only 6 cases of abnormal male genitalia (2 hypospadias (Cases 1 and 6), 1 penoscrotal web with mild chordee (Case 3), 1 micropenis (Case 4), and 2 buried penises (Case 8 and 9) were diagnosed postnatally (66.7 %) (Figures 1–6), whereas 3 (Case 2, 5, and 7) were diagnosed as normal after birth (ultrasound in second- and third-trimester fetal screenings. 7). The “tulip sign” was seen in Case 1, 2, and 6 (Figure 1). In 4 cases (Case 1, 4, 6, and 9), prenatal and postnatal diagnoses were same, whereas prenatal and postnatal diagnoses were different in 2 cases (Case 3 and 8) (Table 1).

Figure 1:

Two- (A) and three- (B) dimensional ultrasound images of hypospadias at 31 weeks and 6 days of gestation (Case 1). Arrows indicate a short penile shaft with blunt tip. The tulip sign was noted using both two- and three-dimensional ultrasound.

Figure 2:

Hypospadias after birth (Case 1). Mixed gonadal dysgenesis (45X/46XY) with a right cord gonad was diagnosed.

Figure 3:

Two- (A) and three- (B) dimensional ultrasound images of a micropenis (arrows) at 29 weeks and 3 days of gestation (Case 4).

Figure 4:

A micropenis after birth (Case 4).

Figure 5:

Two- (A) and three- (B) dimensional ultrasound images of suspected hypospadias with a penoscrotal web at 31 weeks and 6 days of gestation (Case 3). Small arrows indicate a short penile shaft. The large arrow shows a penoscrotal web (B). The penoscrotal web and mild chordee were identified after birth. However, hypospadias was not detected.

Figure 6:

Two- (A) and three- (B) dimensional ultrasound images of a suspected buried penis (arrows) at 29 weeks of gestation (Case 9). Buried penis was noted after birth.

Mixed gonadal dysgenesis (45X/46XY) was diagnosed in 1 neonate with hypospadias (Case 1). In 1 neonate with a penoscrotal web and mild chordee (Case 3), he was doing well at the time of writing without any treatment or surgery. One neonate with a micropenis had a right aortic arch and persistent foramen ovale (Case 4). In this neonate, the karyotype was 46XY, and hormonal results were normal. Penile lengths at 1 and 6 months after delivery were 1.4 and 2.4 cm, respectively. The neonate was doing well at the time of writing. In one neonate with hypospadias (Case 6), he was doing well at the time of writing without any treatment or surgery. Concerning 2 neonates with a buried penis (Case 8 and 9), they were also doing well at the time of writing without any treatment or surgery.

In 2 fetuses with suspected clitoromegaly (Cases 10 and 11), the clitoral length was above 6.5 mm [15] (Table 1). In both cases, the “horseshoe sign” was evident using 3D ultrasound (Figures 8 and 9). However, the external female genitalia were normal after birth.

Figure 7:

Two- (A) and three- (B) dimensional ultrasound images of a suspected buried penis (arrows) at 29 weeks and 2 days of gestation (Case 7). Neonatal external genitalia were normal after birth.

Figure 8:

Two- (A) and three- (B) dimensional ultrasound images of transient clitoromegaly (arrows) at 29 weeks and 5 days of gestation (Case 10). The “horseshoe sign” was evident using 3D ultrasound (B). Neonatal external genitalia were normal after birth.

Figure 9:

Two- (A) and three- (B) dimensional ultrasound images of transient clitoromegaly (arrows) at 29 weeks and 2 days of gestation (Case 11). The “horseshoe sign” was evident using 3D ultrasound (B). Neonatal external genitalia were normal after birth.

In 1 fetus with an external genital tumor, a round echogenic mass (38 x 37 mm) was noted on the anal side of the pudendal slit at 27 weeks and 1 day of gestation (Figure 10A) (Table 1). Three-dimensional ultrasound revealed a round mass on the female genitalia (Figure 10B). The size of this mass remained unchanged with advancing gestation, and disappeared at 36 weeks and 1 day. After birth, the external female genitalia were normal.

Figure 10:

Two-dimensional sonographic image of a female external genital mass (arrow) (A) at 27 weeks and 1 day and a three-dimensional ultrasound image (arrow) (B) at 31 weeks and 1 day of gestation (Case 12). Neonatal external genitalia were normal after birth.

In normal male and female fetuses in the third trimester as a comparison, 2D and 3D ultrasound clearly showed normal genitalia (Figures 11 and 12).

Figure 11:

Two- (A) and three- (B) dimensional ultrasound images of normal male genitalia at 28 weeks and 4 days of gestation.

Figure 12:

Two- (A) and three- (B) dimensional ultrasound images of normal female genitalia at 29 weeks and 4 days of gestation.

Discussion

The positive predictive value for the prenatal sonographic diagnosis of hypospadias was 73.3 %, and the positive predictive value of prenatal ultrasound for any abnormal external genitalia was 90 % [16]. The overall positive predictive values of 2D sonography in diagnosing fetal hypospadias and external genital malformations were 81 and 88 %, respectively [17]. Moreover, the accuracy of 2D sonography with 3D ultrasound was 84 %, whereas that of 2D sonography alone was 74 % [16]. Cursino et al. [18] reported that when the external genitalia were female or poorly virilized, prenatal sonography indicated a female sex, but in cases with a higher degree of virilization, sonography showed similar rates of male, female, or undetermined sex. The accuracy of the prenatal diagnosis of external genital anomalies was 94.3 % [8]. In the current study, the accuracy of the prenatal diagnosis of male external genital abnormalities was 66.7 % using 2D sonography with 3D ultrasound. The reason for the difference in the accuracy of prenatal 2D and 3D sonographic diagnosis of abnormal external genitalia of the fetus among the current study and previous investigations is currently unknown. Uygur et al. [16] suspected that a slightly less specific diagnosis of hypospadias reflects overlapping ultrasound findings of different external genital anomalies. Certainly, 2D and 3D ultrasound features of hypospadias, a buried penis, and micropenis were very similar in the current study (Figures 1–7). Three cases (Case 2, 5, and 7) were diagnosed as normal after birth, and prenatal and postnatal diagnoses were different in 2 cases (Case 3 and 8). In only 4 cases (Case 1, 4, 6, and 9), prenatal and postnatal diagnoses were same in this study. Moreover, the penile length was below the lower 90th confidence interval [14] in 9 fetuses with suspected abnormal male genitalia in the current study. The reference range used in this study was from Israeli male fetuses [14] because there were no appropriate reference ranges for Japanese male fetuses. There are marked differences in fetal penile length among different races [19]. This may be another reason for the lower accuracy of prenatally diagnosing male external genital abnormalities in the current study. In this study, there were no severe abnormal external genitalia in any of the 6 male cases diagnosed after birth. This may also be another reason for the lower accuracy of prenatal diagnosing male external genital abnormalities. Further studies using new diagnostic criteria involving high-end 2D and 3D ultrasound are mandatory to improve the accuracy of diagnosing abnormal external genitalia.

In the current study, one case of mixed gonadal dysgenesis (45X/45XY) with hypospadias was noted (Case 1). Its rate is less than 1 per 15,000 births [20]. The majority of fetuses (80 %) with a 45X/46XY genotype present with a male phenotype and normal male genitalia [21]. However, other fetuses present with hypospadias, a micropenis, an abnormal scrotum, unilateral cryptorchidism, or a scrotal hydrocele in phenotypic males [21]. In our case, hypospadias and a right cord gonad were noted after birth. However, there were no other anomalies. The neonate was doing well at the time of writing.

Castets et al. [15] proposed that fetal clitoromegaly can be defined as a clitoral length >6.5 mm. In 2 fetuses with suspected clitoromegaly in this study, the clitoral length exceeded 6.5 mm early in the third trimester. Moreover, the “horseshoe sign” as a characteristic feature of clitoromegaly by 3D ultrasound was evident in both fetuses. However, neonatal external genitalia showed a normal female appearance. Zimmer et al. [22] reported fetal transient clitoromegaly and transient hypertrophy of the labia minora in early and mid-pregnancy. Cheikhelard et al. [23] reported 16 fetal clitoromegaly cases diagnosed at 19.5–34 weeks, of which 10 were transient. The cause of the transient clitoromegaly is unknown. Zimmer et al. [22] suggested that transient changes in the size of the fetal clitoris may occur in parallel with transient hormonal changes in the immature adrenal glands. Mitani-Konno et al. [24] reported that transient clitoral preputial edema is often mistaken for clitoromegaly in neonates. The mechanism of transient clitoral preputial edema is also unknown. One possible explanation for it is maternal estrogen exposure during pregnancy, which causes hymenal polyps, because the incidence of such polyps in their study was 71 % [24] whereas it was 6–13 % in normal female neonates [25], 26].

Zhang et al. [27] reported prenatal 2D sonographic diagnosis of congenital hymen prolapse as an external iso-echoic genital mass at 32 weeks and 1 day of pregnancy. After birth, the hymen gradually returned, and genitalia became normal. Mor et al. [25] reported a high incidence of hymen tags (polyps) (5.75 %) and hymen bands (2.7 %) within the first 24 h of newborn life; hymen tags usually disappear spontaneously as the effects of maternal estrogen diminish. In the current study, we were the first to demonstrate a female external genital mass using 2D and 3D ultrasound at 27 weeks and 1 day of gestation. The size of this mass remained unchanged with advancing gestation, and it disappeared at 36 weeks and 1 day. After birth, external female genitalia were normal. These findings suggest that the female external genital mass in our case might have been a hymen prolapse or tags (polyps). Further studies may be needed to classify fetal female external genital variations using 2D and 3D ultrasound in order to differentiate normal from abnormal female genitals.

Prenatal diagnosis of abnormal external genitalia may still be difficult even with the use of 3D ultrasound. Race-based fetal reference ranges of penile and clitoral sizes may be necessary to more accurately evaluate abnormal external genitalia. Furthermore, postnatal cross-examination by pediatric experts should be mandatory when abnormal external genitalia are suspected prenatally.