Patients with ovotesticular disorder of sex development (DSD) and mixed gonadal dysgenesis (MGD) usually present with asymmetric gonads and have wide phenotypic variations in internal and external genitalia. The differential diagnosis of these conditions is based on karyotype and pathological findings of the gonads. This study investigated the clinical features at presentation, karyotype, sex of rearing, and pubertal outcomes of patients with ovotesticular DSD and MGD.
The study comprised 23 patients with DSD who presented with asymmetric gonads. The presenting features, karyotype, sex of rearing, and pubertal outcomes were reviewed retrospectively.
All 23 patients presented with ambiguous genitalia at a median age of 1 month (range, 1 day–1.6 years). Müllerian duct remnants were identified in 15 of 23 patients (65.2%). Fourteen patients were diagnosed with ovotesticular DSD, whereas the other 9 were diagnosed with MGD. Eight of 14 patients (57.1%) with ovotesticular DSD were raised as males, while 7 of 9 patients with MGD (77.8%) were assigned as males. One male-assigned patient with ovotesticular DSD changed to female sex at age 20 years.
Patients with ovotesticular DSD and MGD manifest overlapping clinical presentations and hormonal profiles. It is difficult to determine the sex of rearing and predict long-term pubertal outcomes. Therefore, long-term follow-up is required to monitor spontaneous puberty, sex outcome, and urological and gynecological complications.
Disorders of sex development (DSD) can be classified into 46,XY DSD; 46,XX DSD; and sex chromosome DSD [
Patients who present with asymmetric gonads may be diagnosed with ovotesticular DSD or mixed gonadal dysgenesis (MGD). Ovotesticular DSD is defined as presence of both ovarian and testicular tissues in the same individual and may be classified as 46,XX DSD or 46,XY DSD, whereas MGD refers to individuals presenting with a differentiated testis on one side and a dysgenetic "streak" gonad on the other [
Variable clinical features frequently lead to confusion in diagnosis of ovotesticular DSD and MGD. Hormonal profiles, karyotypes, and an internal genital duct are not helpful in differential diagnosis [
Several retrospective studies have reported the clinical characteristics, sex of rearing, and long-term outcomes for a small number of children with ovotesticular DSD and MGD [
This study comprised 23 patients with DSD who presented with asymmetric gonads at the Department of Pediatrics at Asan Medical Center Children's Hospital in Seoul, Korea. The presenting features, endocrinological findings, karyotypes, presence of Müllerian duct remnants, pathological findings of the gonads, sex of rearing, and pubertal outcomes were reviewed retrospectively.
Patients with sex chromosome DSD whose diagnoses were not confirmed pathologically were excluded from this study. Sex assignment was based on integrative assessments of the external genitalia, presence of a uterus, functioning testicular tissues, hormonal profiles, and karyotypes and was performed using a multidisciplinary approach with informed consent from the parents of each patient.
External genitalia were rated using the external masculinization score (EMS) [
A human chorionic gonadotropin (hCG) stimulation test was performed in 10 patients to evaluate Leydig cell function. Serum testosterone level was measured at baseline and on the fourth day after consecutive intramuscular hCG injections at a dose of 1,000 units/day for 3 days. The testosterone response to hCG was regarded as positive if the level increased to at least twice baseline or above the upper limit of the prepubertal testosterone level [
Chromosomal analysis was performed in all subjects by examining metaphase G bands prepared from peripheral blood lymphocytes using conventional techniques [
Gonadectomy or biopsy was performed at a median age of 2.9 years (range, 1 month–15.1 years). Subsequently, 14 patients were diagnosed with ovotesticular DSD, and 9 were diagnosed with MGD. The positions and histology of the gonads are summarized in
In the 14 patients with ovotesticular DSD, the most common karyotype was 46,XX (10 of 14, 71.4%), followed by 45,X/46,XY (3 of 14, 21.4%) and 46,XX/46,XY(1 of 14, 7.1%). A gonadal combination of testis and ovary was the most common finding (10 of 14, 71.4%), followed by bilateral ovotestes (2 of 14, 14.3%), ovary and ovotestis (1 of 14, 7.1%), and testis and ovotestis (1 of 14, 7.1%).
In the 9 patients diagnosed with MGD, the most common karyotype was 45,X/46,XY (6/9, 66.7%). Other mosaicisms were identified in the other 3 patients (33.3%): 45,X/46,X,del(Y) (q11.23), 45,X/46,X,add(Y)(p.11.3), and 45,X/47,XY,+del(Y) (q12).
All 23 patients presented with ambiguous genitalia, such as a micropenis, cryptorchidism, hypospadias, or clitoromegaly, at a median age of 1 month (range, 1 day–1.6 years). Eleven of 14 patients with ovotesticular DSD (78.6%) and all 9 patients with MGD (100%) presented with asymmetric gonads. The appearance of the genitalia included prominent labia majora or absent scrotal rugae (13 of 23, 56.5%), hypospadias (15 of 23, 65.2%), clitoromegaly (8 of 23, 34.8%), cryptorchidism (5 of 23, 21.7%), and micropenis (4 of 23, 17.4%). The EMSs ranged between 2.5 and 11.5. None of the patients exhibited the stigmata of Turner syndrome. Müllerian duct remnants were identified in 10 of 14 patients with ovotesticular DSD (71.4%) and in 5 of 9 patients with MGD (55.6%).
Level of 17α-hydroxyprogesterone was measured in 16 subjects and was normal in all, excluding the possibility of congenital adrenal hyperplasia. The hCG stimulation test was performed in 8 subjects with ovotesticular DSD and in 2 subjects with MGD during the prepubertal period (range, 4–11 months). Seven of the 8 subjects (87.5%) with ovotesticular DSD and both subjects (100%) with MGD showed a positive response.
Eight of the 14 patients (57.1%) with ovotesticular DSD were assigned as male, and 7 of these patients (50%) had preserved testis. The remaining 6 patients (42.9%) were raised as female, and the ovaries were preserved in 3 of these 6 patients (50%). Among the 8 male-assigned patients, unilateral gonadectomy was performed in 7 at a median age of 1.5 years (range, 4 months–15.1 years). In these 7 patients, the ovotestis or ovary was removed, whereas the testis was preserved to induce spontaneous puberty. Subject 3, a male-assigned patient with bilateral ovotestes in the scrotum, underwent bilateral gonadectomy at age 15.1 years due to spontaneous rupture of the left gonad. Of 6 female-assigned patients, 3 underwent bilateral or unilateral gonadectomy at a median age of 12 months (range, 1 month–9.2 years). Eight patients with ovotesticular DSD (5 males and 3 females) reached pubertal age during the study period, which was defined as ≥12 years for males and ≥10 years for females. Of these 8 patients, 6 with ovotesticular DSD (4 males and 2 females) showed spontaneous puberty (
Seven of the 9 patients with MGD (77.8%) were raised as males, whereas the remaining 2 patients were raised as females. Six of the male-assigned patients underwent a unilateral gonadectomy. The 2 female-assigned patients underwent a bilateral (n=1) or unilateral (n=1) gonadectomy to avoid virilization. Two patients with MGD reached pubertal age. Of these, puberty occurred spontaneously in one phenotypic male at the age of 11.8 years (subject 19) with MGD, and sex hormone replacement was not necessary during the follow-up period (
This study demonstrated that patients with ovotesticular DSD and MGD present a wide clinical and cytogenetic spectrum encompassing phenotypic females, with or without virilization, and phenotypic males, presenting with a micropenis, hypospadias, or cryptorchidism. It is difficult to differentiate ovotesticular DSD from MGD based on clinical features, hormonal profiles, and cytogenetic analysis. The nature of the internal and external genitalia does not form the basis for a differential diagnosis between ovotesticular DSD and MGD. In our study, remnants of the Müllerian duct structure, a rudimentary uterus, and fallopian tubes were identified in 10 of 14 (71.4%) ovotesticular DSD patients and in 5 of 9 (55.6%) MGD patients. Therefore, histological findings of gonads are critical for differential diagnosis of ovotesticular DSD and MGD [
Various types of chromosomal abnormalities have been described in patients with ovotesticular DSD or MGD. The most frequent karyotype of ovotesticular DSD is 46,XX, followed by 46,XX/XY; 46,XY; and 45,X/46,XY [
Clinically, the presence of functional testicular tissue can be determined with the hCG stimulation test in adults. There are limited published data on hCG stimulation tests in patients with ovotesticular DSD [
Puberty has been reported to occur spontaneously in patients with MGD or ovotesticular DSD [
There are many issues to be considered when assessing gender: gonadal function, phenotype, internal genitalia, potential of fertility and sexuality, risk of gonadal malignancy, and prenatal brain virilization [
Gender identity can be predicted by several factors, such as presence of a Y chromosome, degree and duration of pre- and postnatal androgen exposure, and phenotypic presentation of external genitalia. However, there are few reports on long-term outcomes in patients with ovotesticular DSD and MGD [
Sex identity, pubertal progression, and potential gonadal tumor occurrence need to be monitored in patients with ovotesticular DSD and MGD. The risk of malignancy in patients with ovotesticular DSD is low (2.6%–4.6%), especially in the absence of a Y chromosome [
There are a few limitations in this study. As this was a retrospective study, there are issues with data integrity, such as missing data, and the follow-up period varied among the patients. The hCG stimulation test was performed only in a small number of patients, and the age at testing differed among patients because the patients were collected over a long duration. In addition, histological findings were analyzed by retrospective chart review and not reviewed by an expert.
In conclusion, this study demonstrated that ovotesticular DSD and MGD manifest a wide spectrum of clinical features and karyotypes. Long-term follow-up of such patients into adulthood will provide important information on comorbidities such as risk of gonadal tumors, urological complications, and neuropsychological outcomes.
No potential conflict of interest relevant to this article was reported.
This study was approved by the Institutional Review Board of Asan Medical Center, Seoul, Korea (IRB number: 2019-0160). Informed consent was obtained from the parents of each patient.
This study was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2017R1D1A1B03029638).
Sex of rearing and pubertal outcomes of patients with ovotesticular disorder of sex development (DSD) and mixed gonadal dysgenesis.
Clinical and cytogenetic features of patients with ovotesticular disorder of sex developmen
Subject No. | Age at presentation | Sex of rearing | Karyotype | Gonad, right/left | Position, right/left | Müllerian duct remnants | EMS | Testosterone response to hCG stimulation |
---|---|---|---|---|---|---|---|---|
1 | 1 mo | F | 46,XX | Ovary/ovotestis | Abdomen/inguinal | Yes | 5 | ND |
2 | 1 mo | F | 46,XX | Testis/ovary | Inguinal/abdomen | No | 7.5 | Yes |
3 | 1.6 yr | M | 46,XX | Ovotestis/ovotestis | Scrotum/scrotum | No | 9 | ND |
4 | 2 day | M | 46,XX | Testis/ovary | Scrotum/scrotum | Yes | 10 | Yes |
5 | 1 mo | M | 46,XX | Ovary/testis | Abdomen/scrotum | Yes | 8 | ND |
6 | 1 mo | M | 46,XX | Ovary/testis | Abdomen/scrotum | Yes | 9 | ND |
7 | 1 mo | F | 46,XX | Ovotestis/ovotestis | Inguinal/inguinal | No | 3 | ND |
8 | 2 mo | M | 46,XX | Ovary/testis | Abdomen/inguinal | Yes | 7.5 | Yes |
9 | 1 mo | F | 46,XX | Testis/ovary | Scrotum/abdomen | Yes | 7.5 | Yes |
10 | 9 mo | F | 46,XX | Testis/ovary | Labium/abdomen | Yes | 2.5 | No |
11 | 1 day | M | 45,X[22]/46,XY[8] | Testis/ovary | Scrotum/inguinal | No | 8 | Yes |
12 | 1 mo | M | 45,X[11]/46,XY[19] | Testis/ovary | Scrotum/abdomen | Yes | 9 | Yes |
13 | 12 mo | F | 45,X[5]/46,XY[20] | Testis/ovotestis | Inguinal/scrotum | Yes | 3.5 | ND |
14 | 1 mo | M | 46,XX[39]/46,XY[11] | Testis/ovary | Scrotum/abdomen | Yes | 8 | Yes |
EMS, external masculinization score; hCG, human chorionic gonadotropin; ND, not done.
Clinical and cytogenetic features of patients with mixed gonadal dysgenesis
Subject No. | Age at presentation | Sex of rearing | Karyotype | Gonad, right/left | Position, right/left | Müllerian duct remnants | EMS | Testosterone response to hCG stimulation |
---|---|---|---|---|---|---|---|---|
15 | 1 month | F | 45,X[18]/46,XY[32] | Testis/dysgenetic gonad | Scrotum/abdomen | Yes | Yes | Yes |
16 | 1 month | M | 45,X[24]/46,XY[16] | Dysgenetic gonad/testis | Inguinal/scrotum | No | 8.5 | ND |
17 | 1 month | M | 45,X[18]/46,XY[12] | Dysgenetic gonad/testis | Inguinal/scrotum | No | 6.5 | Yes |
18 | 1 month | F | 45,X[25]/46,XY[15] | Dysgenetic gonad/testis | Abdomen/inguinal | Yes | 3 | ND |
19 | 1 month | M | 45,X[36]/46,XY[4] | Dysgenetic gonad/testis | Abdomen/inguinal | Yes | 7.5 | Yes |
20 | 1 month | M | 45,X[15]/46,XY[85] | Dysgenetic gonad/testis | Abdomen/scrotum | No | 8 | ND |
21 | 1 month | M | 46,X,del(Y)(q11.23)[21]/45,X[9] | Testis/dysgenetic gonad | Scrotum/abdomen | Yes | 10.5 | ND |
22 | 2 months | M | 45,X[93]/46,X,add(Y)(p.11.3)[7] | Testis/dysgenetic gonad | Scrotum/abdomen | Yes | 8 | ND |
23 | 4 months | M | 47,XY,+del(Y)(q12)[43]/45,X[7] | Dysgenetic gonad/testis | Inguinal/scrotum | No | 11.5 | ND |
EMS, external masculinization score; hCG, human chorionic gonadotropin; ND, not done.
Endocrine characteristics of patients who reached pubertal age
Subject No. | Current age (yr) | Sex of rearing | MPH SDS | Height SDS | Weight SDS | Age at pubertal onset (yr) | Basal hormone levels at pubertal onset |
Gonadectomy | Age at sex hormone replacement therapy (yr) | |||
---|---|---|---|---|---|---|---|---|---|---|---|---|
LH (mIU/mL) | FSH (mIU/mL) | Estradiol (pg/mL) | Testosterone (ng/mL) | |||||||||
3 | 16.1 | M | NA | -0.05 | -0.73 | No | 28.1 | 42.1 | 21.8 | 2.0 | Bilateral | 15.1 |
4 | 14.0 | M | 0.45 | -0.28 | -0.95 | 12.7 | 10.4 | 11.0 | ND | 4.3 | Left | ND |
6 |
22.9 | M | NA | -0.69 | 0.16 | No | 22.0 | 25.8 | 4.0 | 0.92 | Right | 22.9 |
7 | 11.1 | F | -0.11 | 0.91 | 0.55 | 9.1 | 6.0 | 5.0 | 24.9 | ND | Bilateral | ND |
10 | 12.7 | F | 0.98 | 0.64 | 1.06 | 12.1 | 3.2 | 7.0 | 4.0 | 0.24 | Right | ND |
11 | 18.6 | M | -0.26 | -2.57 | 0.26 | 12.8 | 3.5 | 6.5 | 12.5 | 2.6 | Left | ND |
12 | 16.6 | M | -0.91 | -1.62 | -1.14 | 11.0 | 2.3 | 12.0 | ND | 0.19 | Left | ND |
13 | 13.0 | F | NA | -1.15 | 1.74 | No | 7.7 | 48.8 | 7.7 | ND | Bilateral | 11.4 |
15 | 21.2 | F | NA | -2.09 | -2.53 | No | 6.9 | 60.5 | 12.3 | 0.04 | Right | 11.5 |
19 | 13.6 | M | -0.54 | -2.10 | 0.96 | 11.8 | 1.6 | 7.1 | ND | 1.2 | Right | ND |
MPH, midparental height; SDS, standard deviation score; LH, luteinizing hormone; FSH, follicle-stimulating hormone; NA, not available; ND, not done.
Changed sex to female at age 20 years.
Patients who showed spontaneous puberty.