| Abstract|| |
Gonadal dysgenesis is a distinct variety of Disorders of Sexual Differentiation (DSD) characterised by incomplete or defective formation of the gonads due to either structural or numerical anomalies of the sex chromosomes or mutations in the genes involved in the development of the gland. Here we present two such rare cases that presented during childhood. Both patients presented with ambiguous genitalia with a 45XO/46XY mosaic chromosome pattern. First case, an infant underwent laparoscopic excision of streak gonad, and a single stage hypospadias repair later. Second case, an adolescent who underwent gonadectomy as a child, presented with a mass which was excised and found to contain uterine and ovarian tissue; second stage hypospadias repair is being planned. Mixed gonadal dysgenesis usually presents with a unilateral testis, a streak gonad on the contralateral side and persistent mullerian structures. The most common karyotype noted is 45XO/46XY. These cases are known to have ambiguous external genitalia. The streak gonads have an increased malignant potential and thus, these patients should be carefully screened and followed up for gonadoblastoma.
Keywords: Mixed gonadal dysgenesis, disorder of sexual differentiation, mosaic chromosome, streak gonad
|How to cite this article:|
Correya MA, Babu R, Archana B, Ravirajendiran S. Disorders of sexual differentiation: Report of two rare cases. Indian J Pathol Microbiol 2021;64:390-3
|How to cite this URL:|
Correya MA, Babu R, Archana B, Ravirajendiran S. Disorders of sexual differentiation: Report of two rare cases. Indian J Pathol Microbiol [serial online] 2021 [cited 2021 May 8];64:390-3. Available from: https://www.ijpmonline.org/text.asp?2021/64/2/390/313282
| Introduction|| |
The term mixed gonadal dysgenesis (MGD) as a distinct variety of Disorder of Sexual Differentiation (DSD) was first introduced by Shoval in 1963, and is also known as Shoval syndrome or asymmetric gonadal dysgenesis. These patients characteristically presented with a unilateral testis, a contralateral streak gonad and persistent mullerian structures like an incompletely formed uterus, fallopian tube on the side of the streak gonad which can be confirmed by laparoscopy and histological examination. Karyotypic analysis of the chromosomal pattern in these individuals most commonly revealed a 45XO/46XY chromosomal pattern. The incidence of this mosaic chromosome pattern was found to be 1.5 in 10,000 new-borns. These individuals commonly present with ambiguous genitalia mostly with undescended testis and hypospadias.
The risk of neoplasia is higher in individuals with MGD. In patients with cryptorchidism, the testis is about 10 times at a risk of undergoing neoplastic transformation. The tumours most commonly found are gonadoblastomas and germ cell tumours and rarely even juvenile granulosa cell tumour has been reported. These tumours are seen in 15-25% of 45XO/46XY individuals. Therefore, all patients with undescended testis and hypospadias must undergo karyotyping to rule out a mosaic chromosome pattern. The two cases presented here highlight the importance of early diagnosis and appropriate management in these individuals.
| Case Report 1|| |
A 6-month-old child reared as a male, was found to have a penoscrotal hypospadias, micropenis and right non palpable testis on examination [Figure 1]. His baseline follicle stimulating hormone (FSH) was 1.7 mIU/ml (normal: 0.8-5.7 IU/L), luteinizing hormone (LH) was <0.2 mIU/ml (normal: 1.2-7.9 IU/L) and testosterone was <10 ng/dl (normal: 2.9-16.6 nmol/L). Human chorionic gonadotrophin (HCG) stimulation test and Karyotyping was advised. Ultrasonogram was inconclusive. Karyotyping revealed mosaic pattern: 45XO (20%)/46XY (80%) [Figure 1]. Pre and post humanHCG stimulated testosterone and dihydrotestosterone (DHT) levels were observed to be very low. Genitogram was inconclusive and genitoscopy revealed a communication at the level of prostatic urethra leading to a vagina with a cervix impression. At 18 months of age, the child underwent diagnostic laparoscopy, which showed the presence of vas and vessels on the left side and streak gonad with a fallopian tube communicating to a hemi uterus on the right side. Excision biopsy of the streak gonad was done to rule out a malignancy. Histopathology confirmed the presence of ovarian stroma with no follicles consistent with streak gonad [Figure 2]. Both epididymis and fallopian tube was present [Figure 3]. Ectopic adrenal rest was also seen [Figure 2]. At 2 years of age, the patient underwent single stage hypospadias repair and has recovered well without fistula or any other complication.
|Figure 1: 6-month-old boy with mixed gonadal dysgenesis (a) Ambiguous genitalia; (b) Karyotype showing mosaic pattern (45XO/ 46XY); (c) laparoscopic appearance of streak gonad; (d) H&E,40X, cross section of fallopian tube; (e) H&E,100X, epididymis|
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|Figure 2: 6-month-old boy with mixed gonadal dysgenesis; (a) H&E,100X, focal area showing ovarian stroma; (b) ER IHC showing strong positivity in the ovarian stroma; (c) H&E,40X, ectopic adrenal tissue|
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| Case Report 2|| |
An 18-year-old male presented with left iliac fossa pain of one week duration. He was a known case of MGD (45XO/46XY) and had undergone laparoscopic mullerian remnant excision and right gonadectomy for streak gonad earlier in his childhood. He has been on testosterone replacement therapy in the form of monthly depot injections. On general examination he was moderately built and nourished with normal axillary, chest and pubic hair distribution. A vague mass was palpable in the left iliac fossa (5 × 5 cm). External genitalia revealed penoscrotal hypospadias with left palpable testis [Figure 3]. Due to hormone replacement therapy, his baseline follicle stimulating hormone (FSH) was 9.4 mIU/ml (normal range: 1.27-19.26), luteinizing hormone (LH) was LH-7.0 mIU/ml (normal range: 1.24-8.62) and testosterone was 242.3 ng/dl (normal range: 175-781). CT scan revealed a 12 cm cyst in the recto vesical space with another 8 cm complex cyst in the left side of pelvis [Figure 3]. Laparotomy and excision of both the cysts were performed. Histopathology revealed a poorly developed testicular tissue with uterine and cervical tissue in the cyst [Figure 4]. The patient has already undergone first stage hypospadias repair and is awaiting a second stage hypospadias repair.
|Figure 3: 18-year-old boy with mixed gonadal dysgenesis (a) Perineal hypospadias with undescended testis; (b) CT scan showing a 12 cm cyst in the rectovesical space and another 8 cm complex cyst in the left side of pelvis; (c) Intraoperative image of excised specimen with cyst|
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|Figure 4: (a) H&E,100X, presence of seminiferous tubules with spermatocytes and Spermatogonia; (b) H&E,10X, cervical tissue, (c) H&E,10X, endometrial tissue; (d) H&E,40X, endometrial tissue|
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| Discussion|| |
Gonadal dysgenesis is a term used for a unique set of DSD characterised by incomplete or defective formation of gonads due to either structural or numerical anomalies of the sex chromosome or mutations in the genes involved in the development of the gonad. It refers to a variety of clinical conditions where there is an abnormal development of foetal gonads and it mainly comprises of 46XY gonadal dysgenesis, mixed gonadal dysgenesis and 45XO turners syndrome.
A mosaic karyotype pattern of 45XO/46XY is commonly noted in MGD patients. However, a case of MGD with a normal karyotype has been observed by Anand et al. Also, Sheilipour et al. report a case of MGD with mosaicism 45, X/46, X,+mar.
MGD is mainly characterised by a streak gonad and contralateral testis or bilateral streak gonads. With 45XO/46XY mosaics genetic abnormality, MGD has a spectrum of anomalies including ambiguous genitalia, short stature, delayed sexual development, hypospadias and dysgenic streak ovaries. Also, these may present as a phenotypically male patient with uterine tissue and one or both fallopian tubes.
Chang et al. did a survey of prenatally diagnosed 45XO/46XY mosaic karyotype patients to ascertain the phenotypic spectrum of this condition. They reported that 95% of foetuses with the mosaic karyotype pattern have a normal external male genitalia and on histologic examination 27% of the gonad were found to have an abnormal histology.
Streak gonads in the presence of Y chromosome are said to have forty fold increase in malignant risk. The most common gonadal neoplasms seen in the MGD are gonadoblastoma, seminoma, teratocarcinoma and choriocarcinoma. Most of these gonadal neoplasms were identified during or after the pre pubertal period, indicating that the malignant potential in these patients is seen to increase after the onset of puberty. Thus, to prevent the onset of malignancy, laparoscopy and excision of the streak gonad are recommended at puberty even if the gonads appear morphologically normal.
| Conclusion|| |
In patients with non-palpable undescended testis and severe hypospadias the possibility of a mixed gonadal dysgenesis should be kept in mind. A multidisciplinary approach involving a paediatric urologist, pathologist, endocrinologist and a geneticist is warranted. If a mosaic (XO/XY) karyotype pattern is observed then these patients should be subjected to a prophylactic streak gonadectomy to avoid development of future malignancy.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
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Conflicts of interest
There are no conflicts of interest.
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Department of Pathology, Sri Ramachandra Medical College, Porur, Chennai, Tamil Nadu - 600 116
Source of Support: None, Conflict of Interest: None
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