Journal of Clinical and Diagnostic Research, ISSN - 0973 - 709X

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Thanking you
With sincere regards
Dr. Rajendra Kumar Ghritlaharey, M.S., M. Ch., FAIS
Associate Professor,
Department of Paediatric Surgery, Gandhi Medical College & Associated
Kamla Nehru & Hamidia Hospitals Bhopal, Madhya Pradesh 462 001 (India)
On May 11,2011

Dr. Shankar P.R.

"On looking back through my Gmail archives after being requested by the journal to write a short editorial about my experiences of publishing with the Journal of Clinical and Diagnostic Research (JCDR), I came across an e-mail from Dr. Hemant Jain, Editor, in March 2007, which introduced the new electronic journal. The main features of the journal which were outlined in the e-mail were extensive author support, cash rewards, the peer review process, and other salient features of the journal.
Over a span of over four years, we (I and my colleagues) have published around 25 articles in the journal. In this editorial, I plan to briefly discuss my experiences of publishing with JCDR and the strengths of the journal and to finally address the areas for improvement.
My experiences of publishing with JCDR: Overall, my experiences of publishing withJCDR have been positive. The best point about the journal is that it responds to queries from the author. This may seem to be simple and not too much to ask for, but unfortunately, many journals in the subcontinent and from many developing countries do not respond or they respond with a long delay to the queries from the authors 1. The reasons could be many, including lack of optimal secretarial and other support. Another problem with many journals is the slowness of the review process. Editorial processing and peer review can take anywhere between a year to two years with some journals. Also, some journals do not keep the contributors informed about the progress of the review process. Due to the long review process, the articles can lose their relevance and topicality. A major benefit with JCDR is the timeliness and promptness of its response. In Dr Jain's e-mail which was sent to me in 2007, before the introduction of the Pre-publishing system, he had stated that he had received my submission and that he would get back to me within seven days and he did!
Most of the manuscripts are published within 3 to 4 months of their submission if they are found to be suitable after the review process. JCDR is published bimonthly and the accepted articles were usually published in the next issue. Recently, due to the increased volume of the submissions, the review process has become slower and it ?? Section can take from 4 to 6 months for the articles to be reviewed. The journal has an extensive author support system and it has recently introduced a paid expedited review process. The journal also mentions the average time for processing the manuscript under different submission systems - regular submission and expedited review.
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Dr. P. Ravi Shankar
KIST Medical College, P.O. Box 14142, Kathmandu, Nepal.
On April 2011

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Dr. Anuradha
On Jan 2020

Important Notice

Case Series
Year : 2022 | Month : March | Volume : 16 | Issue : 3 | Page : ER07 - ER13 Full Version

Disorders of Sexual Development-Pathological Profile of 45 Cases at a Tertiary Care Centre

Published: March 1, 2022 | DOI:
Gwendolyn Fernandes, Pooja Mhashete, Minal Desale

1. Professor (Additional), Department of Pathology, G.S. Medical College and K.E.M. Hospital, Mumbai, Maharashtra, India. 2. Fellow in Uropathology, Department of Pathology, G.S. Medical College and K.E.M. Hospital, Mumbai, Maharashtra, India. 3. Ex-fellow in Uropathology, Department of Pathology, G.S. Medical College and K.E.M. Hospital, Mumbai, Maharashtra, India.

Correspondence Address :
Dr. Gwendolyn Fernandes,
C-802, Swayam, Poonam Gardens, Mira Road, Thane-401107, Maharashtra, India.


Disorders of Sexual Development (DSD) are rare syndromes, which show congenital discordance between chromosomal, gonadal and phenotypic sex. A retrospective analysis was performed to analyse the histopathological profile and spectrum of a large number of cases of DSD received at a tertiary care centre. There were 45 cases of DSD encountered over a period of eight years, from January 2012 to December 2020. Detailed evaluation of each case with respect to demographic details, clinical features, imaging and pathology was done. All cases were classified as per Chicago Consensus Classification (2006) modified in 2010. The 46, XY DSD were the most common 26 (57.78%) cases, followed by sex chromosomal DSD 14 (31.1%) and 46, XX, DSD 5 (11.1%). Among 46, XY DSD, Complete Gonadal Dysgenesis (CGD) (Swyer syndrome) and Complete Androgen Insensitivity Syndrome (CAIS) had the highest number of cases, with 30.77% cases of each. Among 46XX, DSD, cases of ovotesticular DSD amounted to 80%. In sex chromosomal DSD, cases of Mixed Gonadal Dysgenesis (MGD) amounted to 78.57%. Out of 45 cases studied in this series, 20% cases showed neoplasms, of which 8.89% were malignancies. Nine out of 45 (20%) patients had neoplasms, out of which 5 (55.6%) had benign tumours while 4 (44.4%) had malignant tumours. Five patients had gonadoblastoma and three of these had co-existent dysgerminoma. Two patients had sertoli cell adenomas, one seminoma and one serous cystadenoma. Frequent clinical features noted were primary amenorrhoea seen in 25 (55.5%) cases and ambiguous genitalia seen in 18 (40%) cases, while the most common location of gonad was intra-abdominal in 30 (66.6%) cases. Streak gonads were seen in CGD, MGD and Turner’s syndrome. Malignant germ cell tumours were seen in CGD and CAIS. Early diagnosis, good histopathology and follow-up are essential in the management of DSDs.


Ambiguous genitalia, Gonadal dysgenesis, Gonadal neoplasms, Intersex, Sertoli cell adenomas

The DSD are syndromes where there is congenital discordance between chromosomal, gonadal or phenotypic sex. Gonadal dysgenesis is defined as incomplete or defective formation of the gonads resulting from abnormal migration of the germ cells and/or their incorrect organisation in the foetal gonadal ridge. It is caused by structural or numerical anomalies of the sex chromosomes, or mutations in one of the genes involved in the formation of the urogenital ridge and sex determination of the gonad (1).

Genital ambiguity in newborns is a medical emergency with long term consequences and psychosocial effects on the patient as well as their families. Immediate gender assignment at birth is often necessary, requiring multidisciplinary team work as it depends on many factors like chromosomal karyotype, status of gonads as well as external genitalia (2),(3).

Pathologists have an important role in identification of the gonads including Mullerian and Wolffian structures as well as identifying in-situ or invasive malignancies (4),(5). Malignant germ cell tumours have been found to arise in DSDs and in patients with gonadal dysgenesis who have a Y chromosome or Y chromosome material. They are at increased risk of developing germ cell tumours and an incidence of 10-30% has been reported in the literature (6),(7),(8). The Chicago Consensus Classification (2006) updated in 2010, is currently used in diagnosing and classifying DSD, and it is primarily based on the karyotype (1).

Case Report

This case series is based on the 45 gonadectomy specimens that were retrospectively reviewed. The specimens belonged to the period from January 2012 to December 2020 received in the Department of Pathology, at the tertiary care university hospital. The IEC approval was obtained vide letter number IEC(II)/OUT/1074/18.

Clinical data was obtained from the accompanying histopathological requisition forms and medical records of the hospital. The gonadal tissues were grossed at the time of receipt of specimens as per standard grossing protocols. Slides were prepared and stained with Haematoxylin and Eosin (H&E) for all cases. Special stains like Periodic acid Schiff, Masson trichrome as well as immunohistochemistry with Placental Alkaline Phosphate (PLAP), C-Kit, CD 30, inhibin, S-100, calretinin were done, wherever required for diagnosis.

Each of these 45 cases were re-evaluated and analysed according to the following criteria:

• Demographic details
• Clinical history and family history
• Physical examination including genital examination
• Karyotype profile (X and Y specific probe detection)
• Hormonal profile {Luteinising Hormone (LH), Follicle Stimulating Hormone (FSH), dihydrotestosterone, testosterone, androstenedione, 17 hydroxyprogesterone, Anti-mullerian Hormone (AMH)}
• The Ultrasonography (USG) and/or Magnetic Resonance Imaging (MRI) of abdomino-pelvic region for localisation of gonad and detection of Mullerian structures
• Routine laboratory investigations
• Pathology: gross, microscopy, immunohistochemistry

Features that suggested DSD were genital ambiguity, apparent male genitalia with micropenis, non palpable testis, isolated perineal hypospadias and apparent female genitalia with cliteromegaly, posterior labial fusion, and inguinal/labial mass.

Microscopic evaluation was done for identification of gonads as ovary/testis/ovotestis, identification of Mullerian or Wolffian structures, and detailed examination of the gonadal tissues for in-situ or invasive malignancies. Identification of any cysts or associated pathology was also done.

Categorisation of DSD

Among these 45 cases, 26 cases (57.78 %) were 46, XY DSD, 14 cases (31.11%) were sex chromosome DSD and 5 cases (11.11%) were 46, XX DSD (Table/Fig 1). Most of the cases (68.89%) were in the age group of 11-20 years. Ambiguous genitalia were seen in 18 cases (40%), male phenotype in 4 cases (8.89%) and female phenotype in 23 cases (51.11%) (Table/Fig 2). Clinical features varied as per aetiology, primary amenorrhoea being the most frequent presenting feature in 25 cases (55.5%), followed by ambiguous genitalia in 18 cases (40%) (Table/Fig 3). The location of the gonads in these patients was variable and included locations of intra-abdominal, inguinal, labio-scrotal, scrotal and inguinal, scrotal and intra-abdominal, inguinal and intra-abdominal. However, the most common location of both gonads was intra-abdominal in 30 cases (66.67%), followed by inguinal in eight cases (17.78%).

46, XY DSD

Eight cases (30.77%) of 46, XY (CGD)/Swyer syndrome were encountered (Table/Fig 4). These showed classical clinical features, bilateral streak gonads and well developed Mullerian structures (fallopian tubal structures). Hypoplastic uterus was identified on radiology of all cases, which was preserved and not sent for histopathological examination. Five out of eight cases showed gonadoblastoma (viable as well as burnt out) and dysgerminoma was seen in three of these cases.

46, XY DSD - CAIS was also second most common DSD and comprised of eight cases (30.77%) (Table/Fig 5). There were well formed testes along with epididymis and spermatic cord. Two of these cases, showed bilateral sertoli cell adenomas as well as multiple hyperplastic sertoli cell nodules which is a very unusual finding. One of the cases showed unilateral seminoma in the background of immature testis.

Three cases of 46, XY 5- alpha reductase type 2 deficiency were seen in this series (Table/Fig 6). All three cases showed easily identifiable, bilateral testis with epididymis and vas deferens.

The remaining 46, XY DSD included seven cases which were grouped under ‘other aetiologies’ (Table/Fig 7); two cases of 17-alpha hydroxylase deficiency, 17-beta hydroxysteroid oxidoreductase deficiency, partial gonadal dysgenesis each and a single case of partial androgen insensitivity syndrome. All showed well-formed testis on gross examination, and immature/ hypoplastic testis on histology.

Sex Chromosome DSD

Among MGDs, every case showed unilateral streak gonad and a contralateral dysgenetic testis/gonad. Seven cases showed fallopian tubal structure and one case showed additional Wolffian duct remnants. There were three cases with dysgenetic testes showing incomplete development of testis with four to five seminiferous tubules lined mainly by sertoli cells and occasionally by germ cells (Table/Fig 8). Hysterectomy was done in five cases and showed small uteri with proliferative endometrium.

Among sex chromosome DSD, there were two cases of Turner syndrome and its variant; and one case of ovotesticular DSD. Both the cases of Turner syndrome showed streak gonads with ovarian stroma and fallopian tubes; while one of these cases also showed Leydig cell clusters. A single case of ovotesticular DSD was also encountered which showed immature testis on the right side, ovarian stroma with primordial follicles on the left side, and structure of uterus (Table/Fig 9).

46, XX DSD

Four cases of 46, XX Ovotesticular DSD and a single case of congenital adrenal hyperplasia with 21 hydroxylase deficiency were also studied (Table/Fig 10). Among the cases of 46, XX ovotesticular DSD, three cases showed unilateral ovotestis and ovarian tissue on the other side and all cases had a uterine structure. The ovarian tissue comprised of ovarian stroma arranged in whorls with cystic follicles. One of these cases was very unusual and also showed a serous cystadenoma of the ovary. The DSD with congenital adrenal hyperplasia showed bilateral ovarian stroma with primordial follicles, fallopian tubes and a structure of uterus.


All the 45 cases of DSD were encountered over a period of eight years. Among these 45 cases, 57.78 % were 46, XY DSD, 31.11% were sex chromosome DSD and 11.11% were 46, XX DSD.

Most of the cases were in the age group of 11-20 years. Clinical features varied as per aetiology; primary amenorrhoea being the usual presenting feature and female phenotype was the most common presentation, while ambiguous genitalia was the next frequent presentation. Bilateral gonads were intra-abdominal in most of the cases. Radiological investigations helped in localisation, size of the gonads and identification of Mullerian or Wolffian structures. They were especially helpful in the identification of streak gonads.

The gross examination of the gonadectomy specimens provided information about size of the gonad, presence of tumours and the presence of tubular structures, which on histopathological examination were Mullerian structures (uterus, fallopian tube) and Wolffian structures (rete testes, epididymis, vas deferens) (Table/Fig 11), (Table/Fig 12). Well-formed testes were seen in 17 cases and were easily identified on gross examination. Heterogeneity of the gonadal tissue was seen and the entire gonad was needed to be sampled. The SOX9 for sertoli cells, FOXL2 for granulosa cells, OCT3/4, PLAP can be used in addition to the usual immunohistochemistry panel (9).

The most common DSD diagnosed in the present study was 45, XO/46, XY DSD-MGD (78.57%), followed by CGD (30.77%), and CAIS (30.77%). Congenital adrenal hyperplasia is the most prevalent DSD presenting with ambiguous genitalia at birth seen in 60-70% followed by MGD (10),(11),(12). Most of these cases of DSD were unfortunately diagnosed at puberty or adulthood, compared to other studies available in literature, where DSD were mainly diagnosed at birth due to routine neonatal screening (2),(10). Poor governmental health policies, lack of routine neonatal screening, deliveries conducted at home or by paramedical staff and overall poor medical facilities could explain this delayed presentation at adulthood.

There were a number of spectacular cases in this study that are discussed here in brief. One of the cases of 46, XX ovotesticular DSD was very unusual and showed a serous cystadenoma of the ovary. This was a 21-year-old individual, with 46, XX karyotype, reared as a male, who presented with genital ambiguity, hirsutism, bilateral gynaecomastia, abdominal pain, cyclical bleeding through a single perineal opening below a 4 cm phallus-like structure and hypospadias. The right gonad was an ovotestis while the left gonad was replaced by an 8×6×4.5 cm, solid-cystic, ovarian neoplasm, composed of two locules with brown serous fluid. A uterus measuring 8.5×5.5×2.5 cm was also present. Histopathology of ovarian cyst confirmed a classic serous cystadenoma. Although the two pathologies have no specific association, their simultaneous occurrence deserves attention as reported by Zhao J et al., in their case report of serous borderline ovarian tumour in a case of 46, XY DSD (13).

Two cases of CAIS showing bilateral sertoli cell adenomas were also studied. One of these was an 18-year-old individual with a 46, XY karyotype, female phenotype with poorly developed secondary sexual characteristics, who presented with bilateral inguinal swellings and primary amenorrhoea. The clinical diagnosis was CAIS where no uterus was visualised and both the gonads showed characteristic sertoli cell adenomas and hyperplastic sertoli cell nodules (14). The hyperplastic nodules were unencapsulated and composed of elongated immature sertoli cells arranged in well-formed tubules. No germ cells were seen admixed with the sertoli cells. Clusters of Leydig cells were seen in between the nodules. The sertoli cell adenomas were grossly encapsulated and golden-yellow, while microscopically composed of tubules lined by sertoli cells and separated by scanty fibrous tissue. Immunohistochemistry with calretinin strongly highlighted and confirmed sertoli cells and Leydig cells. These sertoli cell adenomas and hyperplastic nodules have been considered neoplastic or hamartomatous, interchangeably in literature (7),(9). The second case was a 16-year-old individual with 46 XY karyotype, apparent female genitalia, bilateral inguinal swellings, absent uterus, short vagina with development of breast and pubic hair. Both the inguinal gonads showed multiple sertoli cell adenomas as well as Leydig cell hyperplasia.

A familial case of CGD was also encountered in which all the four children presented with classical clinical features of Swyer syndrome. They had germ cell tumour in the backround of streak gonads. The eldest sibling had bilateral gonadoblastoma with dysgerminoma of the left gonad, the second sibling had bilateral gonadoblastoma with streak gonads, the third sibling had right sided gonadoblastoma and left sided streak gonad while the youngest sibling had bilateral streak gonads. The gonadoblastomas (GB) showed varying growth patterns and comprised of circumscribed nests of neoplastic germ cells with sex cord stromal cells surrounded by basement membrane deposits and superimposed by calcifications (9). Most of the cases of GB in this study showed rounded basement membrane deposits and individual germ cells surrounded by a palisade of sex-cord cells. Dysgerminoma showed characteristic histomorphological features comprising of polyhedral cells with large nuclei, prominent nucleoli and clear cytoplasm. Immunohistochemistry for PLAP and CD117 was done for confirmation of the diagnosis. A similar study had been reported by Eunice M et al., with one of the siblings having gonadoblastoma and the other two having streak gonads (15).

Malignant germ cell tumours were seen in CGD and CAIS (16) and gonadoblastomas were seen exclusively in CGD and were similar to studies in literature. Streak gonads were seen in CGD, MGD and Turner syndrome. Hence, streak gonads, though small and fibrotic need to be removed as they can harbour germ cell malignancies. sertoli cell adenomas as well as Leydig cell hyperplastic nodules were seen only in CAIS. Well-formed testes with epididymis and vas deferens were seen in 5-alpha reductase type two deficiency. CGD and MGD showed a strong family history of the disease.

We could not find many detailed pathology studies of DSD in literature despite the extensive search done, for comparative purposes; as most of the studies in literature are clinical studies. The studies which included histopathology were restricted to case reports and small series of cases of individual syndromes (15),(17). Hence, we have very few aetiological comparative studies and some with single entity, in this paper (2),(12),(15),(17) (Table/Fig 13).

The DSDs require a multidisciplinary approach for diagnosis and treatment. Treatment includes gender assignment, surgical genital reconstruction, prophylactic gonadectomies, hormonal supplementation, psychosocial counselling and periodic follow-ups to rule out the development of neoplasms.


Role of histopathology is crucial to the diagnosis of DSD for identification of gonads, identification of Mullerian and/or Wollfian structures and identification of malignancies. An entire spectrum of morphologies was seen on the histopathology of gonads in DSD. Cases of 46 XY, DSD (57.78%) were the most frequently encountered in this tertiary centre. Among these, CGD (Swyer syndrome) and CAIS were the highest of all other aetiologies, amounting to 30.77% cases each. But the most common aetiological cause of DSD was MGD with 78.57% cases in contrast to the common causes of DSD as reported in literature. Out of 45 cases studied in this series, 20% cases showed neoplasms, of which 8.89% were malignancies, thus stressing over the importance of early diagnosis, good histopathology and follow-up of these cases. Streak gonads were seen in CGD, MGD and Turner’s syndrome. Malignant germ cell tumours were seen in CGD and CAIS.

Even though DSD cases are not frequent in histopathological reporting, a systematic approach for histological gonadal evaluation is required. Molecular diagnostics can pave the way as a future diagnostic modality for DSD.


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DOI and Others

DOI: 10.7860/JCDR/2022/53120.16165

Date of Submission: Nov 02, 2021
Date of Peer Review: Jan 07, 2022
Date of Acceptance: Jan 25, 2022
Date of Publishing: Mar 01, 2022

• Financial or Other Competing Interests: None
• Was Ethics Committee Approval obtained for this study? Yes
• Was informed consent obtained from the subjects involved in the study? Yes
• For any images presented appropriate consent has been obtained from the subjects. NA

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