Complete Gonadal Dysgenesis Research Articles

Expanding the spectrum of syndromic PPP2R3C-related XY gonadal dysgenesis to XX gonadal dysgenesis.

Homozygous variants in PPP2R3C have been reported to cause a syndromic 46,XY complete gonadal dysgenesis phenotype with extragonadal manifestations (GDRM, MIM# 618419) in patients from four unrelated families, whereas heterozygous variants have been linked to reduced fertility with teratozoospermia (SPGF36, MIM# 618420) in male carriers. We present eight patients from four unrelated families of Turkish and Indian descent with three different germline homozygous PPP2R3C variants including a novel in-frame duplication (c.639_647dupTTTCTACTC, p.Ser216_Tyr218dup). All patients exhibit recognizable facial dysmorphisms allowing gestalt diagnosis. In two 46,XX patients with hypergonadotropic hypogonadism and nonvisualized gonads, primary amenorrhea along with absence of secondary sexual characteristics and/or unique facial gestalt led to the diagnosis. 46,XY affected individuals displayed a spectrum of external genital phenotypes from ambiguous genitalia to complete female. We expand the spectrum of syndromic PPP2R3C-related XY gonadal dysgenesis to both XY and XX gonadal dysgenesis. Our findings supported neither ocular nor muscular involvement as major criteria of the syndrome. We also did not encounter infertility problems in the carriers. Since both XX and XY individuals were affected, we hypothesize that PPP2R3C is essential in the early signaling cascades controlling sex determination in humans.

Age at diagnosis in patients with chronic congenital endocrine conditions: a regional cohort study from a reference center for rare diseases

BackgroundFor chronic congenital endocrine conditions, age at diagnosis is a key issue with implications for optimal management and psychological concerns. These conditions are associated with an increase in the risk of comorbid conditions, particularly as it concerns growth, pubertal development and fertility potential. Clinical presentation and severity depend on the disorder and the patient’s age, but diagnosis is often late.ObjectiveTo evaluate age at diagnosis for the most frequent congenital endocrine diseases affecting growth and/or development.Patients and MethodsThis observational cohort study included all patients (n = 4379) with well-defined chronic congenital endocrine diseases—non-acquired isolated growth hormone deficiency (IGHD), isolated congenital hypogonadotropic hypogonadism (ICHH), ectopic neurohypophysis (NH), Turner syndrome (TS), McCune-Albright syndrome (MAS), complete androgen insensitivity syndrome (CAIS) and gonadal dysgenesis (GD)—included in the database of a single multisite reference center for rare endocrine growth and developmental disorders, over a period of 14 years. Patients with congenital hypothyroidism and adrenal hyperplasia were excluded as they are generally identified during neonatal screening.ResultsMedian age at diagnosis depended on the disease: first year of life for GD, before the age of five years for ectopic NH and MAS, 8–10 years for IGHD, TS (11% diagnosed antenatally) and CAIS and 17.4 years for ICHH. One third of the patients were diagnosed before the age of five years. Diagnosis occurred in adulthood in 22% of cases for CAIS, 11.6% for TS, 8.8% for GD, 0.8% for ectopic NH, and 0.4% for IGHD. A male predominance (2/3) was observed for IGHD, ectopic NH, ICHH and GD.ConclusionThe early recognition of growth/developmental failure during childhood is essential, to reduce time-to-diagnosis and improve outcomes.

Cytogenetic and molecular characterization in gonadal tissue of patients with ovotesticular syndrome and gonadal dysgenesis 46,XY and 46,XX

Abstract Objectives: Etiology of gonadal dysgenesis and ovotesticular syndrome is unknown in a majority of cases. To perform cytogenetic and molecular characterization of a group of patients with ovotesticular syndrome and complete gonadal dysgenesis from peripheral blood and gonadal tissue samples. Materials and methods: A total of 6 patients were included, 3 with diagnosis of 46,XX ovotesticular syndrome, one diagnosed with 46,XY ovotesticular syndrome; one with suspected 46,XX gonadal dysgenesis, and one with 46,XY complete gonadal dysgenesis. Results: All patients were evaluated with karyotype, fluorescent in situ hybridization (FISH) for SRY, multiplex ligation-dependent probe amplification (MLPA) and comparative genomic hybridization (aCGH) on peripheral blood samples. In cases with available gonadal tissue, the levels of genetic expression of SOX3, SRY, and SOX9 were determined through real-time PCR and immunofluorescence. Rearrangements involving SRY gene were ruled out. No deletions/duplications or copy-number variations (CNV) were detected as the etiology for sexual development disorder in any of the patients studied. In a case of 46,XX ovotesticular syndrome, the gonadal karyotype was different from the karyotype in peripheral blood. Aberrant expression of SOX3 and SOX9 in gonadal tissue of a case with 46,XX ovotesticular syndrome was observed. Conclusions: Lower levels of expression of SRY and SOX9 compared to the levels in human cellular lines of embryonic testicle and Sertoli were documented in the gonadal tissue of a case with 46,XY ovotesticular syndrome. Cytogenetic and molecular studies of the gonads as a complement to peripheral blood study have the potential to enrich the understanding of sexual development disorders in patients who are XX or XY in peripheral blood.

Cytogenetic and molecular characterization in gonadal tissue of patients with ovotesticular syndrome and gonadal dysgenesis 46,XY and 46,XX

Abstract 
 Objectives: Etiology of gonadal dysgenesis and ovotesticular syndrome is unknown in a majority of cases. To perform cytogenetic and molecular characterization of a group of patients with ovotesticular syndrome and complete gonadal dysgenesis from peripheral blood and gonadal tissue samples.
 Materials and methods: A total of 6 patients were included, 3 with diagnosis of 46,XX ovotesticular syndrome, one diagnosed with 46,XY ovotesticular syndrome; one with suspected 46,XX gonadal dysgenesis, and one with 46,XY complete gonadal dysgenesis.
 Results: All patients were evaluated with karyotype, fluorescent in situ hybridization (FISH) for SRY, multiplex ligation-dependent probe amplification (MLPA) and comparative genomic hybridization (aCGH) on peripheral blood samples. In cases with available gonadal tissue, the levels of genetic expression of SOX3, SRY, and SOX9 were determined through real-time PCR and immunofluorescence.
 Rearrangements involving SRY gene were ruled out. No deletions/duplications or copy-number variations (CNV) were detected as the etiology for sexual development disorder in any of the patients studied. In a case of 46,XX ovotesticular syndrome, the gonadal karyotype was different from the karyotype in peripheral blood. Aberrant expression of SOX3 and SOX9 in gonadal tissue of a case with 46,XX ovotesticular syndrome was observed.
 Conclusions: Lower levels of expression of SRY and SOX9 compared to the levels in human cellular lines of embryonic testicle and Sertoli were documented in the gonadal tissue of a case with 46,XY ovotesticular syndrome. Cytogenetic and molecular studies of the gonads as a complement to peripheral blood study have the potential to enrich the understanding of sexual development disorders in patients who are XX or XY in peripheral blood.

Confusion in Gonadal Dysgenesis Terminology Persisting beyond Chicago Consensus Statement on Disorders of Sexual Development.

The terminology of gonadal dysgenesis conditions is considerably abstruse and variable. Despite some efforts in the 2006 Chicago Consensus Statement on DSD , it is still difficult to assign a category and name for some distinct conditions in this document. The rest of the literature has used redundant and variable words, e.g. partial, pure, and complete gonadal dysgenesis suffering equivocality and redundancy, aggravating this inconclusiveness. We attempted to highlight this problem and propose an easier terminology blueprint. Abstract: The terminology of gonadal dysgenesis conditions is considerably abstruse and variable. Despite some efforts in the 2006 Chicago Consensus Statement on DSD , it is still difficult to assign a category and name for some distinct conditions in this document. The rest of the literature has used redundant and variable words, e.g. partial, pure, and complete gonadal dysgenesis suffering equivocality and redundancy, aggravating this inconclusiveness. We attempted to highlight this problem and propose an easier terminology blueprint.

The radiologist's role in assessing differences of sex development.

When infants are identified with a difference of sex development (DSD), a thoughtful approach to imaging is essential to appropriate clinical management. This review provides a comprehensive guide for radiologists who are tasked with performing this critical assignment. We review the embryologic basis of DSDs, with attention to the imaging findings that can indicate specific diagnoses. We also discuss techniques for optimal imaging, including strategies for identifying the gonads by US, tactics for performing genitograms with fluoroscopy and contrast-enhanced US, and the appropriate utilization of MRI. Finally, we review the clinical data and imaging findings that characterize some of the most common DSDs, including congenital adrenal hyperplasia, complete androgen insensitivity syndrome and gonadal dysgenesis.

Disorders of Sex Development.

Disorders of Sex Development.

Expanding DSD Phenotypes Associated with Variants in the DEAH-Box RNA Helicase DHX37

Missense variants in the RNA-helicase DHX37 are associated with either 46,XY gonadal dysgenesis or 46,XY testicular regression syndrome (TRS). DHX37 is required for ribosome biogenesis, and this subgroup of XY DSD is a new human ribosomopathy. In a cohort of 140 individuals with 46,XY DSD, we identified 7 children with either 46,XY complete gonadal dysgenesis or 46,XY TRS carrying rare or novel DHX37 variants. A novel p.R390H variant within the RecA1 domain was identified in a girl with complete gonadal dysgenesis. A paternally inherited p.R487H variant, previously associated with a recessive congenital developmental syndrome, was carried by a boy with a syndromic form of 46,XY DSD. His phenotype may be explained in part by a novel homozygous loss-of-function variant in the NGLY1 gene, which causes a congenital disorder of deglycosylation. Remarkably, a homozygous p.T477H variant was identified in a boy with TRS. His fertile father had unilateral testicular regression with typical male genital development. This expands the DSD phenotypes associated with DHX37. Structural analysis of all variants predicted deleterious effects on helicase function. Similar to all other known ribosomopathies, the mechanism of pathogenesis is unknown.

Complete gonadal dysgenesis analysis in the population of Latvia: malignant outcomes and a review of literature.

Complete gonadal dysgenesis or Swyer syndrome is a rare genetic disorder characterized by 46,XY karyotype and female phenotype with undeveloped streak gonads and high malignancy risk. The condition usually manifests in teenage and young adults with delayed puberty and primary amenorrhea. The purpose of this study was to investigate the incidence and potential malignant outcomes of complete gonadal dysgenesis in Latvia. 37 patients were included in a retrospective study from 1996 to 2016. In fifteen cases, additional patient information was available. Information from medical records was collected on age at the time of diagnosis: anamnesis data, laboratory results, histology of gonads, and treatment. Complete gonadal dysgenesis with karyotype 46,XY was proven in 36 (97.3%) cases and one (2.7%) case with karyotype 47,XY,+21. The average age of patients at the time of diagnosis was 15.4 ± 8.0 years. The study included 15 cases: eight patients (53.3%) were investigated for primary amenorrhea, and incomplete development of secondary sexual characteristics, 5 patients (33.3%) with abdominal pain and lower abdominal mass, 2 patients (13.3%) were diagnosed at birth. Gonadectomy was performed in 12 cases (80%). The median time between diagnosis and gonadectomy was 0.4 ± 4.3 years. The histopathology results from the gonadal biopsy showed malignancy in 7 cases (58.3%). The most commonly diagnosed tumors were dysgerminoma and gonadoblastoma. Early diagnosis of Swyer syndrome is necessary in view of the risk of malignancy that can develop at a young age. In several cases, the diagnosis of the syndrome was made only after the malignant process development. The study showed the median time between diagnosis and gonadectomy was suboptimal. Therefore, women with amenorrhea and lack of secondary sexual characteristics require careful investigation.

Swyer Syndrome, 46, XY complete gonadal dysgenesis in a patient with spontaneous menarche

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Prenatal androgen exposure and gender behavior in disorders of sex development

Summary Aim Comparison of gender personality traits in CAH-affected 46,XX patients with those in 46,XY patients with complete androgen insensitivity syndrome (AIS) or gonadal dysgenesis (GD). Patients and methods Thirty-six 46,XX CAH, three 46,XY AIS, four 46, XY GD patients. The Bem Sex-Role Inventory (BSRI) was used to measure masculinity, femininity and to research gender roles. Results The lowest femininity values were in the patients with CAH, the highest in patients with AIS. Age at study was not associated with the value of BSRI score. CAH patients with the Prader score 4 had lower median femininity score values than those who had the Prader score 3, however, the difference was statistically insignificant. Conclusion More masculinizied personality behavioral traits in females with CAH most likely result from exposure of the fetal brain to high levels of androgens.

59. Tamoxifen for Puberty Induction and Bone Mineral Density Protection in a Gender Non Binary Patient With 46, XY Complete Gonadal Dysgenesis: A Case Report

<h3>Background</h3> 46XY complete gonadal dysgenesis patients present with primary amenorrhea and delayed puberty. There is an increased risk of gonadoblastoma and often undergo surgical resection. Following diagnosis, sex hormone replacement therapy is started for puberty induction. Tamoxifen prevents loss of bone mineral density in postmenopausal women and has been used to treat gynecomastia in prepubertal males. We present a case of a nonbinary patient with 46XY complete gonadal dysgenesis where typical sex hormone replacement therapy would be incongruent with the patient's gender identity and instead, tamoxifen was used for puberty induction and bone health protection. <h3>Case</h3> A 15 year old patient with autism and ADHD presented with primary amenorrhea. Breast development occurred 1.5 years prior without development of pubic or axillary hair. They had previously identified as gender neutral. They had an elevated FSH (51mIU/mL), elevated LH (16mIU/mL), low estradiol (<2.5pg/mL), low testosterone (10ng/dL), and karyotype 46XY SRY+ of unknown molecular etiology. Sonography showed a prepubertal uterus (4.5 × 0.5 × 2.5cm) and intraabdominal gonads. The workup was suggestive of 46XY complete gonadal dysgenesis. DEXA scan showed decreased bone mineral density for chronologic age (Z score -2.3, whole body BMD:0.71 g/cm2). They were counseled regarding the risk of gonadoblastoma in intraabdominal gonads and elected to undergo a laparoscopic gonadectomy. They expressed concerns about sex hormone replacement and did not wish to develop secondary sex characteristics that would be incongruent with their nonbinary identity. A selective estrogen receptor modulator (tamoxifen) was started for bone health protection without the development of secondary sex characteristics. At 4 months, their height had increased 2cm and had a reduction in breast tissue. At 1 year, their height had increased 5cm and the increase in growth velocity showed pubertal induction. Repeat ultrasound demonstrated a uterus size of 6 × 1.3 × 2.2 cm and a non-visualized endometrial stripe. DEXA showed improvement (Z score -2.2, whole body BMD:0.81 g/cm2). Tamoxifen was titrated up to a goal dose of 15-20mg daily. Mental health and psychosocial adaptation was regularly screened following the DSD-TRN protocol. The patient has not had any menstrual bleeding, continues on the tamoxifen, and plans to undergo a hysterectomy at the age of 18. <h3>Comments</h3> Following gonadectomy in patients with 46XY complete gonadal dysgenesis, hormone replacement therapy is imperative for overall heath, puberty induction, and bone health. In patients who require sex hormone replacement but whose gender is not consistent with a male or female gender identity, a selective estrogen receptor modulator can be used.

Association between Down Syndrome and Disorders of Sex Development: Report of Three Cases and Review of 188 Cases in the Literature

In this study, we present 3 cases of Down syndrome (DS) associated with disorders/differences of sex development (DSD) and review the literature on this topic. Case 1: 1-year-old child with male genitalia and DS phenotype, 47,XX,+21 karyotype and testicular DSD. Case 2: 11-month-old child with male genitalia and few DS dysmorphisms, 45,X/47,XY,+21 karyotype, and mixed gonadal dysgenesis. Case 3: 4-month-old child with female genitalia and DS phenotype, 47,XY,+21 karyotype and XY complete gonadal dysgenesis. In the literature, among 188 patients, 107 (57%) had Klinefelter syndrome and 61 (33%) Turner syndrome, 12 (6%) had mixed gonadal dysgenesis, 2 (1%) had partial androgen insensitivity, 2 (1%) ovotesticular DSD, and the others had congenital adrenal hyperplasia, XY partial gonadal dysgenesis, XY complete gonadal dysgenesis, and complete androgen insensitivity (1 case each). A typical DS phenotype was found in all individuals of the revision, with the exception of one case, but DSD features were not always reported. In conclusion, the association of DS with sex chromosome DSD is the most frequently observed, whereas associations with 46,XX and 46,XY DSD is extremely rare.

Frasier Syndrome: A Rare Disorder in a Patient With Nephrotic Syndrome

Frasier syndrome is a rare genetic disorder characterized by the association of progressive renal glomerulopathy, 46,XY complete gonadal dysgenesis with a high risk of developing gonadoblastoma. Mutations in the Wilms' tumor suppressor gene (WT1) located in 11p23 responsible for this syndrome. Patients with this syndrome commonly present with normal female genitalia, streak gonads, and 46, XY karyotyping. Nephropathy in Frasier syndrome conferred as a nephrotic syndrome (NS) with proteinuria that begins early in childhood and progressively increases with age, mainly due to nonspecific focal and segmental glomerular sclerosis (FSGS). We herein discuss a 4 year-old-girl who presented as a steroid-resistant nephrotic syndrome and later on diagnosed as a Frasier syndrome.

Demetylation of the sex-determining region Y gene promoter and incidence of disorder of sex development in cloned dog males.

Canine cloning is occasionally accompanied by abnormal sexual development. Some male donor cells produce cloned pups with female external genitalia and complete male gonadal dysgenesis, which is classified as an XY disorder of sex development (XY DSD). In this study, we examine the potential of 5-aza-2'-deoxycytidine (5-aza-dC), a DNA methyltransferase inhibitor, to reduce the phenotypic abnormality XY DSD in somatic cell nuclear transfer (SCNT)- derived pups. We used a 9-year-old normal male German Shepherd dog as a cell donor. Donor cells were treated with 10 nM 5-aza-dC for 4 days before being used for SCNT. At the same stage of cell development, significantly lower levels of DNA methylation of the sex-determining region Y (SRY) promoter was observed in the treated donor cells compared to that in the untreated cells (95.2% versus 53.3% on day 4 for the control and treated groups, respectively). No significant differences were observed in the control or treatment groups concerning fusion rate, pregnancy rate (30 days or entire period), the number of pups, or the incidence of XY DSD. However, more XY DSD dogs were observed in the control group (31.25%) than in the treatment group (14.29%). Hypermethylation of the SRY promoter was observed in the XY DSD cloned pups in both the treatment (84.8%) and control groups (91.1 ± 1.4%) compared to the methylation level in the phenotypically normal male pups of the treatment (23.2 ± 20.9%) and control groups (39.1 ± 20.1%). These results suggest that 5-aza-dC treatment of donor cells can reduce the methylation level of the SRY promoter in donor cells, and thus, 5-aza-dC is advantageous for reducing the incidence of XY DSD in canine cloning.

A non-surgical approach to 46,XY differences in sex development through hormonal suppression at puberty: a single-center case series study.

We aim to report outcomes and safety with hormonal suppression to facilitate gonadal preservation in a select group of patients with 46,XY differences in sex development (DSD) who are raised and identify as female yet have diagnoses with potential for androgenization at puberty. We performed a retrospective review of the past 10 years of DSD patients treated by a multidisciplinary program. Inclusion criteria were 46,XY DSD, female sex of rearing, risk of androgenization at puberty, and plan for hormonal suppression at puberty. Patients on hormonal suppression had at least 6 months of follow-up from initiation. We excluded those with complete gonadal dysgenesis or complete androgen insensitivity. Four patients met inclusion criteria. Initial evaluation by DSD team was at a mean age of 6.6 years (3 weeks-16 years). All patients were evaluated in a coordinated multidisciplinary clinic. The diagnoses are listed in Table 1. Mean follow-up was 5.7 years (1.2-10.9 years). One patient presented as an infant, and is being monitored until Tanner stage 2 and/or serum hormonal evidence to initiate hormonal suppression. Three patients have been receiving hormonal suppression for 1.4 years (1.1-1.9 years) without side effects or complication. Three patients were initiated with estrogen replacement to promote desired breast development. At last follow-up, all patients had retained their gonads, all have female gender identity with no reported gender dysphoria, and no progression of androgenization. In our initial experience, gonadal preservation with hormonal suppression is a tool in multidisciplinary management of select DSD patients with female gender identity with conditions associated with androgenization at puberty. Patients' growth, bone health, and overall psychosocial well-being will need to be monitored closely.

Primary amenorrhea with Swyer syndrome: a rare case report

Swyer syndrome with complete gonadal dysgenesis is associated with an absence of testicular differentiation in a phenotypic female with a 46, XY karyotype. The diagnosis is usually made at adolescence when primary amenorrhea is investigated. Here is an interesting case report of 18-year-old unmarried girl, who presented with primary amenorrhea and non-development of breasts. Her body built was musculin with broad shoulders, prominent Adam’s apple and deep voice. Examination of her secondary sexual charaistisctcs revealed no breast development, absent axillary hair and sparse pubic hairs with female type of external genitalia. Laboratoryanalyses revealed serum follicle-stimulating hormone and luteinizing hormone levels compatible with hypergonodotropichypogonadism. Pelvicultrasonography showed an infantile uterus and streak gonads. Chromosome analysis revealed 46, XYkaryotype. Laparoscopic removal of streak gonads was done as there is a risk of gonadoblastoma in such cases. The patient was started on hormonal replacement therapy. Swyersyndrome results mainly due to mutation in certain genes such as SRY gene, which leads to failure of development of testis.&#x0D; Birdem Med J 2020; 10(2): 130-132

DHH pathogenic variants involved in 46,XY disorders of sex development differentially impact protein self-cleavage and structural conformation.

In humans, pathogenic variants in the DHH gene underlie cases of 46,XY gonadal dysgenesis. DHH is part of the Hedgehog family of proteins, which require extensive processing, including self-cleavage of the precursor for efficient signalling. In our work, we have assessed the effect of several human DHH pathogenic variants involved in recessive complete or partial gonadal dysgenesis, on protein processing and sub-cellular localization. We found that a subset of variants was unable to perform self-cleavage, which correlated albeit not perfectly with an altered subcellular localization of the resulting proteins. For the processing-proficient variants, we used structural modelling tools and molecular dynamic (MD) simulations to predict the potential impact of the variants on protein conformation and/or interaction with partners. Our study contributes to a better understanding of the molecular mechanisms involved in DHH dysfunction leading to 46,XY disorders of sex development.

Psychiatric view for disorders of sex development: a 12-year experience of a multidisciplinary team in a university hospital.

Background Psychiatric consultation is important in the follow-up of disorders of sex development (DSD) patients. In this study, we aimed to present the 12-year psychiatric follow-up data of the patients who were referred by Ege University Medical Faculty DSD Multidisciplinary Team and followed up in Child and Adolescent Psychiatry. Methods Psychiatric data of 118 patients, who were followed by the DSD multidisciplinary team between 2007 and 2019, were reviewed retrospectively. The psychiatric diagnoses of the patients were evaluated according to semi-structured interview form Schedule for Affective Disorders and Schizophrenia for School-Age Children/Present and Lifetime Turkish Version. Results The mean age of the 118 cases was 13.21 years (±7.18). Endocrine diagnoses of the cases were 46 XX DSD in 35 (29.6%), 46 XY DSD in 81 (68.7%), and chromosome disorders in 2 (1.7%). There was at least psychiatric diagnosis in 36 (30.5%) cases. The most common psychiatric diagnosis was attention deficit and hyperactivity disorder (ADHD) (n = 18, 15.3%). ADHD was most common in congenital adrenal hyperplasia (n = 4, 22.4%) and androgen synthesis defects (ASD) (n = 4, 22.4%); depression was most common in complete gonadal dysgenesis and ASD (n = 3, 23.1%); and mental retardation was most common in ASD (n = 3, 37.5%). Conclusions In order to provide a healthy perspective for cases with DSD, it is important to make a psychiatric evaluation and to share observations and clinical findings in regular team meetings.

Disorders of Sexual Development: Presentation and Categorization at Allied Hospital / Punjab Medical College Faisalabad, Pakistan

Background: Ambiguous genitalia is a condition in which external genitalia of the patients are ambiguous (not clearly male or female) or their external genitalia do not match with the chromosomal sex. It’s a rare condition and its incidence is 1.7%, or others say 1/5500 live births. Current nomenclature defines it as “disorder of sexual development” (DSD). It is generally divided into six categories; 46 XY DSD,46 XX DSD, chromosomal DSD, ovo-testicular DSD, 46 XY complete gonadal dysgenesis & 46XX testicular DSD. I_DSD registry (Glasgow) is the largest organization which registers such cases for clinical research and standardizes the information. Data from 51 centers from 36 countries across the globe is being uploaded there. Urology Department of Allied Hospital Faisalabad is the only center from Pakistan which registers its cases. Objectives: To identify and categorize different presentations of DSD according to the standard nomenclature. 2-To register the cases of DSD to I-DSD registry in Glasgow to be included in further clinical research. Study Design: Retrospective study. Settings: Urology Department Allied Hospital Faisalabad, Pakistan. Duration: From 01-09-2008 to 31-08-2019. Inclusion Criteria: All the patients with indeterminate sex / ambiguous genitalia presenting to OPD of Allied hospital Faisalabad irrespective of age Exclusion Criteria: Patients previously operated for DSD / with unrecorded data at first presentation. Methodology: Relevant data was retrieved from patients’ charts taken from hospital records, with the permission of hospital administration to publish their data. Patients had been evaluated with history/examination for phenotypical sex, with karyotyping for chromosomal sex, and ultrasonography & hormonal analysis (serum testosterone, FSH, LH and Estradiol) for gonadal sex. Specific tests like 17-OH levels performed in selected patients (CAH). Gender assignment was done according to chromosomal sex, after counselling of parents and adult patients. Results: Total 34 patients were enrolled. Mean age at presentation was 16.38 ± 9.38 years (range 10 months to 42 years). Nine of 34 patients were brought up as females, one as intersex and 24 as males. After categorization of various clinical presentations according to standard nomenclature, 27(79.4%) belonged to 46XY DSD category, 03(8.80%) to 46XX DSD, 02 (5.88%) to chromosomal DSD, 01(2.90%) was 46XY complete gonadal dysgenesis and 01(2.90%) patient belonged to ovo-testicular DSD. None of the patients had 46XX testicular DSD. Among the presumed female patients, six were chromosomally male and were having perineal hypospadias and were later assigned the male gender. Among the presumed male patients, two were diagnosed as CAH patients with XX genetic makeup. Three patients were having exstrophy epispadias complex, 15 patients were having perineal hypospadias (majority with undescended testes) and 7 had penoscrotal hypospadias. Conclusion: Identification & categorization of indeterminate sex and gender assignment is mandatory for social & psychological well-being of patients and their families.