Disorders Of Sexual Differentiation Research Articles

Genetic diagnosis of endocrine disorders in Cyprus through the Cyprus Institute of Neurology and Genetics: an ENDO-ERN Reference Center

The report covers the current and past activities of the department Molecular Genetics-Function and Therapy (MGFT) at the Cyprus Institute of Neurology and Genetics (CING), an affiliated Reference Center for the European Reference Network on Rare Endocrine Conditions (Endo-ERN).The presented data is the outcome of > 15 years long standing collaboration between MGFT and endocrine specialists from the local government hospitals and the private sector. Up-to-date > 2000 genetic tests have been performed for the diagnosis of inherited rare endocrine disorders. The major clinical entities included Congenital Adrenal Hyperplasia (CAH) due to pathogenic variants in CYP21A2 gene and Multiple Endocrine Neoplasia (MEN) type 2 due to pathogenic variants in the RET proto-oncogene. Other rare and novel pathogenic variants in ANOS1, WDR11, FGFR1, RNF216, and CHD7 genes were also found in patients with Congenital Hypogonadotropic Hypogonadism. Interestingly, a few patients with Disorders of Sexual Differentiation (DSD) shared rare pathogenic variants in the SRD5A2, HSD17B3 and HSD3B2 while patients with Glucose and Insulin Homeostasis carried theirs in GCK and HNF1A genes. Lastly, MGFT over the last few years has established an esteemed diagnostic and research program on premature puberty with emphasis on the implication of MKRN3 gene on the onset of the disease and the identification of other prognosis biomarkers.As an Endo-ERN member MGFT department belongs to this large European network and holds the same humanistic ideals which aim toward the improvements of health care for patients with rare endocrine conditions in respect to improved and faster diagnosis.

Pregnancy outcomes with undescended testis husbands: influenced by wive’s life style and surgical correction before 1 year

Background The most prevalent sexual differentiation disorder in males is undescended testis (UDT), which occurs when the testis is absent from the scrotum or cannot be brought down during a physical examination. Pregnancy outcome may be influenced by the wife’s lifestyle and surgical correction within the past year
 Objectives This study aims to determine pregnancy outcome in Assisted Reproductive Technology (ART) on a wive with a UDT husband assessed by the wive’s life style and surgery correction before 1 year.
 Methods A cross-sectional study was conducted. Data were taken from patients who underwent Assisted Reproductive Technology at AMC Hospital, Yogyakarta. Data collection from 2018 to 2021. Samples in the unilateral and bilateral groups were 20 husbands. Wilcoxon Signed Rank Test helped carry out the analyses.
 Results There was an association between infertility and UDT either unilaterally or bilaterally (p = 0.009). Most UDT husbands had a BMI in the overweight category and the average age was 28 and 29. Other factors such as the wive’s life style and surgery correction before 1 year , including smoking habit, alcohol consumption, addictive drug and hormonal drug, had no significant effect on the success of pregnancy outcome (p > 0.05).
 Conclusions Although pregnancy outcome in unilateral and bilateral UDT patients was not statistically significant, clinically, the pregnancy outcome was better in husbands with unilateral UDT by IUI than in IVF.
 Bangladesh Journal of Medical Science Vol. 23 No. 02 April’24 Page : 455-462

Androgen insensitivity syndrome: preventive gonadectomy, pros and cons

Androgen insensitivity syndrome is a genetic disorder characterized by complete or partial androgen insensitivity in individuals with a 46XY genotype. It is also the most common cause of disorders of sexual differentiation in patients with a 46XY karyotype. This condition is caused by a defect in the androgen receptor gene (AR), leading to abnormal development of male genitalia, impaired formation of male secondary sexual characteristics, and phenotypic features resembling the female sex.One of the important aspects related to the management of androgen insensitivity syndrome is the necessity of preventive gonadectomy. However, the rationale for prophylactic removal of gonads remains a subject of debate. This article presents a clinical case of a 37-year-old woman with complete androgen insensitivity syndrome who, despite recommendations for gonadectomy based on suspicious MRI characteristics of the gonads, made the decision to decline surgical intervention, justifying her choice by the positive impact of gonadal hormonal activity on her external appearance and physical characteristics. This clinical case highlights the complexity of decision-making in the management of androgen insensitivity syndrome, where patient preferences and needs may play a significant role, despite potential risks and concerns surrounding the preservation of gonads.

Application of management algorithm to a series of patients of disorders of sexual differentiation from Southern India: A case series 

No abstract available

Molecular Diagnosis of Sexual Differentiation Disorders in Burkina Faso

Molecular Diagnosis of Sexual Differentiation Disorders in Burkina Faso

Extensive Literature Review of 46, XX Newborns with Congenital Adrenal Hyperplasia (CAH) and Severe Genital Masculinization: Should They be Assigned and Reared Male?

46, XX individuals born with severely masculinized genitals due to congenital adrenal hyperplasia (CAH) who have been assigned males at birth and reared male can successfully establish a male gender identity/role, find employment, marry, function sexually with a female partner, and develop positive mental health status. While there were a few individuals who reportedly did not fare well or who changed gender to female, the majority of those identifying as males appear to have an overall good quality of life. Parental/family support, along with the support of others, appears essential to a positive outcome as a male or as a female. Reasons are given to support why serious consideration of a male gender assignment and rearing, in certain situations, is justified and should be seriously considered. Disorders of Sex Differentiation (DSD) teams should inform parents of the option of male assignment and rearing in 46, XX CAH infants with severe genital masculinization, a rare condition. To provide this option is concordant with the principles of ethics, transparency and with the Endocrine Society Guidelines and the American Academy of Pediatrics' policy of fully informed consent.

Complete or partial loss of the Y chromosome in an unselected cohort of 865 non-vasectomized, azoospermic men

BackgroundStructural abnormalities as well as minor variations of the Y chromosome may cause disorders of sex differentiation or, more frequently, azoospermia. This study aimed to determine the prevalence of loss of Y chromosome material within the spectrum ranging from small microdeletions in the azoospermia factor region (AZF) to complete loss of the Y chromosome in azoospermic men.ResultsEleven of 865 azoospermic men (1.3%) collected from 1997 to 2022 were found to have a karyotype including a 45,X cell line. Two had a pure 45,X karyotype and nine had a 45,X/46,XY mosaic karyotype. The AZF region, or part of it, was deleted in eight of the nine men with a structural abnormal Y-chromosome. Seven men had a karyotype with a structural abnormal Y chromosome in a non-mosaic form. In addition, Y chromosome microdeletions were found in 34 men with a structural normal Y chromosome. No congenital malformations were detected by echocardiography and ultrasonography of the kidneys of the 11 men with a 45,X mosaic or non-mosaic cell line.ConclusionsIn men with azoospermia, Y chromosome loss ranging from small microdeletions to complete loss of the Y chromosome was found in 6.1% (53/865). Partial AZFb microdeletions may give a milder testicular phenotype compared to complete AZFb microdeletions.

Disorders of sexual differentiation. A clinical case

The biological sex of a person is anatomical, physiological, and genetic features that help distinguish a male organism from a female one. One distinguishes genetic, gonadal, and phenotypic sex of a person. Sexual differentiation is a process of development, during which the biological male or female sex is formed, it occurs under the influence of genetic and hormonal factors during fetal development. In this regard, any damage at this stage can lead to disorder of sexual development of a newborn. Disorder of sexual differentiation is a complex of medical conditions in which there is a mismatch between a person’s genetic, gonadal and phenotypic sex.Sometimes it is difficult to visually determine the sex of a child born with disorder of the sexual development due to an abnormal, undefined structure of the external genitalia. For example, they may have the appearance of hypertrophied labia majora and/or a hypertrophied clitoris and the absence of testicles, or vice versa, the child’s genitals may have a normal appearance, but at the same time the internal genitals may be improperly developed.To determine which gender to choose for a child with disorder of sexual differentiation, a number of examinations, including genetic ones, should be carried out. Disorder of sexual differentiation is a complex medical and social problem involving a multidisciplinary team of doctors and the patient’s family. This article describes a clinical case of a child with disorder of sexual differentiation at the stage of diagnosis verification. An interdisciplinary approach is an integral part of accompanying a child with disorder of sexual differentiation, where the joint efforts of doctors, psychologists, teachers and other specialists contribute to the creation of inclusive and safe conditions for the development of each person.

An Unusual Clinical and Radiological Presentation of Ovotesticular Disorders of Sex Development with Male and Female External Genitalia: A Case Report

Background: Ovotesticular disorders of sex development (ODSD), previously known as true hermaphroditism, is a rare disorder of sexual differentiation that causes ambiguity in external genitalia and the presence of both ovarian and testicular elements in the gonads. The condition is characterised by the existence of testicular tissue with distinctive tubules and ovarian tissue in the same gonad (ovotestis), or separately in an individual. The most common cytogenetic karyotype is 46,XX. The age and presentation of symptoms vary, but typically include hypospadias, urogenital sinus, inguinal hernia, cryptorchidism, and gynaecomastia during the peripubertal age, as well as lower abdominal mass. Case Presentation: A 15-year-old female exhibited typical male genitalia, including a normal penile shaft, scrotal sac, palpable testes, and a urethral opening, with a separate vaginal opening located between the penile shaft and scrotum. Pelvic MRI confirmed the presence of both testes within the scrotal sac and an infantile-sized uterus with a central endometrium, as well as a left-sided ovary in the pelvic region. The right ovary was not seen. Correlative ultrasound confirmed these findings and indicated that the testes had a normal echo texture and vascularity. The patient was diagnosed with ODSD, and further hormonal testing was recommended. Conclusions: ODSD is a rare cause of genital ambiguity. Typically, both paramesonephric and mesonephric duct derivatives are seen, and most of the affected individuals present as neonates or infants with ambiguous external genitalia. At peripubertal age, the symptoms typically include hypospadias, urogenital sinus, inguinal hernia, unilateral or bilateral cryptorchidism, and gynaecomastia. Fertility is not uncommon and has been reported in female-reared patients. The ovotestis is the commonest gonad in people with ODSD and are known to be predisposed to germ cell tumours. Over 500 cases of ODSD have been reported in the literature. Ultrasound is the first line of investigation used to see the pelvic organs. The non-invasive test of choice for detecting paramesonephric and mesonephric duct derivatives is an MRI pelvis. The purpose of this paper is to describe various clinical and radiological features associated with ODSD.

(199) Anterolateral Thigh Flap Phalloplasty for Micropenis

Abstract Introduction Congenital micropenis is defined as a normally formed penis with a stretched penile length less than 2.5 standard deviations below the mean for that man’s age and ethnicity. Micropenis may present as an isolated condition or with other genital or multi-system abnormalities. Penile reconstruction or phalloplasty may be required where topical and systemic hormonal treatment have failed. The most common flap used for phalloplasty is the radial artery forearm free flap phalloplasty. Other alternatives include the anterolateral thigh (ALT), musculocutaneous latissimus dorsi and abdominal flaps. Objective The aim of this video is to illustrate the technique for penile reconstruction using a pedicled ALT flap without integrated urethra. Methods A 21-year-old man with micropenis and hypospadias from a disorder of sexual differentiation (46XY) presents for penile reconstruction following multiple failed attempts at hypospadias repair. He requested an ALT flap without integrated urethra because he is dependent on a long-term suprapubic catheter due to a hypocontractile bladder. Intraoperative vascular doppler identified 3 perforators from the descending branch of the lateral circumflex iliac artery of the left leg. The flap was designed centred on the perforators with dimensions of 14cm (length), 13cm (width at base) and 12cm (width at tip). The flap was raised carefully and transferred to the recipient groin. The neophallus was constructed and microsurgical anastomosis of the lateral cutaneous of the thigh to one of the dorsal penile nerves with 8/0 nylon was completed. The partially divided left vastus lateralis muscle was re-approximated and the skin edges drawn in and flattened. The left thigh was then resurfaced with a 14/1000 of an inch split-thickness skin graft from the contralateral thigh. All wounds were dressed. Results The man had an uneventful post-operative course with careful vascular monitoring, and he was discharged on day 10. He is currently awaiting glans-sculpting and will eventually proceed with insertion of an inflatable erectile device. Conclusions Penile reconstruction using an ALT flap can be offered to a well-informed and motivated man with a micropenis following appropriate assessment. As shown, the technique requires careful dissection of the perforator vessels and can usually be transferred as a pedicled flap. Pedicled flaps do not require microvascular anastomosis and therefore have a lower risk of vascular compromise. Further esthetic and functional refinements like the insertion of an erectile device are possible in later stages, if desired. Disclosure No

46 XY disorder of sex development: Case report

Disorders of sexual differentiation in 46, XY patients cover a wide spectrum of clinical pictures (female phenotype, posterior hypospadias, cryptorchidism). Their causes are varied and affect the stages of testicular determination (gonadal dysgenesis) or defects in testosterone production or action (testosterone secretion abnormalities, androgen insensitivity, 5⍺-reductase deficiency). They require rational and rapid management, within a multidisciplinary team. We report a rare case of this disorder in a patient of 18 years with the therapeutic obstacles that we faced in its management.

Anti-Müllerian hormone - clinical use and future possibilities.

Anti-Müllerian hormone (AMH) is a protein produced already in human fetus. It has an essential role in the differentiation of the reproductive tract, regulation of the ovaries and testes. The determination of serum AMH levels is used in clinical practice. Today, especially in reproductive medicine in the assessment of ovarian reserve and in the prediction of the response to ovarian stimulation. However, in young cancer patients, it can also predict the risk of ovarian failure after anticancer treatment. It finds further use in pediatric endocrinology in the diagnosis of sexual differentiation disorders. In oncology, it is used as a tumor marker for monitoring patients with granulosa tumors. In the future, however, it is also promising to use the knowledge of AMH function for the treatment of gynecological as well as other solid malignancies expressing a tissue-specific receptor for AMH.

V11-03 PENILE RECONSTRUCTION FOR CONGENITAL MICROPENIS WITH THE ANTEROLATERAL THIGH PEDICLED FLAP

You have accessJournal of UrologyCME1 Apr 2023V11-03 PENILE RECONSTRUCTION FOR CONGENITAL MICROPENIS WITH THE ANTEROLATERAL THIGH PEDICLED FLAP Aurélie Schirmann, Nim Christopher, David Ralph, and Wai Gin Lee Aurélie SchirmannAurélie Schirmann More articles by this author , Nim ChristopherNim Christopher More articles by this author , David RalphDavid Ralph More articles by this author , and Wai Gin LeeWai Gin Lee More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003337.03AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Congenital micropenis is defined as a normally formed penis with a stretched penile length less than 2.5 standard deviations below the mean for that man’s age and ethnicity. Micropenis may present as an isolated condition or with other genital or multi-system abnormalities. Penile reconstruction or phalloplasty may be required where topical and systemic hormonal treatment have failed. The most common flap used for phalloplasty is the radial artery forearm free flap phalloplasty. Other alternatives include the anterolateral thigh (ALT), musculocutaneous latissimus dorsi and abdominal flaps.The aim of this video is to illustrate the technique for penile reconstruction using a pedicled ALT flap without integrated urethra. METHODS: A 21-year-old man with micropenis and hypospadias from a disorder of sexual differentiation (46XY) presents for penile reconstruction following multiple failed attempts at hypospadias repair. He requested an ALT flap without integrated urethra because he is dependent on a long-term suprapubic catheter due to a hypocontractile bladder.Intraoperative vascular doppler identified 3 perforators from the descending branch of the lateral circumflex iliac artery of the left leg. The flap was designed centred on the perforators with dimensions of 14cm (length), 13cm (width at base) and 12cm (width at tip). The flap was raised carefully and transferred to the recipient groin. The neophallus was constructed and microsurgical anastomosis of the lateral cutaneous of the thigh to one of the dorsal penile nerves with 8/0 nylon was completed. The partially divided left vastus lateralis muscle was re-approximated and the skin edges drawn in and flattened. The left thigh was then resurfaced with a 14/1000 of an inch split-thickness skin graft from the contralateral thigh. All wounds were dressed. RESULTS: The man had an uneventful post-operative course with careful vascular monitoring, and he was discharged on day 10. He is currently awaiting glans-sculpting and will eventually proceed with insertion of an inflatable erectile device. CONCLUSIONS: Penile reconstruction using an ALT flap can be offered to a well-informed and motivated man with a micropenis following appropriate assessment. As shown, the technique requires careful dissection of the perforator vessels and can usually be transferred as a pedicled flap. Pedicled flaps do not require microvascular anastomosis and therefore have a lower risk of vascular compromise. Further aesthetic and functional refinements like the insertion of an erectile device are possible in later stages, if desired. Source of Funding: None declared © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e999 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Aurélie Schirmann More articles by this author Nim Christopher More articles by this author David Ralph More articles by this author Wai Gin Lee More articles by this author Expand All Advertisement PDF downloadLoading ...

Prevalence, distribution, and risk markers for the development of gonadal germ cell tumors in patients with certain types of disorders of sexual differentiation with Y chromosome - A retrospective study.

To study the prevalence, subtypes, and risk markers for the development of gonadal germ cell tumors (GCT's) among disorders of sexual differentiation (DSD) patients with the Y chromosome. Design: A retrospective review of the patient's case records from 2010 to 2020 in Government Medical College, Thiruvananthapuram, India was studied. The study participants included 54 subjects with DSD containing the Y chromosome. Demographic data, external masculinization scoring, associated congenital anomalies, karyotyping, intraoperative findings such as gonadal location and internal genital ducts, histopathology of the resected gonads, and its immunohistochemistry were collected. The prevalence of gonadal GCT's was estimated from paraffin-embedded gonadectomy samples (S = 82). The median age of occurrence of gonadal GCT's was 18 years. The prevalence of malignant gonadal GCT's was highest among the PAIS group (19.2%) followed by gonadal dysgenesis (15.8% each in MGD and CGD) and least among CAIS (7.7%) (p < 0.01). The most common type of malignant gonadal GCT's in the descending order of frequency was dysgerminoma, seminoma, mixed GCT, and yolk sac tumor. Multivariance logistic analysis showed post-puberty and the presence of congenital anomalies were associated with the occurrence of gonadal GCT's ( P < 0.01). The overall prevalence of gonadal GCT's (malignant and premalignant) among DSD with Y chromosomes is nearly 25%. Dysgerminoma is the most common malignant gonadal GCT's. Age at or above 18 years and the presence of congenital anomalies like renal agenesis, retroperitoneal vascular defects, and congenital diaphragmatic hernia were independent risk markers for the development of gonadal GCT's.

Posterior Sagittal Approach for Nonanorectal Malformation: Widening Spectrum.

Posterior sagittal is a very well accepted approach in the treatment of anorectal malformations. This approach provides good access and exposure through the perineum to the deep pelvic structures. It reduces risk of injury to important structures as dissection remains in midline. To access feasibility of posterior sagittal approach for non-anorectal malformation indications and to widen the spectrum. We present a series of 10 cases of non-anorectal malformations operated by this approach for 4 years. Six patients included in the study were of Disorders of Sexual Differentiation with pseudovagina, three of Y duplication of the urethra, and one of cervical atresia. All patients had good results. Posterior sagittal approach is feasible, safe with minimal bleeding, and no postoperative incontinence. It can safely be used for non-anorectal indications.

An approach to the management and care of an individual with 46, XX ovotesticular disorder of sexual differentiation

Ovotesticular disorder of sexual differentiation (OT-DSD) is a rare condition defined by the presence of both testicular and ovarian elements in the same individual. Definitive diagnosis is made based on histological assessment of the gonad/s confirming both ovarian and testicular components. In this paper, we describe how a diagnosis of 46XX, OT-DSD was made in a 20-year-old individual with enlarged breasts and ambiguous genitalia. The initial impression was congenital adrenal hyperplasia (CAH) based on 46, XX karyotype and absence of testes on physical examination and imaging. However, biochemical tests were inconsistent with CAH, hence a more probable diagnosis of 46, XX OT-DSD was considered. The patient suffered from gender dysphoria and after extensive counseling, he decided to undergo gender-affirming surgery: laparoscopic excision of the left gonad, subtotal hysterectomy, bilateral mastectomy, and a masculinizing genitoplasty. Histopathology of the left gonad revealed an ovotestes which confirmed the diagnosis of 46, XX OT-DSD.

Adolescent females with 46, XY Disorders of Sexual Differentiation

Disorders of sex development are congenital conditions where chromosomal, gonadal and anatomical sex of an individual is atypical. The sex of an individual is governed by chromosomal complement, which in turn decides the development of bi-pontential gonad and differentiation of external as well as internal genitalia into a definitive human sex either male or female. Though this is the general plan of sex development, most of the times in spite of being normal chromosomal complement, the gonadal and/ or genital sex is discordant leading to conditions known as disorders of sex development. Depending upon the chromosomal complement, these conditions are classified as (a) sex chromosome DSD (b) 46, XY DSD and (c) 46, XX DSD. Though most of the DSDs present at infancy with genital ambiguity and other clinical features, some of these conditions may not present or get recognized until adolescence and presenting as lack of pubertal development or primary amenorrhea. This leads to a social stigma to the patient as well as the family members and proper counselling and management of these cases can be improved by understanding the molecular pathology of these conditions. This review helps to understand the molecular genetics of 46, XY DSD in adolescent females who present as lack of puberty and primary amenorrhea.

Co-Occurrence of a Pathogenic HSD3B2 Variant and a Duplication on 10q22.3-q23.2 Detected in Newborn Twins with Salt-Wasting Congenital Adrenal Hyperplasia

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders caused by enzyme deficiencies required for cortisol biosynthesis in the adrenal cortex. The majority of CAH are due to the deficiency of the 21-hydroxylase enzyme, while 3β-hydroxysteroid dehydrogenase type 2 deficiency accounts for less than five percent of all CAH cases. We report two Moroccan twins from a spontaneous triplet pregnancy. The 46,XY newborn exhibited a disorder of sexual differentiation (DSD) with hypo virilization, while the 46,XX newborn had normal female external genitalia. In the first week of life, they showed hyponatremia and primary adrenal insufficiency with a slight 17OHP elevation and increased DHEAS and renin levels. The aCGH-SNP analysis disclosed a 8.36 Mb long contiguous stretch of homozygosity (LCSH) on chromosome 1p13.2-p11.2 including the candidate HSD3B2 gene, a LCSH of 7.3 Mb on 14q31.1-q32.11, and a 7 Mb duplication on 10q22.3-q23.2. Clinical exome sequencing revealed the biallelic c.969T > G (p.Asn323Lys) HSD3B2, likely pathogenic, variant in both of the affected twins. This case emphasizes the importance of a prompt molecular diagnosis performed through the combination of aCGH and clinical exome, both for establishment of correct therapy and for follow-up, as the newborns also carry a genomic rearrangement with possible clinical implications.

RF02 | PMON309 Two Siblings with p.Arg92Trp Variant in NR5A1 Presenting with Testicular Disorder of Sexual Differentiation

Abstract Introduction Disorders of sexual differentiation (DSD) are conditions of abnormal chromosomal development leading to atypical gonadal and anatomic sexual characteristics. We present the case of two siblings with 46, XX testicular DSD due to a mutation in the nuclear receptor subfamily 5 group A member 1 gene (NR5A1). While there is extensive literature about pathogenic variants of this gene, this is the first variant that has been shown to cause DSD in XX individuals, rather than XY. Case presentation This is the case of a sibling pair with male phenotype and history of hypospadias and hypogonadism in the setting of 46, XX karyotype. Sibling A presented with hypospadias at birth and hypergonadotropic hypogonadism in childhood, initially managed with testosterone. Testicular biopsy revealed bilateral germ cell aplasia with degeneration of seminiferous tubules. Sibling B presented at age 8 with precocious puberty. He had a history of hypospadias and cryptorchidism at birth. Gonadotropins and testosterone levels were prepubertal. Testicular biopsy showed only Sertoli cells. Their adrenal gland and thyroid function was normal, their bone age was advanced. FISH was negative for the SRY gene in both cases, no ovaries or mullerian structures found in pelvic imaging. DSD genetic panels were sent, resulting positive for the R92W variant in NR5A1. Neither of them have intellectual disability; however, sibling B has attention deficit and hyperactivity disorder (ADHD) and obsessive compulsive disorder (OCD). Family history is remarkable for two uncles that have been unable to conceive. Their mother had oligomenorrhea and difficulty conceiving, typical presentation of a female carrier of this mutation. Discussion and conclusions The majority of DSD in individuals with a 46, XX karyotype are due to congenital adrenal hyperplasia (CAH) secondary to 21-hydroxylase deficiency, however, mutations in NR5A1 have been among the most frequently identified genetic causes of gonadal development disorders and are associated with a wide phenotypic spectrum. NR5A1 is an essential transcription factor that regulates target genes crucial for normal reproductive physiology and endocrine function, controlling several steps of adrenal and gonadal development. While there is extensive literature about the phenotype caused by variants of NR5A1 in XY individuals, the recurrent heterozygous p.Arg92Trp NR5A1 variant R92W that our patients have, is the only one that has been shown to cause DSD in XX individuals, with variable degrees of testis development. It has previously been described, however, in women with primary ovarian insufficiency (POI). Morevariants of this gene will continue to arise, playing a pivotal role in reproductive endocrinology. Presentation: Saturday, June 11, 2022 1:00 p.m. - 1:05 p.m., Saturday, June 11, 2022 1:00 p.m. - 1:05 p.m., Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Development of the human ovary: Fetal through pubertal ovarian morphology, folliculogenesis and expression of cellular differentiation markers

A definition of normal human fetal and early postnatal ovarian development is critical to the ability to accurately diagnose the presence or absence of functional ovarian tissue in clinical specimens. Through assembling an extensive histologic and immunohistochemical developmental ontogeny of human ovarian specimens from 8 weeks of gestation through 16 years of postnatal, we present a comprehensive immunohistochemical mapping of normal protein expression patterns in the early fetal through post-pubertal human ovary and detail a specific expression-based definition of the early stages of follicular development. Normal fetal and postnatal ovarian tissue is defined by the presence of follicular structures and characteristic immunohistochemical staining patterns, including granulosa cells expressing Forkhead Box Protein L2 (FOXL2). However, the current standard array of immunohistochemical markers poorly defines ovarian stromal tissue, and additional work is needed to identify new markers to advance our ability to accurately identify ovarian stromal components in gonadal specimens from patients with disorders of sexual differentiation.