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Differences of sex development (DSDs) are a heterogeneous group of congenital conditions in which chromosomal, gonadal, or anatomical sex does not match. The broad spectrum of phenotypes associated with DSDs requires accurate diagnosis, which influences the care and quality of life of affected patients. The decreasing costs of next-generation sequencing (NGS) and international research collaborations in rare diseases have allowed the identification of new genes associated with DSDs. Recently, Hughes et al. in 2020 reported the association of loss-of-function (LoF) variants in PPP1R12A with morphological anomalies of the midline, including holoprosencephaly and urogenital malformations, also known as genitourinary and/or brain malformation syndrome (OMIM #618820). In this report, we describe a Mexican individual with hypertelorism, multiple skin hemangiomas, testicular atrophy, and sex reversal, in whom a c.1880delC frameshift variant in PPP1R12A was detected by exome sequencing. Segregation analysis confirmed it as a de novo variant through Sanger sequencing. The main objective of this report is to expand PPP1R12A-related urogenital and/or brain malformation syndrome.

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Intersex, an umbrella term, describes individuals with sex characteristics that cannot be exclusively categorized into binary definitions of male or female. The intersex community faces a lack of social visibility perpetuated by a history of medical discrimination and pathologization shaped by "normalizing" genital surgeries without the child's consent. Despite efforts to reform clinical practice, there remains a paucity of research centering the needs of the intersex community and their families. This study explored parents' perspectives on how healthcare professionals (HCPs), such as genetics professionals, can provide patient-centered education and support when parents first learn of their child's intersex variation, with the aim of offering recommendations to HCPs to promote parental adjustment and protect intersex children's right to autonomy. Thirteen qualitative semi-structured interviews were conducted with 14 parents of intersex children. Through reflexive thematic analysis, under the framework of an agency-based approach to intersex health, thematic categories were inductively conceptualized, including barriers and facilitators to HCPs' sensitivity and to parental adjustment in the early disclosure environment. Barriers to HCPs' sensitivity were imposed by educational, religious, or medical institutions, along with sociocultural prejudices and pathologizing language. Barriers to parental adaptation included uncertainty regarding their child's future, sociocultural gender norms, and unsuitable information provision. Incorporating parental needs in the disclosure environment can facilitate familial acceptance, including normalization of variations of sex characteristics (VSCs), enhanced medical education, facilitation of patients' navigation, and prioritization of parents' social support needs.

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NR2F2 encodes COUP-TFII, an orphan nuclear receptor required for the development of the steroidogenic lineages of the murine fetal testes and ovaries. Pathogenic variants in human NR2F2 are associated with testis formation in 46,XX individuals, however, the function of COUP-TFII in the human testis is unknown. We report a de novo heterozygous variant in NR2F2 (c.737G > A, p.Arg246His) in a 46,XY under-masculinized boy with primary hypogonadism. The variant, located within the ligand-binding domain, is predicted to be highly damaging. In vitro studies indicated that the mutation does not impact the stability or subcellular localization of the protein. NR5A1, a related nuclear receptor that is a key factor in gonad formation and function, is known to physically interact with COUP-TFII to regulate gene expression. The mutant protein did not affect the physical interaction with NR5A1. However, in-vitro assays demonstrated that the mutant protein significantly loses the inhibitory effect on NR5A1-mediated activation of both the LHB and INSL3 promoters. The data support a role for COUP-TFII in human testis formation. Although mutually antagonistic sets of genes are known to regulate testis and ovarian pathways, we extend the list of genes, that together with NR5A1 and WT1, are associated with both 46,XX and 46,XY DSD.

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Objective: Evaluation of the participant satisfaction with a newly developed interdisciplinary, modular education program for children, adolescents, and young adults with differences of sex development (DSD) and their parents. Methods: The two-day program including tailored medical information, peer consultation and psychological support aimed to improve diagnosis-specific knowledge and empowerment. Post-training satisfaction was measured using an adapted ZUF-8 questionnaire, scoring from 5 (worst) to a maximum of 26 (best) for persons aged 6-17 and from 10 to 40 points for adults, including 2 open-ended questions. Results: The questionnaire, completed by 89 children (6-13 years), 92 adolescents (14-17 years), 47 young adults (18-24 years), and 345 parents, revealed consistent high satisfaction with the program regardless of age or diagnosis (children 24.4 ± 2.1, adolescents 23.5 ± 2.7; young adults 36.0 ± 4.0, parents 36.6 ± 3.4). Neither sociodemographic factors nor diagnosis burden, shame, or informedness showed relevant associations with satisfaction levels. Participants highlighted exchange and open atmosphere as key satisfaction elements. Conclusion: Satisfaction with the new education program was high in all examined groups. Implementing it in routine care requires further analysis to determine the program's long-term effects on well-being and knowledge. Innovation: The first educational program for young people with DSD addressing their specific challenges through inclusive language, an open approach to sex and gender and the inclusion of self-help groups.

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Background and Aims: Of late, there are many legal representations from select quarters to halt all medical interventions in children with differences of sex development (DSD). In this survey on management decisions in DSD, we distil the views of Indian stakeholders: parents, physicians, and grown-up patients with DSD on their management decisions to identify decisional satisfaction or gender dysphoria. Methods: The survey domains included the patient demographics, final diagnosis, decision on the sex of rearing, surgical interventions, opinion of the stakeholders on the preferred age of sex assignment, final sex of rearing, and agreement/disagreement about sex assignment (gender dysphoria). Results: A total of 106 responses were recorded (66% parents, 34% grown-up patients aged 12-50 years). Among parents, 65/70 (95%) preferred the sex to be assigned soon after birth. All grown-up patients preferred sex to be assigned soon after birth. Regarding decisions on surgery, 74% of physicians and 75% of the grown-up patients felt parents should be allowed to decide interventions. Among Indian parents, 90% felt they should have the right to decide surgery in the best interest of their child for a safe social upbringing. Overall, gender dysphoria among Indian DSD patients was <1% (1/103, 0.97%). Conclusions: The predominant preference and opinion of major Indian stakeholders (physicians, parents, and grown-up DSD patients) support the existing approach toward DSD management, including early sex assignment and necessary medical intervention.

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INTRODUCTION: Achieving evidence-based, high-quality medical care is the overarching goal of healthcare quality management. Quality indicators (QIs) serve as proxies to show whether good quality is reached or not. This article describes the development of QI for the evaluation of healthcare quality in the area of differences of sex development (DSD). METHODS: Following the model of Donabedian, the aim was to develop QI to assess defined relevant aspects of the quality of structures, processes, and outcomes of care in DSD. Ten DSD clinical centres and two self-advocacy groups in Germany included in the DSDCare project were involved in the development of the QI and a benchmarking system. The development of the QI involved several structured steps: analysis of guidelines and recommendations, literature review, qualitative interviews with key stakeholders in the field of DSD, and patients or their carers. QIs were discussed in a multi-stage systematic consensus process and assessed in terms of their relevance, feasibility, and practicability. RESULTS: In a multi-stage systematic consensus process involving medical and psychological experts from a range of disciplines, people with DSD and their families, and representatives of self-advocacy groups, we have developed a set of 37 QIs (22 structure, seven process, and eight outcome quality). The QIs serve to evaluate care in the field of DSD and may add to the German criteria for certification of Centres for Rare Conditions formulated by the National Action League for People with Rare Diseases (NAMSE) in this area of expertise. CONCLUSION: We have succeeded in developing and jointly adopting a set of QIs that consider a wide range of perspectives on the quality of care for people with DSD and their families. These QIs have been found to be relevant, feasible, and practicable, and they are now used for a yearly quality benchmarking in the participating DSD centres.

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Background: Differences of Sex Development (DSD) are congenital conditions where the chromosomal, gonadal and anatomical sex characteristics do not strictly belong to male or female categories, or that belong to both at the same time. Surgical interventions for individuals with DSD remain controversial, among affected individuals, caregivers, and health-care providers. A lack of evidence in support of, for deferring, or for avoiding surgery complicates the decision-making process. This study explores Norwegian health-care professionals' (HCPs) perspectives on decision-making in DSD-related surgeries and the dilemmas they are facing in this process. Methods: Focus group interviews with 14 HCPs integrated into or collaborating with multidisciplinary DSD teams were analyzed using reflexive thematic analysis. Results: Two overarching dilemmas shed light on the intricate considerations and challenges that HCPs encounter when guiding affected individuals and caregivers through surgical decision-making processes in the context of DSD. The first theme describes how shared decision-making was found to be influenced by fear of stigma and balancing the interplay between concepts of normality, personal experiences and external expectations when navigating the child's and caregivers' needs. The second theme illuminated dilemmas due to a lack of evidence-based practice. The core concepts within each theme were the dilemmas health-care professionals face during consultations with caregivers and affected individuals. Conclusion: HCPs were aware of the controversies with DSD-related surgeries. However, they struggled to reconcile knowledge with parents' wishes for surgery and faced dilemmas making decisions in the best interests of the child. This study draws attention to the benefits of increased knowledge on the consequences of performing or withholding surgery as well as incorporating tools enabling shared decision-making between HCPs and affected individuals/caregivers.

DSD-related surgeries are controversial and subject to debate.Health-care professionals grapple with dilemmas during shared decision-making, as revealed in focus group interviews.Health-care professionals were concerned that parents' and affected individuals' fear of stigmatization would influence the shared decision-making process. Lack of evidence-based knowledge on practice, left health care professionals without clear guidelines on how to navigate decision-making.

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OBJECTIVE: The present study aimed to identify distinct trajectories of parental illness uncertainty among parents of children born with atypical genital appearance due to a difference of sex development over the first year following diagnosis. It was hypothesized that four trajectory classes would emerge, including "low stable," "high stable," "decreasing," and "increasing" classes, and that select demographic, familial, and medical factors would predict these classes. METHODS: Participants included 56 mothers and 43 fathers of 57 children born with moderate to severe genital atypia. Participants were recruited from eleven specialty clinics across the U.S. Growth mixture modeling (GMM) approaches, controlling for parent dyad clustering, were conducted to examine classes of parental illness uncertainty ratings over time. RESULTS: A three-class GMM was identified as the best-fitting model. The three classes were interpreted as "moderate stable" (56.8%), "low stable" (33.0%), and "declining" (10.3%). Findings suggest possible diagnostic differences across trajectories. CONCLUSIONS: Findings highlight the nature of parents' perceptions of ambiguity and uncertainty about their child's diagnosis and treatment the year following their child's birth/diagnosis. Future research is needed to better understand how these trajectories might shift over the course of the child's development. Results support the development of tailored, evidence-based interventions to address coping with uncertainty among families raising a child with chronic health needs.

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OBJECTIVE: Differences of sex development (DSD) can affect the physical health, appearance, and psychosocial functioning of affected individuals, but little is known about how subjective appearance perceptions (body image) impact psychosocial outcomes. This study evaluated body image and its associations with psychosocial outcomes including quality of life, resilience, and psychosocial adjustment. METHODS: This cross-sectional, multi-method study assessed body image and psychosocial outcomes including quality of life, adjustment, and resilience in 97 youth and young adults with DSD (mean age = 17 ± 3.7 years; 56% assigned female in infancy) using psychometrically sound instruments. A subsample (n = 40) completed qualitative interviews. RESULTS: Quantitative results indicated that overall, participants were satisfied with their physical appearance, although less so with their primary sex characteristics. Body image dissatisfaction was associated with poorer psychosocial adjustment, quality of life, and resilience. Qualitatively, youth and young adults reported a variety of perceptions, both positive and negative, related to their body image and the impact of living with a DSD condition. Themes identified included appearance management; effects of DSD on body image; diagnostic factors and features; attitudes about diagnosis; and treatment. CONCLUSIONS: Body image is significantly associated with psychosocial outcomes in youth and young adults with DSD, with qualitative findings highlighting both positive and negative body image experiences. Results have implications for clinical care including screening for appearance concerns, normalization of appearance variations, and intervention development to better support healthy body image and psychosocial functioning in youth and young adults with DSD.

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BACKGROUND: Androgen insensitivity syndrome (AIS) is a common condition among individuals with differences of sexual development (DSD) and results from germline allelic variants in the androgen receptor (AR) gene. Understanding the phenotypic consequences of AR allelic variants that disrupt the activation function 2 (AF2) region is essential to grasping its clinical significance. OBJECTIVES: This study aims to provide insights into the phenotypic characteristics and clinical impact of AR mutations affecting the AF2 region in AIS patients. We achieve this by reviewing reported AR variants in the AF2 region among individuals with AIS, including identifying a new phenotype associated with the c.2138T>C variant (p.Leu713Pro) in the AR gene. MATERIALS AND METHODS: We comprehensively reviewed AR variants within the AF2 region reported in AIS and applied molecular dynamics simulations to assess the impact of the p.Leu713Pro variant on protein dynamics. RESULTS: Our review of reported AR variants in the AF2 region revealed a spectrum of phenotypic outcomes in AIS patients. Molecular dynamics simulations indicated that the p.Leu713Pro variant significantly alters the local dynamics of the AR protein and disrupts the correlation and covariance between variables. DISCUSSION: The diverse phenotypic presentations observed among individuals with AR variants in the AF2 region highlight the complexity of AIS. The altered protein dynamics resulting from the p.Leu713Pro variant further emphasize the importance of the AF2 region in AR function. CONCLUSION: Our study provides valuable insights into AR mutations' phenotypic characteristics and clinical impact on the AF2 region in AIS. Moreover, the disruption of protein dynamics underscores the significance of the AF2 region in AR function and its role in the pathogenesis of AIS.

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Patients with differences of sex development (DSDs) have complex anatomy and surgical needs related to both Mullerian and non-Mullerian structures. Approaches to vaginal reconstruction for these conditions are guided by individual anatomy, with the goal of establishing unobstructed outflow for the reproductive, urinary, and gastrointestinal tracts. Patients may have anatomy requiring vaginoplasty for either outflow tract obstruction or chosen sexual function. In this article, the authors focus on management of differences in vaginal anatomy with delayed vaginoplasty for the newborn with DSD.

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INTRODUCTION: Endometriosis typically presents in postmenarchal patients with cyclic and acyclic pelvic pain. However, there are reports of endometriosis in premenarchal patients. CASE: We report a 10-year-old individual with 46,XY difference of sex development who was found to have endometriosis at the time of laparoscopic gonadectomy for gonadoblastoma. CONCLUSIONS: Although rare, endometriosis can occur in 46,XY individuals prior to puberty, highlighting the complex origin of the disease.

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In mammals, the development of male or female gonads from fetal bipotential gonads depends on intricate genetic networks. Changes in dosage or temporal expression of sex-determining genes can lead to differences of gonadal development. Two rare conditions are associated with disruptions in ovarian determination, including 46,XX testicular differences in sex development (DSD), in which the 46,XX gonads differentiate into testes, and 46,XX ovotesticular DSD, characterized by the coexistence of ovarian and testicular tissue in the same individual. Several mechanisms have been identified that may contribute to the development of testicular tissue in XX gonads. This includes translocation of SRY to the X chromosome or an autosome. In the absence of SRY, other genes associated with testis development may be overexpressed or there may be a reduction in the activity of pro-ovarian/antitesticular factors. However, it is important to note that a significant number of patients with these DSD conditions have not yet recognized a genetic diagnosis. This finding suggests that there are additional genetic pathways or epigenetic mechanisms that have yet to be identified. The text will provide an overview of the current understanding of the genetic factors contributing to 46,XX DSD, specifically focusing on testicular and ovotesticular DSD conditions. It will summarize the existing knowledge regarding the genetic causes of these differences. Furthermore, it will explore the potential involvement of other factors, such as epigenetic mechanisms, in developing these conditions.

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CONTEXT: Steroidogenic factor 1 (NR5A1/SF-1) is a nuclear receptor that regulates sex development, steroidogenesis and reproduction. Genetic variants in NR5A1/SF-1 are common among differences of sex development (DSD) and associate with a wide range of phenotypes, but their pathogenic mechanisms remain unclear. OBJECTIVE: Novel, likely disease-causing NR5A1/SF-1 variants from the SF1next cohort of individuals with DSD were characterized to elucidate their pathogenic effect. METHODS: Different in silico tools were used to predict the impact of novel NR5A1/SF-1 variants on protein function. An extensive literature review was conducted to compare and select the best functional studies for testing the pathogenic effect of the variants in a classic cell culture model. The missense NR5A1/SF-1 variants were tested on the promoter luciferase reporter vector -152CYP11A1_pGL3 in HEK293T cells and assessed for their cytoplasmic/nuclear localization by Western blot. RESULTS: Thirty-five novel NR5A1/SF-1 variants were identified in the SF1next cohort. Seventeen missense NR5A1/SF-1 variants were functionally tested. Transactivation assays showed reduced activity for 40% of the variants located in the DNA binding domain and variable activity for variants located elsewhere. Translocation assessment revealed three variants (3/17) with affected nuclear translocation. No clear genotype-phenotype, structure-function correlation was found. CONCLUSIONS: Genetic analyses and functional assays do not explain the observed wide phenotype of individuals with these novel NR5A1/SF-1 variants. In nine individuals, additional likely disease-causing variants in other genes were found, strengthening the hypothesis that the broad phenotype of DSD associated with NR5A1/SF-1 variants may be caused by an oligogenic mechanism.

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Intersex individuals, encompassing people with diverse sex characteristics that do not fit binary frameworks of sex, have long faced a history of medical secrecy, discrimination, and societal stigma, contributing to their limited social visibility. In recent years, increased awareness of intersex issues and a robust advocacy movement have drawn significant attention to the experiences of intersex individuals and their families. This study contributes to the existing literature by examining the experiences and needs of parents of intersex individuals within genetic healthcare systems, bridging a critical gap, and advocating for more comprehensive and supportive healthcare practices. Semi-structured interviews were conducted with 14 parents of intersex individuals, and reflexive thematic analysis was used to inductively generate four major themes. Themes highlighted the need for improved accessibility of intersex healthcare, the importance of multidisciplinary healthcare teams, and the significance of clinical diagnosis provided by genetics professionals. Furthermore, the study highlighted the necessity of a thoughtful approach to information provision and the impact of genetic investigations on family dynamics. Genetics professionals can play a pivotal role in raising awareness about intersex variations, improving diagnostic processes, collaborating within healthcare teams, and providing specialized support to address psychosocial concerns. The study underscores the importance of treating families as a collective entity and addressing the impact of genetic investigations on the family unit. By addressing the challenges and implementing the recommendations outlined, healthcare institutions can create a more compassionate, inclusive, and effective healthcare environment for the intersex community.

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Several aspects of clinical management of 46,XX congenital adrenal hyperplasia (CAH) remain unsettled and controversial. The North American Disorders/Differences of Sex Development (DSD) Clinician Survey investigated changes, over the last two decades, in clinical recommendations by specialists involved in the management of newborns with DSD. Members of the (Lawson Wilkins) Pediatric Endocrine Society and the Societies for Pediatric Urology participated in a web-based survey at three timepoints: 2003-2004 (T1, n = 432), 2010-2011 (T2, n = 441), and 2020 (T3, n = 272). Participants were presented with two clinical case scenarios-newborns with 46,XX CAH and either mild-to-moderate or severe genital masculinization-and asked for clinical recommendations. Across timepoints, most participants recommended rearing the newborn as a girl, that parents (in consultation with physicians) should make surgical decisions, performing early genitoplasty, and disclosing surgical history at younger ages. Several trends were identified: a small, but significant shift toward recommending a gender other than girl; recommending that adolescent patients serve as the genital surgery decision maker; performing genital surgery at later ages; and disclosing surgical details at younger ages. This is the first study assessing physician recommendations across two decades. Despite variability in the recommendations, most experts followed CAH clinical practice guidelines. The observation that some of the emerging trends do not align with expert opinion or empirical evidence should serve as both a cautionary note and a call for prospective studies examining patient outcomes associated with these changes.

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OBJECTIVE: This study retrospectively analyzes the clinical data of 18 children with 45,X/46,XY differences of sex development (DSD), summarizes their clinical features and explores gonadal and Müllerian duct remnants surgical treatment methods. METHODS: The clinical data of 18 children with karyotype 45,X/46,XY diagnosed in the Department of Urology of Hunan Children's Hospital from March 2011 to October 2021 were collected. All children underwent HCG stimulation testing, laparoscopic exploration, urethroscopy and bilateral gonadal biopsy. After DSD multidisciplinary team (MDT) meeting, some children underwent gonadectomy and genitalia reconstructive surgeries. RESULTS: The median age at first diagnosis was 1 year and 4 months (range: 10 months ∼ 16 years and 3 months). 5 children presented with female gender; they all maintained their gender assignment. The external masculinisation score (EMS) of patients raised as female was 1 (0∼3) [median (range)]. 13 children presented with male gender, 10 maintained a male gender, 3 were assigned a neutral gender. The EMS of the children raised as male was 5 (2-8) [median (range)], the EMS of the children raised as neutral gender was 4 (3.5-9.5) [median (range)]. The HCG stimulation test was positive in 11 cases, partially positive in 2 case, and negative in 5 cases. There was no relationship between the percentage of chimerism (45X ratio) and the appearance and severity of genital abnormalities. (t=-1.08, P=0.298). There was 1 case of complete gonadal dysgenesis (CGD), 10 cases of mixed gonadal dysgenesis (MGD), 5 cases of partial gonadal dysgenesis (PGD), 1 case of bilateral normal testes and 1 case of ovotesticular DSD (split-lateral type). No gonadal specimen showed germ cell tumor changes. Five cases selected to maintain the female gender, among which 3 cases underwent bilateral gonadectomy and genitalia reconstructive surgeries. Among the 10 children who chose to maintain the male gender, unilateral streak gonadectomy was performed in 4 (57.1%) with MGD, unilateral dysgenetic orchiectomy in 1 (25%) with PGD, and right ovariectomy in 1 with OTDSD. Nine of them underwent genitalia reconstructive surgeries. Four of them preserved their uterus and vagina did not have any complications during the follow-up period. CONCLUSION: Hypospadias combined with cryptorchidism and residual Müllerian duct structures is the most common phenotype of children with 45, X/46, XY DSD. Mixed gonadal dysgenesis (MGD) is the most common gonadal type. Gender assignment should be carefully selected after a thorough evaluation, while genitalia reconstructive surgery can be considered in selected patients. In children who choose the male gender, the Müllerian duct can be preserved.

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The management of Differences of Sex Development (DSD) has evolved considerably in recent years. The questioning of systematic early childhood treatment of DSD requires a better understanding of the outcomes of such treatments and long-term studies are therefore essential to better evaluate the prognosis of DSD. Unfortunately, limitations are numerous including the limited size of the series, the absence of standardized methodology, the evaluation of managements that no longer take place today and the absence of prospective and comparative studies. Despite these difficulties, the purpose of this paper is to present the current data on the long-term follow-up of patients with DSD from the urological, sexual and fertility points of view. Even if it remains difficult at present to establish precise recommendations, we recapitulate the most important points that should drive follow-up of these patients especially the constitution of a multidisciplinary team with a holistic approach, the organization of the transition between adolescence and adulthood, a particular attention to psychological care, a careful communication with the patients and his/her family and the use of standardized data collection systems.

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BACKGROUND: Steroidogenic factor 1 (SF-1/NR5A1) is essential for human sex development. Heterozygous NR5A1/SF-1 variants manifest with a broad range of phenotypes of differences of sex development (DSD), which remain unexplained. METHODS: We conducted a retrospective analysis on the so far largest international cohort of individuals with NR5A1/SF-1 variants, identified through the I-DSD registry and a research network. FINDINGS: Among 197 individuals with NR5A1/SF-1 variants, we confirmed diverse phenotypes. Over 70% of 46, XY individuals had a severe DSD phenotype, while 90% of 46, XX individuals had female-typical sex development. Close to 100 different novel and known NR5A1/SF-1 variants were identified, without specific hot spots. Additionally, likely disease-associated variants in other genes were reported in 32 individuals out of 128 tested (25%), particularly in those with severe or opposite sex DSD phenotypes. Interestingly, 48% of these variants were found in known DSD or SF-1 interacting genes, but no frequent gene-clusters were identified. Sex registration at birth varied, with <10% undergoing reassignment. Gonadectomy was performed in 30% and genital surgery in 58%. Associated organ anomalies were observed in 27% of individuals with a DSD, mainly concerning the spleen. Intrafamilial phenotypes also varied considerably. INTERPRETATION: The observed phenotypic variability in individuals and families with NR5A1/SF-1 variants is large and remains unpredictable. It may often not be solely explained by the monogenic pathogenicity of the NR5A1/SF-1 variants but is likely influenced by additional genetic variants and as-yet-unknown factors. FUNDING: Swiss National Science Foundation (320030-197725) and Boveri Foundation Zürich, Switzerland.

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INTRODUCTION: The presence of an ovotestis is a rare difference of sex development. The diagnosis can be difficult with the gold standard being the presence of both testicular cords and ovarian follicles within the same gonad. OBJECTIVE: Herein we describe two new markers of ovotesticular syndrome: ovotesticular cords and ovotesticular follicles. STUDY DESIGN: Twenty human gonads with a previous diagnosis of ovotestis were re-stained with markers for testicular cords (SOX9, TSPY, SALL4, DDX4, cP450, AR, α-actin) and ovarian tissue (FOXL2, SALL4, DDX4). Ovotesticular cords were defined as structures expressing both testicular Sertoli cell marker (SOX9) and an ovarian follicular cell marker (FOXL2), and in Y chromosome positive specimens, TSPY-positive testicular germ cells. Ovotesticular follicles were defined as a hybrid ovarian follicle containing FOXL2-positive granulosa cells and a central oocyte, but also containing cells expressing the testicular Sertoli cell marker, SOX9, intermingled within FOXL2-positive granulosa cells and male and female germ cells. RESULTS: Six of twenty ovotestis did not meet our criterion for the diagnosis of ovotestis lacking the histologic evidence of both testicular and ovarian tissue. The remaining 13 patients in which 14 separate specimens were evaluated, contained ovotestis defined by the presence of testicular cords and ovarian follicles. Eleven of the 14 ovotestis specimens (79 %) contained ovotesticular cords. Four of 11 ovotestis specimens (36 %) contained ovotesticular follicles. DISCUSSION: We recommend using eight immunohistochemical markers to diagnose an ovotestis: 1) SOX9, TSPY, SALL4, DDX4, cytochrome P450, AR, smooth muscle α-actin for the testicular component and FOXL2 and SALL4, DDX4 for the ovarian component. SOX9 and TSPY (useful only in the presence of a Y karyotype) are specific testicular markers and FOXL2 the only specific ovarian marker. We found ovotesticular cords and ovotesticular follicles in both human bipolar and mixed ovotestis specimens both with and without the presence of the Y chromosome. The clinical significance of ovotesticular cords and follicles remains unknown. We did not observe any obvious abnormalities in cellular architecture with the juxtaposition of testicular cells and ovarian cells. CONCLUSION: We have identified two new structures in humans with ovotestis, ovotesticular cords and ovotesticular follicles (Figure), which appears to be additional markers to facilitate the diagnosis of ovotesticular gonads.