Atypical Sex Development Research Articles

Challenges faced in management of a neonate with ambiguous genitalia

A neonate born with atypical sex development presents with challenges to the clinician as well as parents. There are challenges in diagnosis, gender assignment, initiating and adherence to treatment, follow up, counseling and prenatal diagnosis and counselling. There are uncertainties in the time of prenatal diagnosis as well. The objective of this case report is to highlight the challenges faced by a parent of a neonate with ambiguous genitalia.

Genetic control of typical and atypical sex development.

Sex development relies on the sex-specific action of gene networks to differentiate the bipotential gonads of the growing fetus into testis or ovaries, followed by the differentiation of internal and external genitalia depending on the presence or absence of hormones. Differences in sex development (DSD) arise from congenital alterations during any of these processes, and are classified depending on sex chromosomal constitution as sex chromosome DSD, 46,XY DSD or 46,XX DSD. Understanding the genetics and embryology of typical and atypical sex development is essential for diagnosing, treating and managing DSD. Advances have been made in understanding the genetic causes of DSD over the past 10 years, especially for 46,XY DSD. Additional information is required to better understand ovarian and female development and to identify further genetic causes of 46,XX DSD, besides congenital adrenal hyperplasia. Ongoing research is focused on the discovery of further genes related to typical and atypical sex development and, therefore, on improving diagnosis of DSD.

Collaborative Portraits for Intersex Justice

Collaborative Portraits for Intersex Justice

Identification of Small Regions of Overlap from Copy Number Variable Regions in Patients with Hypospadias.

Hypospadias is a common form of congenital atypical sex development that is often associated with other congenital comorbidities. Many genes have been associated with the condition, most commonly single sequence variations. Further investigations of recurrent and overlapping copy number variations (CNVs) have resulted in the identification of genes and chromosome regions associated with various conditions, including differences of sex development (DSD). In this retrospective study, we investigated the DECIPHER database, as well as an internal institutional database, to identify small recurrent CNVs among individuals with isolated and syndromic hypospadias. We further investigated these overlapping recurrent CNVs to identify 75 smallest regions of overlap (SROs) on 18 chromosomes. Some of the genes within these SROs may be considered potential candidate genes for the etiology of hypospadias and, occasionally, additional comorbid phenotypes. This study also investigates for the first time additional common phenotypes among individuals with hypospadias and overlapping CNVs. This study provides data that may aid genetic counseling and management of individuals with hypospadias, as well as improve understanding of its underlying genetic etiology and human genital development overall.

Genetics of human sexual development and related disorders.

The aim of this study was to provide a basic overview on human sex development with a focus on involved genes and pathways, and also to discuss recent advances in the molecular diagnostic approaches applied to clinical workup of individuals with a difference/disorder of sex development (DSD). Rapid developments in genetic technologies and bioinformatics analyses have helped to identify novel genes and genomic pathways associated with sex development, and have improved diagnostic algorithms to integrate clinical, hormonal and genetic data. Recently, massive parallel sequencing approaches revealed that the phenotype of some DSDs might be only explained by oligogenic inheritance. Typical sex development relies on very complex biological events, which involve specific interactions of a large number of genes and pathways in a defined spatiotemporal sequence. Any perturbation in these genetic and hormonal processes may result in atypical sex development leading to a wide range of DSDs in humans. Despite the huge progress in the understanding of molecular mechanisms underlying DSDs in recent years, in less than 50% of DSD individuals, the genetic cause is currently solved at the molecular level.

Did Bioethics Matter? A History of Autonomy, Consent, and Intersex Genital Surgery.

This article argues that the rise of bioethics in the post-WWII era and the emergence of the legal doctrine of informed consent in the late 1950s should have had a greater impact on patients with intersex traits (atypical sex development) than they did, given their emphasis on respect for autonomy and beneficence toward patients. Instead, these progressive trends collided with a turn in intersex management toward infants, who were unable to provide autonomous consent about their medical care. Patient autonomy took a back seat as parents heeded physicians' advice in an environment even more hierarchical than we know today. Intersex care of both infants and adults continues to need improvement. It remains an open question whether the abstract ideals of bioethics-respect, patient autonomy, and the requirement of informed consent-are alone adequate to secure that improvement, or whether legal actions (or the threat of litigation) or some other reforms will be required to effect such change.

Attitudes toward ‘Disorders of Sex Development’ nomenclature among physicians, genetic counselors, and mental health clinicians

In 2006, nomenclature referencing atypical sex development (i.e., 'intersex') was updated, and the term disorder of sex development (DSD) was formally introduced. Clinicians, patients, and parents, however, have not universally accepted the new terminology, and some continue to use different nomenclature. This inconsistency in terminology can lead to confusion among clinicians and patients, affect clinician-patient relationships, and interfere with the recommended multidisciplinary model for DSD care. This study sought to(1) evaluate frequency of use and comfort with specific DSD terminology, (2) assess why clinicians are not using specific terms, and (3) determine what terms are being heard within the medical community and by the public in a sample of physicians, genetic counselors, and licensed mental health clinicians. A Web-based survey assessing the use of DSD terminology was distributed to endocrinologists, urologists, genetic counselors, and mental health clinicians. The survey assessed frequency of use and comfort with specific terms, negative experiences related to specific nomenclature use, and the context in which terms are used (e.g. case conference, literature, patient/parents, and media). A qualitative analysis of open-ended responses was conducted to characterize reasons for avoiding specific terms. The survey was completed by 286 clinicians. There were significant differences between specialties in comfort and frequency of use of specific terms, and significant differences were based on clinician gender, patient volume, length of time in practice, and practice setting. The study results also showed a difference in the nomenclature used within the medical community versus the media. Study findings are consistent with previous research exploring medical professionals' use of the new term: disorder of sex development. However, there continues to be inconsistency in the uptake of this new terminology. Words that have been purposed in the literature to replace disorder, such as difference and variation, would be accepted by clinicians, and the word divergent would not. This study expands on the existing literature documenting high uptake of disorder of sex development nomenclature among medical professionals. In addition, this study demonstrates that the most common diagnostic terms used by the medical community are not the same terms being presented to the public by the media. Medical professionals have varying preferences for terminology use when describing DSD, which can affect patient care. These results can be used in the future to compare with what patients and advocates prefer to develop a more universally accepted approach to nomenclature.

Experienced Outcomes of Medical Interventions in Individuals With Gender Incongruence and Atypical Sex Development

De man-vrouw dichotomie is waarschijnlijk de meest uitgesproken onderverdeling in het menselijk bestaan. De complexe menselijke geslachts- en (gender)identiteitsontwikkeling kan atypisch verlopen en/of resulteren in genderincongruentie. Nederland telt naar schatting meer dan 100.000 mensen met een variatie van geslacht (intersekse) of gender (transgender). De laatste jaren is de maatschappelijke bekendheid voor deze groepen sterk vergroot.

Body image and self-esteem in disorders of sex development: A European multicenter study.

Disorders/differences of sex development (DSD) refer to congenital conditions with atypical sex development and are associated with psychosexual issues. The aim of this study was to assess body image and self-esteem across the DSD spectrum and to study the impact of diagnosis and mediating characteristics. Data collection was part of dsd-LIFE, a cross-sectional study conducted by 14 European expert clinics on wellbeing and health care evaluation of adults diagnosed with DSD. Main outcome measures in the present analyses were the Body Image Scale and Rosenberg Self-Esteem Scale. Additional data were obtained on treatments, openness, body embarrassment, sexual satisfaction, anxiety, and depression. The participating sample (n = 1,040) included 226 classified as Congenital Adrenal Hyperplasia, 225 as Klinefelter Syndrome, 322 as Turner Syndrome, and 267 as conditions with 46,XY karyotype. Many participants had received hormonal and surgical treatments. Participants scored lower on body image and self-esteem compared to control values, whereas each diagnosis showed different areas of concern. Limited openness, body embarrassment, and sexual issues were frequently reported. Overall body satisfaction was associated with BMI, hormone use, openness, body embarrassment, anxiety, and depression; genital satisfaction with age at diagnosis, openness, sexual satisfaction, and body embarrassment. Body embarrassment, anxiety, and depression predicted lower self-esteem. While each DSD showed specific issues related to body image and self-esteem, our findings indicate that the related factors were similar across the conditions. Clinical care on this subject could be improved by giving specific attention to factors like openness, body embarrassment, sexuality, anxiety, and depression. (PsycINFO Database Record

Biallelic and monoallelic ESR2 variants associated with 46,XY disorders of sex development

PurposeDisorders or differences of sex development (DSDs) are rare congenital conditions characterized by atypical sex development. Despite advances in genomic technologies, the molecular cause remains unknown in 50% of cases.MethodsHomozygosity mapping and whole-exome sequencing revealed an ESR2 variant in an individual with syndromic 46,XY DSD. Additional cases with 46,XY DSD underwent whole-exome sequencing and targeted next-generation sequencing of ESR2. Functional characterization of the identified variants included luciferase assays and protein structure analysis. Gonadal ESR2 expression was assessed in human embryonic data sets and immunostaining of estrogen receptor-β (ER-β) was performed in an 8-week-old human male embryo.ResultsWe identified a homozygous ESR2 variant, c.541_543del p.(Asn181del), located in the highly conserved DNA-binding domain of ER-β, in an individual with syndromic 46,XY DSD. Two additional heterozygous missense variants, c.251G>T p.(Gly84Val) and c.1277T>G p.(Leu426Arg), located in the N-terminus and the ligand-binding domain of ER-β, were found in unrelated, nonsyndromic 46,XY DSD cases. Significantly increased transcriptional activation and an impact on protein conformation were shown for the p.(Asn181del) and p.(Leu426Arg) variants. Testicular ESR2 expression was previously documented and ER-β immunostaining was positive in the developing intestine and eyes.ConclusionOur study supports a role for ESR2 as a novel candidate gene for 46,XY DSD.

Are Physicians Blameworthy for Iatrogenic Harm Resulting from Unnecessary Genital Surgeries?

We argue that physicians should, in certain cases, be held accountable by patients and their families for harm caused by "successful" genital surgeries performed for social and aesthetic reasons. We explore the question of physicians' blameworthiness for three types of genital surgeries common in the United States. First, we consider surgeries performed on newborns and toddlers with atypical sex development, or intersex. Second, we discuss routine neonatal male circumcision. Finally, we consider cosmetic vaginal surgery. It is important for physicians not just to know when and why to perform genital surgery, but also to understand how their patients might react to wrongful performance of these procedures. Equally, physicians should know how to respond to their own blameworthiness in socially productive and morally restorative ways.

Steroid hormone analysis in diagnosis and treatment of DSD: position paper of EU COST Action BM 1303 'DSDnet'.

Disorders or differences in sex development (DSD) comprise a heterogeneous group of conditions with an atypical sex development. For optimal diagnosis, highly specialised laboratory analyses are required across European countries. Working group 3 of EU COST (European Cooperation in Science and Technology) Action BM 1303 ‘DSDnet’ ‘Harmonisation of Laboratory Assessment’ has developed recommendations on laboratory assessment for DSD regarding the use of technologies and analytes to be investigated. This position paper on steroid hormone analysis in diagnosis and treatment of DSD was compiled by a group of specialists in DSD and/or hormonal analysis, either from participating European countries or international partner countries. The topics discussed comprised analytical methods (immunoassay/mass spectrometry-based methods), matrices (urine/serum/saliva) and harmonisation of laboratory tests. The following positions were agreed upon: support of the appropriate use of immunoassay- and mass spectrometry-based methods for diagnosis and monitoring of DSD. Serum/plasma and urine are established matrices for analysis. Laboratories performing analyses for DSD need to operate within a quality framework and actively engage in harmonisation processes so that results and their interpretation are the same irrespective of the laboratory they are performed in. Participation in activities of peer comparison such as sample exchange or when available subscribing to a relevant external quality assurance program should be achieved. The ultimate aim of the guidelines is the implementation of clinical standards for diagnosis and appropriate treatment of DSD to achieve the best outcome for patients, no matter where patients are investigated or managed.

“Differently normal” and “normally different”: Negotiations of female embodiment in women's accounts of ‘atypical’ sex development

During recent decades numerous feminist scholars have scrutinized the two-sex model and questioned its status in Western societies and medicine. Along the same line, increased attention has been paid to individuals' experiences of atypical sex development, also known as intersex or ‘disorders of sex development’ (DSD). Yet research on individuals' experiences of finding out about their atypical sex development in adolescence has been scarce. Against this backdrop, the present article analyses 23 in-depth interviews with women who in their teens found out about their atypical sex development. The interviews were conducted during 2009–2012 and the interviewees were all Swedish. Drawing on feminist research on female embodiment and social scientific studies on diagnosis, I examine how the women make sense of their bodies and situations. First, I aim to explore how the women construe normality as they negotiate female embodiment. Second, I aim to investigate how the divergent manners in which these negotiations are expressed can be further understood via the women's different access to a diagnosis. Through a thematic and interpretative analysis, I outline two negotiation strategies: the “differently normal” and the “normally different” strategy. In the former, the women present themselves as just slightly different from ‘normal’ women. In the latter, they stress that everyone is different in some manner and thereby claim normalcy. The analysis shows that access to diagnosis corresponds to the ways in which the women present themselves as “differently normal” and “normally different”, thus shedding light on the complex role of diagnosis in their negotiations of female embodiment. It also reveals that the women make use of what they do have and how alignments with and work on norms interplay as normality is construed.

Humane images: visual rhetoric in depictions of atypical genital anatomy and sex differentiation

Visual images are widely used in medical and patient education to enhance spoken or written explanations. This paper considers the role of such illustrations in shaping conceptions of the body;...

Bodies in doubt: an American history of intersex

What does it mean to be human? To be human is, in part, to be physically sexed and culturally gendered. Yet not all bodies are clearly male or female. Bodies in Doubt traces the changing definitions, perceptions, and medical management of intersex (atypical sex development) in America from the colonial period to the present day. From the beginning, intersex bodies have been marked as other, as monstrous, sinister, threatening, inferior, and unfortunate. Some nineteenth-century doctors viewed their intersex patients with disrespect and suspicion. Later, doctors showed more empathy for their patients' plights and tried to make decisions regarding their care. Yet definitions of correct in matters of intersex were entangled with shifting ideas and tensions about what was natural and normal, indeed about what constituted personhood or humanity. Reis has examined hundreds of cases of hermaphroditism and intersex found in medical and popular literature and argues that medical practice cannot be understood outside of the broader cultural context in which it is embedded. As the history of responses to intersex bodies has shown, doctors are influenced by social concerns about marriage and heterosexuality. Bodies in Doubt considers how Americans have interpreted and handled ambiguous bodies, how the criteria and the authority for judging bodies changed, how both the binary gender ideal and the anxiety over uncertainty persisted, and how the process for defining the very norms of sex and gender evolved. Bodies in Doubt breaks new ground in examining the historical roots of modern attitudes about intersex in the United States and will interest scholars and researchers in disability studies, social history, gender studies, and the history of medicine.