Etiological classification and clinical spectrum of Egyptian pediatric patients with disorder of sex development, single center experience.

INTRODUCTION: The aim of the current work was to review the clinical profile, aetiological classification, as well as the management of Egyptian paediatric patients with disorders of sex development (DSD) presenting at a tertiary centre in Cairo. MATERIAL AND METHODS: The study was a cross-sectional observational study that included Egyptian patients who attended the Endocrinology clinic during a period of one year from January to December 2019. All patients with overt genital ambiguity aged from 0 to 18 years were recruited in the study. Diagnosis of DSD was based on clinical features and hormonal profile. RESULTS: Out of 100 patients, 71% had 46XY DSD, 24% had 46XX DSD, while sex chromosome DSD was identified in 5%. The median age of presentation was 12 months with 19% presented during infancy. The most common cause of 46XY DSD was due to either defect in androgen synthesis or action (40%) with the majority due to androgen insensitivity syndrome (28%). Most of the 46XX DSD (21/24) patients were diagnosed as classic congenital adrenal hyperplasia secondary to deficiency of 21 hydroxylase enzyme, with 90% being salt wasters. CONCLUSION: Our series revealed that 46XY DSD was the most frequent DSD aetiological diagnosis, with androgen insensitivity syndrome representing the commonest cause. CAH with classic salt wasting type was the second most common disorder. Management of children with DSD is challenging especially with lack of adequate resources. The crucial issues that stand against proper diagnosis and management are late presentation combined with economic constrains, and social and cultural issues.

Gender Identity and Assignment Recommendations in Disorders of Sex Development Patients: 20 Years' Experience and Challenges

Objective: Gender assignment in infants and children with disorders of sex development (DSD) is a stressful situation for both patient/families and medical professionals. Methods: The purpose of this study was to investigate the results of gender assignment recommendations in children with DSD in our clinic from 1999 through 2019. Results: The mean age of the 226 patients with DSD at the time of first admission were 3.05±4.70 years. 50.9% of patients were 46,XY DSD, 42.9% were 46,XX DSD and 6.2% were sex chromosome DSD. Congenital adrenal hyperplasia (majority of patients had 21-hydroxylase deficiency) was the most common etiological cause of 46,XX DSD. In 46,XX patients, 87 of 99 (89.7%) were recommended to be supported as a female, 6 as a male, and 4 were followed up. In 46,XY patients, 40 of 115 (34.8%) were recommended to be supported as a female, and 70 as male (60.9%), and 5 were followed up. In sex chromosome DSD patients, 3 of 14 were recommended to be supported as a female, 9 as a male. The greatest difficulty in making gender assignment recommendations were in the 46,XY DSD group. Conclusion: In DSD gender assignment recommendations, the etiologic diagnosis, psychiatric gender orientation, expectation of the family, phallus length and Prader stage were effective in the gender assignment in DSD cases, especially the first two criteria. It is important to share these experiences among the medical professionals who are routinely charged with this difficult task in multidisciplinary councils.

Plea for a standardized imaging approach to disorders of sex development in neonates: consensus proposal from European Society of Paediatric Radiology task force.

This consensus article elaborated by the European Society for Paediatric Radiology task force on gastrointestinal and genitourinary imaging is intended to standardize the imaging approach in newborns with disorders of sex development. These newborns represent a difficult and stressful situation necessitating a multidisciplinary team approach. Imaging plays an important role in the work-up but needs to be optimized and customized to the patient. Ultrasound plays the central role in assessing the genital anatomy. The examination must be conducted in a detailed and systematic way. It must include transabdominal and transperineal approaches with adapted high-resolution transducers. The pelvic cavity, the genital folds, the inguinal areas and the adrenals must be evaluated as well as the rest of the abdominal cavity. A reporting template is proposed. The indications of magnetic resonance imaging and cysto- and genitography are discussed as well as they may provide additional information. Imaging findings must be reported cautiously using neutral wording as much as possible.

Intersex Variations, Human Rights, and the International Classification of Diseases.

Over time, the World Health Organization (WHO) has reviewed and removed pathologizing classifications and codes associated with sexual and gender minorities from the International Classification of Diseases (ICD). However, classifications associated with intersex variations, congenital variations in sex characteristics or differences of sex development, remain pathologized. The ICD-11 introduces additional and pathologizing normative language to describe these as "disorders of sex development." Current materials in the ICD-11 Foundation also specify, or are associated with, unnecessary medical procedures that fail to meet human rights norms documented by the WHO itself and Treaty Monitoring Bodies. This includes codes that require genitoplasties and gonadectomies associated with gender assignment, where either masculinizing or feminizing surgery is specified depending upon technical and heteronormative expectations for surgical outcomes. Such interventions lack evidence. Human rights defenders and institutions regard these interventions as harmful practices and violations of rights to bodily integrity, non-discrimination, equality before the law, privacy, and freedom from torture, ill-treatment, and experimentation. WHO should modify ICD-11 codes by introducing neutral terminology and by ensuring that all relevant codes do not specify practices that violate human rights.

Caring for individuals with a difference of sex development (DSD): a Consensus Statement.

The term differences of sex development (DSDs; also known as disorders of sex development) refers to a heterogeneous group of congenital conditions affecting human sex determination and differentiation. Several reports highlighting suboptimal physical and psychosexual outcomes in individuals who have a DSD led to a radical revision of nomenclature and management a decade ago. Whereas the resulting recommendations for holistic, multidisciplinary care seem to have been implemented rapidly in specialized paediatric services around the world, adolescents often experience difficulties in finding access to expert adult care and gradually or abruptly cease medical follow-up. Many adults with a DSD have health-related questions that remain unanswered owing to a lack of evidence pertaining to the natural evolution of the various conditions in later life stages. This Consensus Statement, developed by a European multidisciplinary group of experts, including patient representatives, summarizes evidence-based and experience-based recommendations for lifelong care and data collection in individuals with a DSD across ages and highlights clinical research priorities. By doing so, we hope to contribute to improving understanding and management of these conditions by involved medical professionals. In addition, we hope to give impetus to multicentre studies that will shed light on outcomes and comorbidities of DSD conditions across the lifespan.

Shifting syndromes: Sex chromosome variations and intersex classifications.

The 2006 'Consensus statement on management of intersex disorders' recommended moving to a new classification of intersex variations, framed in terms of 'disorders of sex development' or DSD. Part of the rationale for this change was to move away from associations with gender, and to increase clarity by grounding the classification system in genetics. While the medical community has largely accepted the move, some individuals from intersex activist communities have condemned it. In addition, people both inside and outside the medical community have disagreed about what should be covered by the classification system, in particular whether sex chromosome variations and the related diagnoses of Turner and Klinefelter's syndromes should be included. This article explores initial descriptions of Turner and Klinefelter's syndromes and their subsequent inclusion in intersex classifications, which were increasingly grounded in scientific understandings of sex chromosomes that emerged in the 1950s. The article questions the current drive to stabilize and 'sort out' intersex classifications through a grounding in genetics. Alternative social and historical definitions of intersex - such as those proposed by the intersex activists - have the potential to do more justice to the lived experience of those affected by such classifications and their consequences.

Contemporary Demographic, Treatment, and Geographic Distribution Patterns for Disorders of Sex Development.

This study aimed to describe the demographic characteristics, hospital utilizations, patterns of inpatient surgical management, and the overall state/regional variation in surgery rate among patients with disorders of sex development (DSD). We analyzed the Nationwide Inpatient Sample from 2001 to 2012 for patients younger than 21 years. DSD-related diagnoses and procedures were identified via International Classification of Diseases, Ninth Revision (ICD-9) codes. We identified a total of 43,968 DSD-related admissions. Of these, 73.4% of the admissions were designated as female and 642 (1.9%) were inpatient surgical admissions. Among neonates, less than 1% underwent any type of genital surgery. Nonsurgical admissions were associated with longer length of stay and higher cost. There was no significant regional variation in the rate of DSD surgeries, but we observed higher concentrations of DSD surgeries in states associated with tertiary referral centers.

Negotiating intersex: A case for revising the theory of social diagnosis.

The theory of social diagnosis recognizes two principles: 1) extra-medical social structures frame diagnosis; and 2) myriad social actors, in addition to clinicians, contribute to diagnostic labels and processes. The relationship between social diagnosis and (de)medicalization remains undertheorized, however, because social diagnosis does not account for how social actors can also resist the pathologization of symptoms and conditions-sometimes at the same time as they clamor for medical recognition-thereby shaping societal definitions of disease in different, but no less important, ways. In this article, we expand the social diagnosis framework by adding a third principle, specifically that 3) social actors engage with social structures to both contribute to, and resist, the framing of a condition as pathological (i.e. medicalization and demedicalization). This revised social diagnosis framework allows for the systematic investigation of multi-directional, dynamic processes, formalizing the link between diagnosis and (de)medicalization. It also responds to long-standing calls for more contextualized research in (de)medicalization studies by offering a framework that explicitly accounts for the social contexts in which (de)medicalizing processes operate. To showcase the utility of this revised framework, we use it to guide our analyses of a highly negotiated diagnosis: intersex.

[Clinical evaluation and management of neonates with disorder of sexual development].

Disorder of sexual development or disorder of sex differentiation (DSD) refers to the inconsistency between karyotype and gonad phenotype and/or gonad anatomy in neonates and is manifested as the difficulty in identifying neonates' sex. According to the karyotype, DSD is classified as 46,XY DSD, 46,XX DSD, and sex chromosome DSD. A combination of detailed medical history, physical examination, and laboratory and imaging examinations is required for the diagnosis and comprehensive assessment of neonatal DSD and the determination of potential causes in clinical practice. Sex identification can only be made after all diagnostic evaluations have been completed. Sex identification of DSD neonates is influenced by various medical and social factors, including genotype (karyotype), sex hormones (levels of testosterone, dihydrotestosterone, and adrenal steroids), sex phenotype (appearance of internal and external genitals), reproduction (fertility potential), feelings of their parents, and even social acceptance and religious customs. A team with multidisciplinary cooperation is required, and patients must be involved in the whole process of sex identification. The major task of neonatal physicians for DSD is to assess the condition of neonates and provide management.

A novel morphological approach to gonads in disorders of sex development.

Disorders of sex development are defined as congenital conditions with discordance between the phenotype, the genotype, the karyotype, and the hormonal profile. The disorders of sex development consensus classification established in 2005 are mainly based on chromosomal and biological data. However, histological anomalies are not considered. The aims of this study were to define the specific pathological features of gonads in various groups of disorders of sex development in order to clarify the nosology of histological findings and to evaluate the tumor risk in case of a conservative approach. One hundred and seventy-five samples from 86 patients with disorders of sex development were analyzed following a strict histological reading protocol. The term 'gonadal dysgenesis' for the histological analysis was found confusing and therefore excluded. The concept of 'dysplasia' was subsequently introduced in order to describe the architectural disorganization of the gonad (various degrees of irregular seminiferous tubules, thin albuginea, fibrous interstitium). Five histological types were identified: normal gonad, hypoplastic testis, dysplastic testis, streak gonad, and ovotestis. The analysis showed an association between undifferentiated gonadal tissue, a potential precursor of gonadoblastoma, and dysplasia. Dysplasia and undifferentiated gonadal tissue were only encountered in cases of genetic or chromosomal abnormality ('dysgenesis' groups in the disorders of sex development consensus classification). 'Dysgenetic testes', related to an embryonic malformation of the gonad, have variable histological presentations, from normal to streak. Conversely, gonads associated with hormonal deficiencies always display a normal architecture. A loss of expression of AMH and α-inhibin was identified in dysplastic areas. Foci of abnormal expression of the CD117 and OCT4 immature germ cells markers in dysplasia and undifferentiated gonadal tissue were associated with an increased risk of neoplasia. This morphological analysis aims at clarifying the histological classification and gives an indication of tumor risk of gonads in disorders of sex development.

Management framework paradigms for disorders of sex development

Until 2005, questions regarding medical treatment and diagnostic information on Disorders of Sex Development (DSD) were not systematically discussed with both the patients and their families; however, the way these patients are currently treated have been changing with time. Interventional changes in the clinical-psychotherapeutic-surgical areas of DSD determine not only different medical recommendations but also help to place the patient and the family into the decisional process of therapy. We must consider two paradigmatic periods that have influenced and transformed the clinical management framework of patients with DSD: a) The "Money era" (1955), which emphasized the role of the gonads as the diagnostic criterion, having the environment as determinant of the sex identity; and b) The Chicago Consensus (2005) phase, in which the role of genetics and molecular biology was critical for an early identification, as well as in building a proper sex identity, emphasizing ethical questions and the "stigma culture". In addition, recent data have focused on the importance of interdisciplinarity and statements on questions concerning Human Rights as key factors in treatment decision making. Despite each of these management models being able to determine specific directions and recommendations regarding the clinical handling of these patients, we verify that a composite of these several models is the clinical routine nowadays. In the present paper, we discuss these several paradigms, and pinpoint clinical differences and their unfolding regarding management of DSD patients and their families.

Management framework paradigms for disorders of sex development.

Until 2005, questions regarding medical treatment and diagnostic information on Disorders of Sex Development (DSD) were not systematically discussed with both the patients and their families; however, the way these patients are currently treated have been changing with time. Interventional changes in the clinical-psychotherapeutic-surgical areas of DSD determine not only different medical recommendations but also help to place the patient and the family into the decisional process of therapy. We must consider two paradigmatic periods that have influenced and transformed the clinical management framework of patients with DSD: a) The "Money era" (1955), which emphasized the role of the gonads as the diagnostic criterion, having the environment as determinant of the sex identity; and b) The Chicago Consensus (2005) phase, in which the role of genetics and molecular biology was critical for an early identification, as well as in building a proper sex identity, emphasizing ethical questions and the "stigma culture". In addition, recent data have focused on the importance of interdisciplinarity and statements on questions concerning Human Rights as key factors in treatment decision making. Despite each of these management models being able to determine specific directions and recommendations regarding the clinical handling of these patients, we verify that a composite of these several models is the clinical routine nowadays. In the present paper, we discuss these several paradigms, and pinpoint clinical differences and their unfolding regarding management of DSD patients and their families.

Classifying Intersex in DSM-5: Critical Reflections on Gender Dysphoria.

The new diagnosis of Gender Dysphoria (GD) in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (American Psychiatric Association, 2013) defines intersex, renamed "Disorders of Sex Development" (DSD), as a specifier of GD. With this formulation, the status of intersex departs from prior editions, especially from the DSM-IV texts that defined intersex as an exclusion criterion for Gender Identity Disorder. Conversely, GD--with or without a DSD--can apply in the same manner to DSD and non-DSD individuals; it subsumes the physical condition under the mental "disorder." This conceptualization, I suggest, is unprecedented in the history of the DSM. In my view, it is the most significant change in the revised diagnosis, and it raises the question of the suitability of psychiatric diagnosis for individuals with intersex/DSD. Unfortunately, this fundamental question was not raised during the revision process. This article examines, historically and conceptually, the different terms provided for intersex/DSD in the DSM in order to capture the significance of the DSD specifier, and the reasons why the risk of stigma and misdiagnosis, I argue, is increased in DSM-5 compared to DSM-IV. The DSM-5 formulation is paradoxically at variance with the clinical literature, with intersex/DSD and transgender being conceived as incommensurable terms in their diagnostic and treatment aspects. In this light, the removal of intersex/DSD from the DSM would seem a better way to achieve the purpose behind the revised diagnosis, which was to reduce stigma and the risk of misdiagnosis, and to provide the persons concerned with healthcare that caters to their specific needs.

Consequences of the Chicago DSD Consensus: A Personal Perspective.

A decade has passed since the Chicago Consensus meeting was convened to consider how to improve the management of individuals and their families with an intersex disorder. It is apposite to review, from an individual perspective, what impact the Consensus has had on clinical practice and research. Emphasis is placed on nomenclature and DSD classification, multidisciplinary team working, striving to reach a causative diagnosis for DSD, the value of uniformity of collective case registries for rare conditions, and the potential for meaningful clinical outcome studies and basic scientific research. The impact of the Consensus can be gauged objectively by an exponential increase in DSD-related publications in the medical and scientific literature and organisation of numerous national and international meetings. Psychologists and social scientists have embraced the subject area and enhanced the holistic approach to management of DSD. Much needs to be done to improve diagnosis, and to identify measures to predict outcome that can be used both in sex assignment decision-making and to improve the quality of life for young adults with DSD. Though challenging, these goals are attainable through specialist multidisciplinary clinics working at local level and the DSD community at large, collaborating at national and international levels to tap the data resources now being developed.

Etiological diagnosis of undervirilized male/XY disorder of sex development.

OBJECTIVE: To do clinical, hormonal and chromosomal analysis in undervirilized male / XY disorder of sex development and to make presumptive etiological diagnosis according to the new Disorder of Sex Development (DSD) classification system. STUDY DESIGN: Case series. PLACE AND DURATION OF STUDY: Endocrine Unit at National Institute of Child Health, Karachi, Pakistan, from January 2007 to December 2012. METHODOLOGY: Patients of suspected XY DSD / undervirilized male visiting endocrine clinic were enrolled in the study. Criteria suggested XY DSD include overt genital ambiguity, apparent female/male genitalia with inguinal/labial mass, apparent male genitalia with unilateral or bilateral non-palpable testes, micropenis and isolated hypospadias or with undescended testis. The older children who had delayed puberty were also evaluated with respect to DSD. As a part of evaluation of XY DSD, abdominopelvic ultrasound, karyotype, hormone measurement (testosterone, FSH, LH), FISH analysis with SRY probing, genitogram, laparoscopy, gonadal biopsy and HCG stimulation test were performed. Frequencies and percentages applied on categorical data whereas mean, median, standard deviation were calculated for continuous data. RESULTS: A total of 187 patients met the criteria of XY DSD. Age ranged from 1 month to 15 years, 55 (29.4%) presented in infancy, 104 (55.6%) between 1 and 10 years and 28 (15%) older than 10 years. Twenty five (13.4%) were raised as female and 162 as (86.6%) male. The main complaints were ambiguous genitalia, unilateral cryptorchidism, bilateral cryptorchidism, micropenis, delayed puberty, hypospadias, female like genitalia with gonads, inguinal mass. The karyotype was 46 XY in 183 (97.9%), 46 XX in 2 (1.1%), 47 XXY in 1 (0.5%), 45 X/46 XY in 1 (0.5%) patient. HCG stimulation test showed low testosterone response in 43 (23 %), high testosterone response in 62 (33.2%), partial testosterone response in 32 (17.1%) and normal testosterone response in 50 (26.7%). Genitogram was carried out in 86 (45.98%) patients. Presumptive etiological diagnosis of androgen sensitivity syndrome/ 5-alpha reductase deficiency, testicular biosynthetic defect/ leydig cell hypoplasia, partial gonadal dysgenesis, ovotesticular DSD, XX testicular DSD, mixed gonadal dysgenesis, testicular vanishing syndrome, klinefelter syndrome, hypogonadotropic hypogonadism, isolated hypospadias and isolated micropenis was made. CONCLUSION: Clinical, chromosomal and hormonal assessment may help in making the presumptive etiological diagnosis. Further molecular genetics analysis are needed in differentiating these abnormalities and to make a final diagnosis.

Long-term management of patients with disorders of sex development (DSD).

Differences or disorders of sex development (DSD) describe a biological discrepancy between chromosomal, gonadal, and phenotypical sex, often affecting the morphology of the genito-reproductive organs. DSD is most often due to genetic abnormalities affecting chromosomal composition or single genes. Most children with 46,XX karyotype and DSD have congenital adrenal hyperplasia due to 21-hydroxylase deficiency and should be regarded as unchallenged females. For children with 46,XY DSD, the situation is even much more complicated since indeed an exact genetic diagnosis is still missing. Depending on the phenotype, this may be true for more than 80% of children with severe hypospadias, in contrast in post-pubertal patients with clinical evidence of complete androgen insensitivity, whom 95% show an underlying mutation within the androgen receptor gene. DSD and numerical aberrations of sex chromosomes, especially 45,X/46,XY mosaicism depends essentially on the assessment of the exact clinical morphology with a focus of the external and internal genital structures and of the endocrine and reproductive function of the gonads with the aim for a best prognosis of the child. This assessment should be done in a center of expertise.