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Best Practice & Research. Clinical... Apr 2018Normal sex development depends on the precise spatio-temporal sequence and coordination of mutually antagonistic activating and repressing factors. These factors... (Review)
Review
Normal sex development depends on the precise spatio-temporal sequence and coordination of mutually antagonistic activating and repressing factors. These factors regulate the commitment of the unipotential gonad into the binary pathways governing normal sex development. Typically, the presence of the SRY gene on the Y chromosome triggers the cascade of molecular events that lead to male sex development. Disorders of sex development comprise a heterogeneous group of congenital conditions associated with atypical development of internal and external genitalia. These disorders are generally attributed to deviations from the typical progression of sex development. Disorders of sex development can be classified into several categories including chromosomal, gonadal, and anatomic abnormalities. Genetic tools such as microarray analyses and next-generation sequencing techniques have identified novel genetic variants among patients with disorders of sexual development. Most importantly, patient management needs to be individualized, especially for decisions related to sex of rearing, surgical interventions, hormone treatment, and potential for fertility preservation.
Topics: Child; Disease Management; Disorders of Sex Development; Female; Humans; Male
PubMed: 29503125
DOI: 10.1016/j.bpobgyn.2017.11.005 -
The Lancet. Diabetes & Endocrinology Jul 2019The diagnosis and management of children born with ambiguous genitalia is challenging for clinicians. Such differences of sex development (DSDs) are congenital... (Review)
Review
The diagnosis and management of children born with ambiguous genitalia is challenging for clinicians. Such differences of sex development (DSDs) are congenital conditions in which chromosomal, gonadal, or anatomical sex is atypical. The aetiology of DSDs is very heterogenous and a precise diagnosis is essential for management of genetic, endocrine, surgical, reproductive, and psychosocial issues. In this Review, we outline a step-by-step approach, compiled in a diagnostic algorithm, for the clinical assessment and molecular diagnosis of a patient with ambiguity of the external genitalia on initial presentation. We appraise established and emerging technologies and their effect on diagnosis, and discuss current controversies.
Topics: Algorithms; Diagnosis, Differential; Disorders of Sex Development; Humans; Infant, Newborn; Intersex Persons; Sexual Development
PubMed: 30803928
DOI: 10.1016/S2213-8587(18)30339-5 -
Frontiers in Endocrinology 2020Disorders of Sex Development (DSD) are congenital anomalies in which there is a discordance between chromosomal, genetic, gonadal, and/or internal/external genital sex.... (Review)
Review
Disorders of Sex Development (DSD) are congenital anomalies in which there is a discordance between chromosomal, genetic, gonadal, and/or internal/external genital sex. In XY individuals, the process of fetal sex differentiation can be disrupted at the stage of gonadal differentiation, resulting in gonadal dysgenesis, a form of early fetal-onset primary hypogonadism characterized by insufficient androgen and anti-Müllerian hormone (AMH) production, which leads to the development of ambiguous or female genitalia. The process of sex differentiation can also be disrupted at the stage of genital differentiation, due to isolated defects in androgen or AMH secretion, but not both. These are forms of fetal-onset hypogonadism with dissociated gonadal dysfunction. In this review, we present a perspective on impaired testicular endocrine function, i.e., fetal-onset male hypogonadism, resulting in incomplete virilization at birth.
Topics: Disorders of Sex Development; Humans; Hypogonadism; Male
PubMed: 32351452
DOI: 10.3389/fendo.2020.00211 -
Nature Reviews. Urology Jul 2023Sex 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... (Review)
Review
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.
Topics: Male; Humans; Female; Disorders of Sex Development; Testis; Sexual Development; Disorder of Sex Development, 46,XY; 46, XX Disorders of Sex Development
PubMed: 37020056
DOI: 10.1038/s41585-023-00754-x -
Nature Reviews. Endocrinology Jul 2018The term differences of sex development (DSDs; also known as disorders of sex development) refers to a heterogeneous group of congenital conditions affecting human sex... (Review)
Review
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.
Topics: Child; Child, Preschool; Consensus; Disease Management; Disorders of Sex Development; Europe; Female; Humans; Infant; Interdisciplinary Communication; Male; Needs Assessment; Practice Guidelines as Topic; Precision Medicine; Psychology; Psychosexual Development; Risk Assessment
PubMed: 29769693
DOI: 10.1038/s41574-018-0010-8 -
Hormone Research in Paediatrics 2016The goal of this update regarding the diagnosis and care of persons with disorders of sex development (DSDs) is to address changes in the clinical approach since the... (Review)
Review
The goal of this update regarding the diagnosis and care of persons with disorders of sex development (DSDs) is to address changes in the clinical approach since the 2005 Consensus Conference, since knowledge and viewpoints change. An effort was made to include representatives from a broad perspective including support and advocacy groups. The goal of patient care is focused upon the best possible quality of life (QoL). The field of DSD is continuously developing. An update on the clinical evaluation of infants and older individuals with ambiguous genitalia including perceptions regarding male or female assignment is discussed. Topics include biochemical and genetic assessment, the risk of germ cell tumor development, approaches to psychosocial and psychosexual well-being and an update on support groups. Open and on-going communication with patients and parents must involve full disclosure, with the recognition that, while DSD conditions are life-long, enhancement of the best possible outcome improves QoL. The evolution of diagnosis and care continues, while it is still impossible to predict gender development in an individual case with certainty. Such decisions and decisions regarding surgery during infancy that alters external genital anatomy or removes germ cells continue to carry risk.
Topics: Disorders of Sex Development; Female; Humans; Male; Quality of Life; Sexual Development
PubMed: 26820577
DOI: 10.1159/000442975 -
Endocrine Practice : Official Journal... Feb 2015To review current literature that supports a biologic basis of gender identity. (Review)
Review
OBJECTIVE
To review current literature that supports a biologic basis of gender identity.
METHODS
A traditional literature review.
RESULTS
Evidence that there is a biologic basis for gender identity primarily involves (1) data on gender identity in patients with disorders of sex development (DSDs, also known as differences of sex development) along with (2) neuroanatomical differences associated with gender identity.
CONCLUSIONS
Although the mechanisms remain to be determined, there is strong support in the literature for a biologic basis of gender identity.
Topics: Disorders of Sex Development; Gender Identity; Humans; Transgender Persons
PubMed: 25667367
DOI: 10.4158/EP14351.RA -
Current Opinion in Obstetrics &... Oct 2019To provide a framework for the evaluation of ambiguous genitalia. (Review)
Review
PURPOSE OF REVIEW
To provide a framework for the evaluation of ambiguous genitalia.
RECENT FINDINGS
The most pressing evaluation of ambiguous genitalia is assessment for life-threatening causes such as salt-wasting congenital adrenal hyperplasia (CAH) or syndromes with underlying anomalies such as neurologic or cardiac malformations. A multidisciplinary team, including specialists in Gynecology, Endocrinology, Urology, Genetics, Clinical Psychology/Psychiatry, Radiology, Nursing, Neonatology, and Pediatric Surgery, should be involved. Each patient should be approached in an individualized manner to assign sex of rearing in the most expeditious yet thoughtful means possible.As knowledge on the natural history of sex preference and fertility of individuals with ambiguous genitalia increases, controversy regarding the indication for and timing of genital surgery continues. Considerations include gender identity, future fertility, malignancy risk, infection prevention, and functional anatomy for sexual activity.
SUMMARY
The evaluation of ambiguous genitalia should involve a multidisciplinary team. A combination of history taking, physical examination, laboratory evaluation, and radiologic assessment can assist with the diagnosis. Care should be taken to emphasize karyotypic sex is not equivalent to gender and to use caution with regards to irreversible medical and surgical therapies which may impact fertility and sexual function and nonconform with future sex identity.
Topics: Disorders of Sex Development; Female; Humans; Infant, Newborn; Karyotyping; Male; Physical Examination; Ultrasonography, Prenatal
PubMed: 31425174
DOI: 10.1097/GCO.0000000000000565 -
Journal of Pediatric Urology Feb 2021Gender assignment in infants born with a difference in sexual development (DSD) remains one of the many difficult decisions faced by the multi-disciplinary treatment... (Meta-Analysis)
Meta-Analysis Review
UNLABELLED
Gender assignment in infants born with a difference in sexual development (DSD) remains one of the many difficult decisions faced by the multi-disciplinary treatment team as some of these children develop gender identity disorder (GID) when they become adults. In this systematic review and meta-analysis we have analyzed the prevalence of GID in adolescent and adults with DSD. The secondary outcome of this review is to help physicians in appropriate sex assignment of DSD children so that development of GID in later life can be reduced.
METHODS
Pubmed/Index medicus were searched for "intersex" [All fields] OR "disorders of sexual differentiation AND "gender identity disorder OR gender dysphoria" [MeSH] for articles published between 2005 and 2020. Typical diagnoses included were congenital adrenal hyperplasia (CAH); complete androgen insensitivity syndrome (CAIS); partial androgen insensitivity syndrome (PAIS); 5 alpha reductase deficiency (5ARD); 17-hydroxysteroid dehydrogenase deficiency (17HSD); mixed gonadal dysgenesis (MGD) and complete gonadal dysgenesis (CGD). GID or gender dysphoria (a strong feeling of dissatisfaction about oneself as male or female) prevalence in DSD patients older than 12 years of age was extracted. Within each condition, GID percentage was compared between female and male rearing.
RESULTS
The I2statistics for prevalence of GID in DSD showed high heterogeneity with I2 of 93% (95% C.I 90-95%) among the 20 articles included. The overall prevalence of GID among those with DSD was 15% (95% C.I 13-17%). CAH reared females had 4% GID while CAH reared males had significantly higher GID at 15% (p = 0.0056). All CAIS patients were raised as females and the prevalence of GID was 1.7%. GID prevalence was 12% in PAIS raised as females while 25% in those raised as males with no significant difference (p = 0.134). GID was significantly high in 5ARD (53%) and 17HSD (53%) reared as females with half of them virilizing at puberty forcing a gender change. Among sex chromosome DSD 22% of those reared as females had GID while none in those raised as male with no significant difference.
CONCLUSIONS
GID is low in women with CAH, CAIS and CGD favoring female sex of rearing in these conditions. GID is high in women with 5ARD/17HSD favoring male sex of rearing in these conditions. GID is variable in PAIS or MGD and no recommendations on sex of rearing could be made in these conditions. Each DSD patient is unique and they warrant multi-disciplinary care and long term psycho sexual support.
Topics: Adolescent; Adult; Child; Disorder of Sex Development, 46,XY; Disorders of Sex Development; Female; Gender Dysphoria; Gender Identity; Humans; Male; Sexual Development; Steroid Metabolism, Inborn Errors
PubMed: 33246831
DOI: 10.1016/j.jpurol.2020.11.017 -
Archives of Disease in Childhood Oct 2017The baby with atypical or ambiguous genitalia is usually born in secondary care. For most clinicians, this is an unfamiliar and challenging scenario with the potential... (Review)
Review
The baby with atypical or ambiguous genitalia is usually born in secondary care. For most clinicians, this is an unfamiliar and challenging scenario with the potential for life-long ramifications arising from a consultation led by an unprepared clinician. Language needs to be used carefully with particular clarity when liaising with parents, local health professionals and the specialist multidisciplinary team. Confidence in the recognition and assessment of atypical or ambiguous genitalia in a newborn will guide the local clinician when deciding on the initial investigations required and is a foundation for subsequent management. The local team have key roles in the initial support for parents as well as managing expectations at a time of great uncertainty. There are numerous different diagnoses that can result in atypical or ambiguous genitalia. The clinical findings should guide the initial investigations, and there are many pitfalls when it comes to interpreting the results. The aim of this article is to provide an initial approach to the management of a baby born with atypical or ambiguous genitalia.
Topics: Diagnosis, Differential; Disorders of Sex Development; Female; Humans; Infant; Infant, Newborn; Male
PubMed: 28442467
DOI: 10.1136/archdischild-2016-311270