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Current Opinion in Pediatrics Dec 2021The 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... (Review)
Review
PURPOSE OF REVIEW
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).
RECENT FINDINGS
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.
SUMMARY
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.
Topics: Disorders of Sex Development; Genomics; Humans; Phenotype; Sexual Development
PubMed: 34654048
DOI: 10.1097/MOP.0000000000001066 -
Sexual Development : Genetics,... 2022Anti-müllerian hormone (AMH) is 1 of the 2 testicular hormones involved in male development of the genitalia during fetal life. When the testes differentiate, AMH is... (Review)
Review
Anti-müllerian hormone (AMH) is 1 of the 2 testicular hormones involved in male development of the genitalia during fetal life. When the testes differentiate, AMH is secreted by Sertoli cells and binds to its specific receptor type II (AMHR2) on the müllerian ducts, inducing their regression. In the female fetus, the lack of AMH allows the müllerian ducts to form the fallopian tubes, the uterus, and the upper part of the vagina. The human AMH gene maps to 19p13.3 and consists of 5 exons and 4 introns spanning 2,764 bp. The AMHR2 gene maps to 12q13.13, consists of 11 exons, and is 7,817 bp long. Defects in the AMH pathway are the underlying etiology of a subgroup of disorders of sex development (DSD) in 46,XY patients. The condition is known as the persistent müllerian duct syndrome (PMDS), characterized by the existence of a uterus and fallopian tubes in a boy with normally virilized external genitalia. Approximately 200 cases of patients with PMDS have been reported to date with clinical, biochemical, and molecular genetic characterization. An updated review is provided in this paper. With highly sensitive techniques, AMH and AMHR2 expression has also been detected in other tissues, and massive sequencing technologies have unveiled variants in AMH and AMHR2 genes in hitherto unsuspected conditions.
Topics: Female; Humans; Male; Anti-Mullerian Hormone; Disorder of Sex Development, 46,XY; Disorders of Sex Development; Mullerian Ducts; Sexual Development; Receptors, Peptide; Receptors, Transforming Growth Factor beta
PubMed: 34515230
DOI: 10.1159/000518273 -
Indian Journal of Pediatrics Oct 2023Disorders of sex development (DSD) is a broad term for congenital conditions with a discrepancy in chromosomal, gonadal, or anatomic sex. Pediatricians are often faced... (Review)
Review
Disorders of sex development (DSD) is a broad term for congenital conditions with a discrepancy in chromosomal, gonadal, or anatomic sex. Pediatricians are often faced with the challenge of managing a newborn/infant with atypical genitalia or an older child with disordered puberty, which come under the purview of DSD. This article provides an update for pediatricians on comprehensive approach to DSD with a focus on atypical genitalia.
Topics: Child; Infant, Newborn; Humans; Adolescent; Disorders of Sex Development; Sexual Development
PubMed: 37354346
DOI: 10.1007/s12098-023-04640-7 -
Endocrine Reviews Dec 2019Differences/disorders of sex development (DSD) are a heterogeneous group of congenital conditions that result in discordance between an individual's sex chromosomes,... (Review)
Review
Differences/disorders of sex development (DSD) are a heterogeneous group of congenital conditions that result in discordance between an individual's sex chromosomes, gonads, and/or anatomic sex. Advances in the clinical care of patients and families affected by 46,XY DSD have been achieved since publication of the original Consensus meeting in 2006. The aims of this paper are to review what is known about morbidity and mortality, diagnostic tools and timing, sex of rearing, endocrine and surgical treatment, fertility and sexual function, and quality of life in people with 46,XY DSD. The role for interdisciplinary health care teams, importance of establishing a molecular diagnosis, and need for research collaborations using patient registries to better understand long-term outcomes of specific medical and surgical interventions are acknowledged and accepted. Topics that require further study include prevalence and incidence, understanding morbidity and mortality as these relate to specific etiologies underlying 46,XY DSD, appropriate and optimal options for genitoplasty, long-term quality of life, sexual function, involvement with intimate partners, and optimizing fertility potential.
Topics: Delivery of Health Care; Disorder of Sex Development, 46,XY; Fertility; Hormone Replacement Therapy; Humans; Sexual Behavior
PubMed: 31365064
DOI: 10.1210/er.2019-00049 -
African Health Sciences Sep 2021In humans, sex determination and differentiation is genetically controlled. Disorders of sex development (DSD) result in anomalies of the development of the external and...
BACKGROUND
In humans, sex determination and differentiation is genetically controlled. Disorders of sex development (DSD) result in anomalies of the development of the external and internal genitalia. Variants in transcription factors such as SRY, NR5A1 and SOX9, can cause changes in gonadal development often associated with ambiguity of the external genitalia.
OBJECTIVES
This study has been conducted to determine the frequency, types and associated genetic alterations in patients with DSD in the Algerian population.
METHODS
Thirty patients were included. Based on their clinical presentation, thirteen patients presented with ambiguous external genitalia, thirteen patients presented with hypospadias and four patients presented with bilateral undescended testes. Karyotype analysis was performed on peripheral blood lymphocytes using standard R-banding. DNA was isolated from blood leukocytes for PCR reaction and mutational analysis of SRY and NR5A1 was done by direct sequencing.
RESULTS
Most patients with ambiguous genitalia had a 46,XY karyotype. One patient had a deletion of SRY, otherwise no point mutations in SRY or NR5A1 genes were identified. However, a single NR5A1 polymorphism (p.Gly146Ala) in patient with 46,XX DSD has been detected.
CONCLUSIONS
The absence of mutations in these genes suggests that there are others genes playing an important role in sex development and differentiation.
Topics: Adolescent; Child; Disorders of Sex Development; Humans; Male; Mutation; Polymerase Chain Reaction; Sex-Determining Region Y Protein; Sexual Development; Steroidogenic Factor 1; Transcription Factors
PubMed: 35222615
DOI: 10.4314/ahs.v21i3.61 -
Human Pathology Jun 2020Classical gonadoblastoma occurs almost entirely in the dysgenetic gonads of an individual who has a disorder of sex development; however, a small number of cases arise...
Classical gonadoblastoma occurs almost entirely in the dysgenetic gonads of an individual who has a disorder of sex development; however, a small number of cases arise in individuals with a normal peripheral karyotype and no evidence of a disorder of sex development. Those gonadoblastomas that occur in an individual who has a Y chromosome or part thereof express testis specific protein Y-encoded 1 (TSPY1). If a gonad in those individuals contains germ cells with delayed maturation and also harbors the TSPY1 gene, the cells can undergo transformation to classical gonadoblastoma. The latter consists of rounded islands composed of germ cells, sex cord elements, and hyaline basement membrane material surrounded by a variably cellular stroma that sometimes contains steroid cells. Classical gonadoblastoma can be interpreted as a noninvasive or an in situ neoplasm that is the precursor of germinoma in some individuals and, indirectly, of other more aggressive germ cell neoplasms. The "dissecting" variant is derived from classical gonadoblastoma and is characterized by unusual growth patterns. Undifferentiated gonadal tissue is the precursor of gonadoblastoma; however, if all germ cells in an individual with undifferentiated gonadal tissue involute, the result is a secondary streak gonad. Undifferentiated gonadal tissue is a non-neoplastic condition resembling a streak gonad but additionally contains germ cells with delayed maturation that express octamer-binding transcription factor 4; however, other germ cells, show normal maturation and express TSPY1.
Topics: Cell Cycle Proteins; Cell Differentiation; Cell Lineage; Chromosomes, Human, X; Chromosomes, Human, Y; Disorders of Sex Development; Female; Germ Cells; Gonadoblastoma; Humans; Male; Ovarian Neoplasms; Risk Factors; Testicular Neoplasms
PubMed: 31805291
DOI: 10.1016/j.humpath.2019.11.005 -
Hormone Research in Paediatrics 2023The suspicion of a disorder of sex development (DSD) often arises at birth, when the newborn presents with ambiguous genitalia, or even during prenatal ultrasound... (Review)
Review
BACKGROUND
The suspicion of a disorder of sex development (DSD) often arises at birth, when the newborn presents with ambiguous genitalia, or even during prenatal ultrasound assessments. Less frequently, the aspect of the external genitalia is typically female or male, and the diagnosis of DSD may be delayed until a karyotype is performed for another health issue, or until pubertal age when a girl presents with absence of thelarche and/or menarche or a boy consults for gynaecomastia and/or small testes.
SUMMARY
In this review, we provide a practical, updated approach to clinical and hormonal laboratory workup of the newborn, the child, and the adolescent with a suspected DSD. We focus on how to specifically address the diagnostic approach according to the age and presentation.
KEY MESSAGE
We particularly highlight the importance of a detailed anatomic description of the external and internal genitalia, adequate imaging studies or surgical exploration, the assessment of reproductive hormone levels - especially testosterone, anti-Müllerian hormone, 17-hydroxyprogesterone, and gonadotropins - and karyotyping.
Topics: Infant, Newborn; Humans; Male; Child; Female; Adolescent; Disorders of Sex Development; Testosterone; Hypogonadism; Sexual Development; Genitalia
PubMed: 34781296
DOI: 10.1159/000519895 -
Pediatric Surgery International Sep 2019Misdiagnosing a cloaca as a disorder of sex development may lead to inappropriate testing, treatment, and negative emotional consequences to families. We were impressed...
AIM OF THE STUDY
Misdiagnosing a cloaca as a disorder of sex development may lead to inappropriate testing, treatment, and negative emotional consequences to families. We were impressed by the fact that a significant number of patients suffering from a cloaca were referred to us with the diagnosis of a "disorder of sex development" previously referred as "ambiguous genitalia" or "intersex". On re-evaluation, none of them truly had a disorder of sex differentiation. This prompted us to conduct the following retrospective review to try to find the cause of the misdiagnosis and the way to prevent it.
METHODS
A retrospective review of our colorectal database was performed to identify the total number of patients with cloacas and the number initially diagnosed as "ambiguous genitalia, intersex"/disorder of sex development. The external appearance of their genitalia and unnecessary testing or treatment received were recorded.
MAIN RESULTS
A total of 605 patients with cloacas were identified. Of these, 77 (12.7%) were referred to us with the diagnosis of "ambiguous genitalia" and 13 of them (17%) went on to receive an intervention that was not indicated: karyotyping (10), steroids (3), and ovarian biopsy (1). The karyotype result in all patients was XX. The misdiagnosis was triggered by the external appearance of the perineum, simulating a case of virilization with a hypertrophic clitoris, but was simply prominent labial skin. Careful examination of the perineal structure allowed us to determine that it consisted of folded skin with no evidence of corpora.
CONCLUSION
Patients born with a cloaca are at risk for mismanagement from being erroneously labeled as disorders of sex development. The diagnosis of a cloacal anomaly is a clinical one. The practitioner must distinguish between phallus-like clitoral hypertrophy and a normal clitoris with prominent labial skin.
Topics: Cloaca; Databases, Factual; Diagnostic Errors; Disorders of Sex Development; Female; Genitalia; Humans; Perineum; Retrospective Studies
PubMed: 31256297
DOI: 10.1007/s00383-019-04511-3 -
Urologie (Heidelberg, Germany) May 2024Human beings with a difference in sexual development (DSD) often underwent gender reassignment surgery during early childhood. However, the medical decision was often... (Review)
Review
BACKGROUND
Human beings with a difference in sexual development (DSD) often underwent gender reassignment surgery during early childhood. However, the medical decision was often not congruent with the gender identity that affected persons developed later on.
OBJECTIVES
To represent the interests of affected persons, an interdisciplinary guideline in cooperation with support groups was written.
MATERIALS AND METHODS
The revision of the first version of the guideline, published in 2016, was edited by 18 professional societies and working groups as well as 3 support groups. A literature search was performed for each of the 12 chapters. Recommendations and statements created by the working groups were voted on during four consensus conferences.
RESULTS
The guideline highlights the right of self-determination of affected persons. In this context, new legal requirements are reported. Other than necessary primary diagnostics, medical procedures should be postponed. Most important is the psychological support of parents and patients. Tumor risk of the gonads and protection of fertility are analyzed and discussed in detail.
CONCLUSION
The content of the guideline represents a paradigm shift in dealing with human beings with a difference of sexual development. Projects as DSD Care and Empower-DSD help to promote the practical implementation of the guideline's recommendations.
Topics: Humans; Male; Practice Guidelines as Topic; Female; Disorders of Sex Development; Germany; Sex Reassignment Surgery; Sexual Development; Urology
PubMed: 38573501
DOI: 10.1007/s00120-024-02326-2 -
Bioethics Jul 2022Is intersexuality a mere difference or disorder? Since the 2006 Chicago consensus statement's disorder of sexual development (DSD) nomenclature, intersex scholars have...
Is intersexuality a mere difference or disorder? Since the 2006 Chicago consensus statement's disorder of sexual development (DSD) nomenclature, intersex scholars have criticized and repudiated the use of "disorder" by arguing that it is medically inaccurate, yields unwarranted surgical implications, unnecessarily pathologizes intersex individuals, and that, most importantly, intersex individuals do not prefer it. They argue for linguistic alternatives such as "difference" and other similar alternatives, for example, "variation," "divergence," and so forth. These criticisms of "disorder" have had significant uptake by scholars writing on intersexuality. While the motivation(s) for using "mere difference" is doubtless rooted in beneficence for intersex persons, medically inaccurate intersex terminology compromises optimal clinical care and should consequently be either abandoned or revised. This focus paper argues (moderately) for the thesis that some cases of intersex are disorders, and some mere differences. The upshot of my proposal is not only that it conceptually disambiguates disorder and mere difference, but by failing to generalize unique intersex individuals their care is prioritized.
Topics: Disorders of Sex Development; Humans
PubMed: 35434797
DOI: 10.1111/bioe.13032