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Best Practice & Research. Clinical... Apr 2010Disorder of sex development (DSD) presents a unique challenge, both diagnostically and in terms of acute and longer-term management. These are relatively rare conditions... (Review)
Review
Disorder of sex development (DSD) presents a unique challenge, both diagnostically and in terms of acute and longer-term management. These are relatively rare conditions usually requiring a multidisciplinary approach from the outset and the involvement of a tertiary centre for assessment and management recommendations. This article describes the structure of the multidisciplinary team (MDT) at our centre, with contributions from key members of the team regarding their individual roles. The focus is on the newborn referred for assessment of ambiguous genitalia, rather than on individuals who present in the adolescent period or at other times, although the same MDT involvement is likely to be required. The approach to the initial assessment and management is discussed and the subsequent diagnosis and follow-up presented, with emphasis on the importance of careful transition and long-term support.
Topics: Adolescent; Adult; Child; Disorders of Sex Development; Endocrinology; Female; Holistic Health; Humans; Infant; Infant, Newborn; Male; Molecular Biology; Patient Care Team; Referral and Consultation; Urology
PubMed: 20541156
DOI: 10.1016/j.beem.2010.01.006 -
Ugeskrift For Laeger Mar 2017Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is a congenital anomaly characterized by uterovaginal agenesis in females with normal secondary sex characteristics and... (Review)
Review
Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is a congenital anomaly characterized by uterovaginal agenesis in females with normal secondary sex characteristics and normal karyotype (46,XX). The prevalence of MRKH syndrome is one in 5,000 live female births as recently confirmed by a nationwide population-based study in Denmark. This review kaleidoscopically summarizes the current knowledge of the history, genetics, diagnostics, treatment of vaginal agenesis, psychosexual aspects, and fertility options in MRKH syndrome.
Topics: 46, XX Disorders of Sex Development; Congenital Abnormalities; Female; Humans; Infertility, Female; Magnetic Resonance Imaging; Mullerian Ducts
PubMed: 28397650
DOI: No ID Found -
Organogenesis Jan 2016Gonadal differentiation has a determinative influence on sex development in human embryos. Disorders of sexual development (DSD) have been associated with persistent... (Review)
Review
Gonadal differentiation has a determinative influence on sex development in human embryos. Disorders of sexual development (DSD) have been associated with persistent embryonal differentiation stages. Between 1998 and 2015, 139 female patients with various (DSD) underwent operations at the Scientific Center of Obstetrics, Gynaecology and Perynatology in Moscow, Russia. Clinical investigations included karyotyping, ultrasound imaging, hormonal measurement and investigations of gonadal morphology. The male characteristics in the embryo are imposed by testicular hormones. When these are absent or inactive, the fetus may be arrested at between developmental stages, or stay on indifferent stage and become phenotypically female. A systematic analysis of gonadal morphology in DSD patients and a literature review revealed some controversies and led us to formulate a new hypothesis about sex differentiation. Proliferation of the mesonephric system (tubules and corpuscles) in the gonads stimulates the masculinization of gonads to testis. Sustentacular Sertoli cells of the testes are derived from mesonephric excretory tubules, while interstitial Leydig cells are derived from the original mesenchyme of the mesonephros. According of the new hypothesis, the original mesonephric cells (tubules and corpuscles) potentially persist in the ovarian parenchyma. In female gonads, some mesonephric excretory tubules regress and lose the tubular structure, but form ovarian theca interna and externa, becoming analogous to the sustentacular Sertoli cells in the testis. The ovarian interstitial Leydig cells are derived from intertubal mesenchyme of the mesonephros, similar to what occurs in male gonads (testis). Surprisingly, the leading determinative factor in sexual differentiation of the gonads is the mesonephros, represented by the embryonic urinary system.
Topics: Disorders of Sex Development; Female; Gonads; Humans; Male; Sex Determination Processes; Sex Differentiation
PubMed: 26950283
DOI: 10.1080/15476278.2016.1145318 -
Human Heredity 2014Disorders of sex development (DSD) are defined as 'congenital conditions in which the development of chromosomal, gonadal, or anatomical sex is atypical' [Lee et al.,... (Review)
Review
Disorders of sex development (DSD) are defined as 'congenital conditions in which the development of chromosomal, gonadal, or anatomical sex is atypical' [Lee et al., Pediatrics 2006;118:e488-e500]. Studies conducted in Western countries, with low rates of consanguinity, show that truly ambiguous genitalia have an estimated incidence of 1:5,000 births. There are indications that the prevalence of DSD is higher in endogamous communities. The incidence of ambiguous genitalia in Saudi Arabia has been estimated at 1:2,500 live births; whilst in Egypt, it has been estimated at 1:3,000 live births. This may be due in part to an increase in disorders of androgen synthesis associated with 46,XX DSD. There is clearly a need for further studies to address the frequency of DSD in communities with high levels of consanguinity. This will be challenging, as an accurate diagnosis is difficult and expensive even in specialized centres. In developing countries with high levels of consanguinity, these limitations can be compounded by cultural, social and religious factors. Overall there is an indication that consanguinity may lead to an increase in incidences of both 46,XY and 46,XX DSD, and a co-ordinated study of populations with higher incidences of consanguinity/endogamy is needed to resolve this.
Topics: Adrenal Hyperplasia, Congenital; Androgens; Cholesterol; Consanguinity; Disorder of Sex Development, 46,XY; Disorders of Sex Development; Female; Humans; Male; Testis
PubMed: 25060274
DOI: 10.1159/000360763 -
Hormone Research in Paediatrics 2023Disorders/differences of sex development (DSD) comprise a heterogeneous group of inborn conditions where the individual's sex chromosomes, gonads, and/or anatomical sex... (Review)
Review
BACKGROUND
Disorders/differences of sex development (DSD) comprise a heterogeneous group of inborn conditions where the individual's sex chromosomes, gonads, and/or anatomical sex are discordant. Since the Chicago Consensus Conference in 2005, multidisciplinary care has been implemented in specialised paediatric tertiary care centres and clinical practice has substantially changed towards a more holistic approach.
SUMMARY
Psychological support has become a key factor in the management of DSD. After paediatric care, one of the main challenges is the transition of patients to expert care in adulthood. Patients frequently experience difficulties in accessing specialised medical care in adulthood, resulting in loss to follow-up affecting the patients' physical and psychological health as well as quality of life. Clinical features and long-term outcomes are highly variable in most DSD conditions. Although medical care has improved, morbidity and mortality are increased in all conditions. A particular challenge in the care of DSD patients in adulthood is optimisation of fertility potential. Ideally, this is addressed already in adolescence and requires close interaction of not only paediatricians and adult endocrinologists but also urologists, andrologists or gynaecologists, and psychologists.
KEY MESSAGES
This review addresses issues relating to transition of DSD care from the paediatric to adult care as well as health-related challenges in adulthood in DSD.
Topics: Adolescent; Humans; Adult; Child; Disorders of Sex Development; Quality of Life; Transition to Adult Care; Fertility; Mental Health
PubMed: 36473446
DOI: 10.1159/000527433 -
Frontiers in Endocrinology 2021Disorders of Sex Development (DSD) are anomalies occurring in the process of fetal sexual differentiation that result in a discordance between the chromosomal sex and... (Review)
Review
Disorders of Sex Development (DSD) are anomalies occurring in the process of fetal sexual differentiation that result in a discordance between the chromosomal sex and the sex of the gonads and/or the internal and/or external genitalia. Congenital disorders affecting adrenal function may be associated with DSD in both 46,XX and 46,XY individuals, but the pathogenic mechanisms differ. While in 46,XX cases, the adrenal steroidogenic disorder is responsible for the genital anomalies, in 46,XY patients DSD results from the associated testicular dysfunction. Primary adrenal insufficiency, characterized by a reduction in cortisol secretion and overproduction of ACTH, is the rule. In addition, patients may exhibit aldosterone deficiency leading to salt-wasting crises that may be life-threatening. The trophic effect of ACTH provokes congenital adrenal hyperplasia (CAH). Adrenal steroidogenic defects leading to 46,XX DSD are 21-hydroxylase deficiency, by far the most prevalent, and 11β-hydroxylase deficiency. Lipoid Congenital Adrenal Hyperplasia due to StAR defects, and cytochrome P450scc and P450c17 deficiencies cause DSD in 46,XY newborns. Mutations in SF1 may also result in combined adrenal and testicular failure leading to DSD in 46,XY individuals. Finally, impaired activities of 3βHSD2 or POR may lead to DSD in both 46,XX and 46,XY individuals. The pathophysiology, clinical presentation and management of the above-mentioned disorders are critically reviewed, with a special focus on the latest biomarkers and therapeutic development.
Topics: Adrenal Hyperplasia, Congenital; Adrenal Insufficiency; Disorders of Sex Development; Humans; Sex Differentiation
PubMed: 34987475
DOI: 10.3389/fendo.2021.770782 -
International Journal of Molecular... Nov 2019Sex development is a complex process involving many genes and hormones. Defects in this process lead to Differences of Sex Development (DSD), a group of heterogeneous... (Review)
Review
Sex development is a complex process involving many genes and hormones. Defects in this process lead to Differences of Sex Development (DSD), a group of heterogeneous conditions not as rare as previously thought. Part of the obstacles in proper management of these patients is due to an incomplete understanding of the genetics programs and molecular pathways involved in sex development and DSD. Several challenges delay progress and the lack of a proper model system for the single patient severely hinders advances in understanding these diseases. The revolutionary techniques of cellular reprogramming and guided in vitro differentiation allow us now to exploit the versatility of induced pluripotent stem cells to create alternatives models for DSD, ideally on a patient-specific personalized basis.
Topics: Animals; Cellular Reprogramming Techniques; Disorders of Sex Development; Gonads; Humans; Induced Pluripotent Stem Cells; Patient-Specific Modeling; Primary Cell Culture
PubMed: 31690065
DOI: 10.3390/ijms20215495 -
Fertility and Sterility Feb 2014Studies on the phenotypes of women and men with mutations disrupting estrogen biosynthesis and action have significantly advanced our knowledge of the physiologic roles... (Review)
Review
Studies on the phenotypes of women and men with mutations disrupting estrogen biosynthesis and action have significantly advanced our knowledge of the physiologic roles of estrogen in humans. Aromatase deficiency results from autosomal recessive inheritance of mutations in the CYP19A1 gene. It gives rise to ambiguous genitalia in 46,XX fetuses. At puberty, affected girls have hypergonadotropic hypogonadism, do not develop secondary sexual characteristics, and exhibit progressive virilization. The affected 46,XY men have normal male sexual differentiation and pubertal maturation. These men, however, are extremely tall and have eunucoid proportions with continued linear growth into adulthood, severely delayed epiphyseal closure, and osteoporosis due to estrogen deficiency. Although estrogen has been shown to be essential for normal sperm production and function in mice, its role in fertility is not clear in men. Thus far, one man and an unrelated woman with estrogen resistance due to mutations in the estrogen receptor α (ESR1) gene have been described. Their clinical presentations are similar to that of aromatase-deficient men and women.
Topics: 46, XX Disorders of Sex Development; Animals; Aromatase; Estrogen Receptor alpha; Female; Genes, Recessive; Gynecomastia; Humans; Infertility, Male; Male; Metabolism, Inborn Errors; Mutation
PubMed: 24485503
DOI: 10.1016/j.fertnstert.2013.12.022 -
Archives of Disease in Childhood Sep 2003The surgical management of children born with ambiguous genitalia has always been difficult, subject to evolving attitudes and techniques, and at times controversial.... (Review)
Review
The surgical management of children born with ambiguous genitalia has always been difficult, subject to evolving attitudes and techniques, and at times controversial. Standard protocols have stressed the need for early diagnosis, gender assignment, and appropriate surgery in infancy.(1) In recent years some authors, backed by patient support groups, have claimed that such surgery is damaging or mutilating and, as it is essentially cosmetic, should not be performed until the fully informed consent of the patient could be obtained-that is, when the child becomes "Gillick competent".(2-)(4) There are, however, so many specific issues related to the different diagnostic groups that such a policy would seem to be too prescriptive.
Topics: Adrenal Hyperplasia, Congenital; Androgen-Insensitivity Syndrome; Child; Child, Preschool; Disorders of Sex Development; Female; Genitalia; Humans; Infant; Infant, Newborn; Male; Sex Determination Analysis; Time Factors
PubMed: 12937103
DOI: 10.1136/adc.88.9.799 -
Hormone Research in Paediatrics 2023DSD encompass a wide range of pathologies that impact gonad formation, development, and function in both 46,XX and 46,XY individuals. The majority of these conditions... (Review)
Review
BACKGROUND
DSD encompass a wide range of pathologies that impact gonad formation, development, and function in both 46,XX and 46,XY individuals. The majority of these conditions are considered to be monogenic, although the expression of the phenotype may be influenced by genetic modifiers. Although considered monogenic, establishing the genetic etiology in DSD has been difficult compared to other congenital disorders for a number of reasons including the absence of family cases for classical genetic association studies and the lack of evolutionary conservation of key genetic factors involved in gonad formation. In recent years, the widespread use of genomic sequencing technologies has resulted in multiple genes being identified and proposed as novel monogenic causes of 46,XX and/or 46,XY DSD.
SUMMARY
In this review, we will focus on the main genomic findings of recent years, which consists of new candidate genes or loci for DSD as well as new reproductive phenotypes associated with genes that are well established to cause DSD. For each gene or loci, we summarize the data that are currently available in favor of or against a role for these genes in DSD or the contribution of genomic variants within well-established genes to a new reproductive phenotype.
KEY MESSAGES
Based on this analysis, we propose a series of recommendations that should aid the interpretation of genomic data and ultimately help to improve the accuracy and yield genetic diagnosis of DSD.
Topics: Humans; Phenotype; Disorders of Sex Development
PubMed: 34963118
DOI: 10.1159/000521381