Materiały źródłowe

• #1 Ambiguous Genitalia and Disorders of Sexual Differentiation – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK557435/

  Infants born with a disorder of sex development (DSD) prompt multiple medical, surgical, ethical, psychosocial, and physical issues for patients and their parents. […] This activity reviews the evaluation and management of infants born with DSD and highlights the interprofessional team’s role in the management of patients with this condition. […] […] Describe the pathophysiology of disorders of sexual development. […] Explain the common physical findings in disorders of sexual development. […] Review the management considerations of patients with disorders of sexual development. […] Outline the importance of improving care coordination among the interprofessional team to enhance the delivery of care for patients with disorders of sexual development. […] The birth of an infant with ambiguous genitalia generates difficult multiple medical, surgical, ethical, psychosocial, and physical issues for patients and their parents. […] When discordance occurs among three processes (chromosomal, gonadal, phenotypic sex determination), a DSD is the result.

• #2 Disorders of sex development – Wikipedia

  https://en.wikipedia.org/wiki/Disorders_of_sex_development

  Disorders of sex development (DSDs), also known as differences in sex development, variations in sex characteristics, sexual anomalies, or sexual abnormalities, are congenital conditions affecting the reproductive system, in which development of chromosomal, gonadal, or anatomical sex is atypical. […] DSDs are subdivided into groups in which the labels generally emphasize the karyotype’s role in diagnosis: 46,XX; 46,XY; sex chromosome; XX, sex reversal; ovotesticular disorder; and XY, sex reversal. […] Sexual anomalies often generate from genetic abnormalities caused by many factors, leading to different sexual development. These genetic abnormalities occur during the prenatal stage of an individual’s fetal development. […] The initial steps of sexual differentiation begin with the development of the gonads and genitals. This process is consistent with both genders spanning over the course of the first 6 weeks following conception, during which the embryo remains pluripotent.

• #3 Ambiguous Genitalia and Disorders of Sexual Differentiation – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK557435/

  Disorders of sexual development are defined as congenital conditions characterized by atypical development of chromosomal, gonadal, or anatomic sex. […] Any deviations from the usual pattern of differentiation can present as DSDs. […] Sexual development in mammals occurs in two sequential stages: the initial phase of sex determination followed by sex differentiation. […] The inheritance of the Y chromosome and the subsequent expression of the SRY gene drives the bipotential gonad toward differentiation into male-specific testes. […] The second stage of sex differentiation is characterized by the secretion of certain hormones and other factors by the differentiated gonad, which guides the internal and external genital development and maturation. […] A multitude of genes plays an important role in orchestrating this complex sequence of events. […] A mutation in any of these above genes may lead to the development of DSD.

• #4 Differences of Sex Development | Lurie Children’s

  https://www.luriechildrens.org/en/specialties-conditions/atypical-genitalia-differences-of-sex-development/

  Sex development occurs in stages. Babies have many opportunities to develop along paths that are not typical for male or female development. When sex development follows a less common path, the result is a difference of sex development (DSD*). Knowing at what point the path changed helps us provide appropriate medical care. […] Human development is a complicated process. Slight differences in the usual process can result in a difference of sex development. Because these developmental differences occur before birth, they are called congenital. […] When an egg and sperm meet, the child’s chromosomal makeup is determined. One parent typically gives an X chromosome and the other either an X or Y chromosome. Usually, an XX individual is a female and an XY individual is a male. Sometimes, however, a child gets an extra chromosome from a parent or a chromosome is absent, resulting in XXY, XO or XYY. These differences lead to a DSD.

• #5 Differences of Sex Development – Clinical Tree

  https://clinicalpub.com/differences-of-sex-development/

  46,XY GD results from abnormal testis development in utero. […] Given the primary importance of SRY in human testis determination, it is surprising that mutations in SRY only account for approximately 15% of all 46,XY DSDs with complete GD. […] This suggests the existence of many other genes involved in primary human sex determination. […] Mutations in genes involved in testis sex determination (SOX9, WT-1, DHH, DMRT1) and duplications of putative anti-testis genes (WNT-4, DAX1/NR0B1) have also been shown to be responsible for a minority of all XY GD. […] The major concern in the treatment of patients with XY GD is the risk of gonadoblastoma, a mixed germ-cell, sex-cord tumor.

• #6 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Disorders-of-Sex-Development-(DSD).aspx

  Differences in sex development (DSD) encompass a range of rare conditions that impact genes, hormones, and reproductive organs, including genitalia. These conditions lead to variations in sex development compared to the typical patterns. […] Sexual differentiation is a multifactorial process that involves differentiation at the chromosomal, gonadal, hormonal, phenotypic, and psychological levels. […] There are various genes involved in facilitating sexual determination, the most notable of which include the SRY, SRY-box transcription factor 9 (SOX9), nuclear receptor subfamily 5 group A member 1 (NR5A1)/steroidogenic factor 1 (SF-1), Desert hedgehog homolog (DHH), dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1 (NR0B1/DAX1), Wilms tumor 1 (WT1), Wingless-type MMTV integration site family, member 4 (Wnt4), and Wnt7a genes.

• #7 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Disorders-of-Sex-Development-(DSD).aspx

  The dosage, expression levels, and function of the protein products of these genes determine gonadal differentiation. Thus, a mutation in any of these genes can contribute to the development of DSD. […] Epigenetic changes in these genes may also lead to abnormal gene expression. For example, hypermethylation of the SRY gene can lead to the silencing of DMRT1, SOX8, SOX9, NR5A1, and anti-Mullerian hormone (AMH) genes. […] DSDs can also arise due to alterations in chromosomal, gonadal, hormonal, and ductal sex, as well as external genitalia characteristics.

• #8 Management guidelines for disorders/different sex development (DSD) | Anales de Pediatría

  https://analesdepediatria.org/en-management-guidelines-for-disorders-different-sex-articulo-S2341287918301637

  Sexual differentiation during prenatal development involves a series of processes whose initiation and regulation involve numerous genes, proteins and hormones. The first stage in gonadal and genital development is shared by both sexes and spans the first 6 weeks following conception, an interval during which the embryo is pluripotent. Gonadal differentiation starts in the 7th week and is regulated by a multitude of genes, with the SRY gene in the Y chromosome playing a key role in the development of the testes. Genital differentiation (internal and external) is regulated by the effects of hormones synthesised by the testes in male embryos, or by their absence in female embryos. Any abnormality of genetic or environmental origin that impacts these processes at any level may result in inadequate development of the gonads (gonadal dysgenesis), the internal genitalia (absence or abnormal features) and/or the external genitalia (insufficient or excessive virilization). These abnormalities may be apparent at birth, manifesting as genital ambiguity or discordance between genotypic and phenotypic sex, during puberty, manifesting as delayed puberty, amenorrhoea or insufficient or excessive virilization, or later in life, manifesting as infertility or early menopause, and it is important to remember that they can be associated to anomalies in other systems or be life-threatening if they are associated with adrenal insufficiency. The approach to their management is also critical in infants when it comes to gender assignment. For all the above reasons, these conditions always require medical and psychosocial care delivered by a multidisciplinary team.

• #9 Differences of Sex Development | Lurie Children’s

  https://www.luriechildrens.org/en/specialties-conditions/atypical-genitalia-differences-of-sex-development/

  When a fetus is just forming during the pregnancy, an organ is present that we call the gonad. It is identical in females and males until midway through the second month of pregnancy. At that time, certain signals inside the fetus direct the gonad to develop into an ovary or a testicle. Any change in these signals can lead to a gonad that doesn’t develop in the typical way. For example, it may contain both ovarian and testicular tissue or may not produce hormones properly. […] Further development leads to a child having organs typically, a uterus, fallopian tubes, clitoris and labia for females or the seminal vesicles, penis and scrotum for males. At first, every fetus has the potential to develop either set of organs on the inside or outside. After the gonad becomes an ovary or a testicle, it makes hormones that help the body determine which type of structures to develop on the inside and outside. Variations in this development can lead to a range of differences.

• #10 apem :: Annals of Pediatric Endocrinology & Metabolism

  https://e-apem.org/m/journal/view.php?number=886

  The genital morphology can vary from predominantly female with a palpable gonad to predominantly male with absent gonads. […] A palpable gonad always has a testicular component and, if present, provides the most important etiological clue of a DSD. […] The presence of one or more openings and the exact location of the urethral meatus (distal penile, midshaft, or perineal) need to be documented. […] The labioscrotal folds should be inspected for rugosity, pigmentation, and labial fusion. […] The genital phenotype may be highly variable. […] In infants with sex chromosomes other than 46,XX, a different array of investigations is necessary to determine the presence of testes and the adequacy of hormone production and action. […] The most common DSD to present in concert with primary amenorrhea is the sex chromosome DSD, Turner syndrome.

• #11 apem :: Annals of Pediatric Endocrinology & Metabolism

  https://e-apem.org/m/journal/view.php?number=886

  The most common 46,XY DSDs that present in adolescent girls are CAIS and complete gonadal dysgenesis (CGD); CAIS is characterized by normal breast development, absent or diminished sexual hair development, and absent uterus, while CGD presents with a lack of breast development, hypergonadotropic hypogonadism, and usually with a rudimentary uterus.

• #12 Ambiguous Genitalia and Disorders of Sexual Differentiation – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK557435/

  A finely balanced hormonal milieu is required for normal sexual development; testosterone is necessary to stabilize the Wolffian ducts, while secretion of anti-Mullerian factors is essential for the regression of Mullerian ducts. […] In summary, any deviation from the intricate sequence of sexual development may give rise to disorders of sexual development.

• #13 Disorder of sex development | PPT

  https://www.slideshare.net/slideshow/disorder-of-sex-development/231226374

  Differentiation of the Wolffian ducts into epididymitis, vasa differentia and seminal vesicles due to effect of testosterone. […] Differentiation of the Mullerian ducts into uterus, fallopian tubes upper vagina due to absence of AMH (anti-Mullerian hormone). […] Development of the external genitalia into penis, scrotum ( due to DHT) or clitoris and labia majora minora (due to estradiol). […] This is done through Testicular Determinant Factor (TDF). TDF locus is on distal short arm of Y -chromosome. TDF begins its action at 7 weeks of gestation. Loss of TDF leads to gonadal dysgenesis. […] The external genitalia of both sexes are identical during the first 7 weeks of gestation. Without the hormonal action of the testosterone dihydrotestosterone (DHT), external genitalia appear phenotypically female.

• #14 Disorder of sex development | PPT

  https://www.slideshare.net/slideshow/disorder-of-sex-development/231226374

  In the gonadal male, differentiation toward the male phenotype actively occurs over the next 8 weeks. This differentiation is moderated by testosterone, which is converted to 5-DHT by the action of an enzyme, 5- reductase. […] The main etiologic causes that lead to under virilized genitalia in 46XY neonate are: abnormal testis determination factor. defects in androgen biosynthesis metabolism. resistance to androgens. malformation syndromes. […] 46,XY DSD Causes: Testicular Hypoplasia. Gonadotrophin deficiency/ resistance. Bilateral Testicular Dysgenesis (Sawyer syndrome). Anti- Mullerian hormone deficiency. Testosterone biosynthesis defects. 5 – reductase deficiency. […] The degree of virilization of the external genitalia depends heavily on the ability of the testicular tissue to secrete testosterone, and whether or not the Mullerian ducts have matured into female structures.

• #15 Differences (disorders) of sex development – Knowledge @ AMBOSS

  https://www.amboss.com/us/knowledge/differences-disorders-of-sex-development/

  Differences (disorders) of sex development (DSDs; formerly known as intersex conditions) are a group of congenital conditions characterized by the atypical development of chromosomal, gonadal, and/or phenotypic sex. […] The underlying genetic mutations can affect the number and function of sex chromosomes (e.g., in Turner syndrome), cause structural changes that influence the sensitivity of hormone receptors (e.g., androgen insensitivity syndrome), and alter the function of enzymes responsible for sex hormone synthesis (e.g., congenital adrenal hyperplasia). […] The diagnosis of DSDs is based on clinical features, evaluation of hormone levels, and genetic testing. […] The clinical management of DSDs involves a multidisciplinary approach guided by clinical necessity, patient choice, and strong ethical principles.

• #16 Differences (disorders) of sex development – Knowledge @ AMBOSS

  https://www.amboss.com/us/knowledge/differences-disorders-of-sex-development/

  Pathophysiology: chromosomal nondisjunction X chromosome monosomy/mosaicism impaired ovarian development malfunctioning streak gonads with connective tissue instead of normal germ cells estrogen and progesterone deficiencies. […] Pathophysiology: AMH deficiency/insensitivity persistence of the Mullerian duct development of uterus, cervix, fallopian tubes, and upper two thirds of the vagina in 46,XY individuals. […] Pathophysiology: 17-hydroxysteroid dehydrogenase 3 conversion of androstenedione to testosterone testosterone levels signs and symptoms of hypoandrogenism.

• #17 13.3: Differences of Sexual Development – Social Sci LibreTexts

  https://socialsci.libretexts.org/Bookshelves/Psychology/Biological_Psychology/Biopsychology_(OERI)_-_DRAFT_for_Review/13%3A_Sexuality_and_Sexual_Development/13.03%3A_Differences_of_Sexual_Development

  CAH is the most common cause of intersex conditions. […] Androgen insensitivity syndrome (AIS) and 5-reductase deficiency are the most common causes of anomalous male (XY) sexual differentiation. […] Individuals with AIS lack receptors for androgens and develop as females. […] Individuals with AIS are genetically male and have an X and a Y chromosome, but they develop and are raised as females. […] The androgen hormone testosterone normally causes the testes to descend and typical male characteristics to develop. […] Individuals with 5-reductase deficiency are born with ambiguous genitalia and are raised as females. […] During puberty, high levels of testosterone result in recognizable masculinization of the body, and these individuals usually transition to male gender identities and are generally attracted to women.

• #18 Androgen insensitivity syndrome: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/androgen-insensitivity-syndrome/

  Androgen insensitivity syndrome is a condition that affects sexual development before birth and during puberty. […] In people with androgen insensitivity syndrome, the body’s cells and tissues are unable to respond to certain male sex hormones (called androgens) that are important for normal male sexual development before birth and during puberty. […] Variants (also called mutations) in the AR gene cause androgen insensitivity syndrome. […] This gene provides instructions for making a protein called an androgen receptor. […] Variants in the AR gene prevent androgen receptors from working properly, which makes them less able to bind to testosterone and regulate gene activity. […] If androgen receptors cannot bind to androgens, the body cannot use androgens, even if there are normal levels of these hormones in the body.

• #19 Causes of differences of sex development – UpToDate

  https://www.uptodate.com/contents/causes-of-differences-of-sex-development

  Causes of differences of sex development […] The causes of DSDs that present with atypical genital appearance are presented here, grouped by karyotype and mechanism. […] The more common causes are: […] Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency in an XX individual.

• #20 Disorders/differences of sex development (DSDs) for primary care: the approach to the infant with ambiguous genitalia – Indyk – Translational Pediatrics

  https://tp.amegroups.org/article/view/16975/html

  The causes of genital ambiguity in newborn period are listed in Table 1. The most common cause of ambiguous genitalia is congenital adrenal hyperplasia. CAH comprises a collection of different adrenal steroid biosynthetic disorders which can result in wide-ranging phenotypes from salt-wasting adrenal crisis in the infant to virilization in young females, delayed puberty in adolescents and even polycystic ovary syndrome (PCOS)-like symptoms in young women. CAH should be the primary consideration in any virilized infant with non-palpable gonads. […] In addition to CAH being often recognized as the most common cause of genital ambiguity in infants and neonates, other notable causes include partial androgen insensitivity syndrome (Partial AIS or PAIS). AIS is caused by mutations in the androgen receptor (AR) gene on the X chromosome, and dictates response to androgen such as testosterone or DHT.

• #21 Differences in sex development

  https://www.nhs.uk/conditions/differences-in-sex-development/

  Differences in sex development (DSD) is a group of rare conditions involving genes, hormones and reproductive organs, including genitals. It means a person’s sex development is different to most other people’s. […] This happens because of a difference with your genes or how you respond to the sex hormones in your body, or both. It can be inherited, but there is often no clear reason why it happens. […] The most common cause is congenital adrenal hyperplasia (CAH). A person who has CAH lacks an enzyme (chemical substance) that their body needs to make the hormones cortisol and aldosterone. […] Without these hormones, their body produces more androgens (sex hormones that are naturally higher in males). If the child is female, the raised androgen levels before birth can cause their genitals to look different, such as a larger clitoris and a vagina that is not open in the usual place.

• #22 13.3: Differences of Sexual Development – Social Sci LibreTexts

  https://socialsci.libretexts.org/Bookshelves/Psychology/Biological_Psychology/Biopsychology_(OERI)_-_DRAFT_for_Review/13%3A_Sexuality_and_Sexual_Development/13.03%3A_Differences_of_Sexual_Development

  This section discusses some of the many ways in which sexual development can differ from typical XX/male and XY/female formats. […] Chromosomal abnormalities (such as Triple X syndrome, Turner syndrome, and Klinefelter syndrome), intersex conditions, anomalous female differentiation (such as congenital adrenal hyperplasia) and anomalous male sexual differentiation (such as 5-reductase deficiency and androgen insensitivity syndrome) demonstrate some of the diverse variations of biological sex found in humans. […] Prenatal exposure to androgens is the most common cause of anomalous sexual differentiation among females. […] Congenital adrenal hyperplasia (CAH) develops when excessive production of androgens by the adrenal cortex occurs due to a missing enzyme. […] In a female (XX) fetus, the elevated androgen levels result in varying degrees of masculinization of the external genitalia.

• #23 Oligogenic Origin of Differences of Sex Development in Humans

  https://www.mdpi.com/1422-0067/21/5/1809

  Sex development is a very complex biological event that requires the concerted collaboration of a large network of genes in a spatial and temporal correct fashion. […] Currently, the genetic cause of less than 50% of DSD individuals has been solved. Oligogenic disease has been proposed. […] In sex development, digenic inheritance has recently been suggested by WES analysis in a 46,XY DSD patient with gonadal dysgenesis (NR5A1 and MAP3K1 variants) and in a family with a 46,XY DSD male (NR5A1 variant) and 46,XY DSD female (NR5A1 and TBX2 variants). […] In most cases with oligogenic inheritance, at least two of the genes were predicted to be pathogenic and/or contribute to the phenotype. […] Recent studies support the concept that the broad range of some DSD phenotypes may be due to digenic or oligogenic origin similarly to results described in other endocrine disorders such as CHH and congenital hypothyroidism.

• #24 Characteristics and possible mechanisms of 46, XY differences in sex development caused by novel compound variants in NR5A1 and MAP3K1 | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-021-01908-z

  A novel NR5A1 variant (c.929AC, p. His310Pro) and a rare MAP3K1 variant (c.2282TC, p. Ile761Thr) were identified in the proband, whereas the proband’s mother and sister who only carry rare MAP3K1 variant have remained phenotypically healthy to the present. […] These two variants were predicted to be pathogenic by bioinformatic analysis. In vitro, NR5A1 variant decreased the SOX9 production by 82.11% compared to wild type NR5A1, while MAP3K1 variant had little effect on the SOX9 production compared to wild type MAP3K1. […] Our findings suggested the novel compound variants of NR5A1 and MAP3K1 can alter the expression of SOX9 and ultimately lead to abnormality of sex development. […] The pathogenic NR5A1 variations are thought to account for 910% of 46, XY DSD and are closely related to the diverse phenotype of 46, XY DSD.

• #25 Characteristics and possible mechanisms of 46, XY differences in sex development caused by novel compound variants in NR5A1 and MAP3K1 | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-021-01908-z

  To explain the underlying molecular mechanism of our genetic results, we conducted in vitro experiments of the NR5A1 and MAP3K1 variants and the accumulative effect of two different variants might be the cause of the clinical phenotype of our patient. […] In summary, our study identified novel compound variants of the NR5A1 and MAP3K1 genes which can alter the expression of SOX9 and ultimately resulted in a specific phenotype of a patient with 46, XY DSD. Digenic inheritance may play a key role in the phenotypic spectrum of 46, XY DSD associated with NR5A1 variants.

• #26 Disorders of Sex Development

  http://library.oumedicine.com/ReturningtoCare/90,P03079

  Girl babies with this condition have male sex organs. The condition is caused by a lack of a certain enzyme in the adrenal gland. It’s the most common cause of atypical genitalia in newborns. […] High levels of male hormones may also enter the placenta via the mother. This could be when the mother is given progesterone to prevent a miscarriage. Or if she has a hormone-producing tumor. […] Sometimes a child with atypical genitalia is at higher risk for tumors in the sex organs. Treatment for atypical genitalia depends on the type of the disorder. But it often includes surgery to remove or create sex organs appropriate for the child’s gender.

• #27 Management guidelines for disorders/different sex development (DSD) | Anales de Pediatría

  https://analesdepediatria.org/en-management-guidelines-for-disorders-different-sex-articulo-S2341287918301637

  Disorders of sex development (DSD) include a wide range of anomalies among the chromosomal, gonadal, and phenotypic (genital) characteristics that define sexual differentiation. At present, a definition as Different sexual development (DSD) is currently preferred. They originate in the pre-natal stage and are classified according to the sex chromosomes present in the karyotype. The known genetic causes are numerous and heterogeneous, although, in some cases, they may be secondary to maternal factors and/or exposure to endocrine-disrupting chemicals (EDCs). The diagnosis and treatment of DSD always requires multidisciplinary medical and psychosocial care. An aetiological diagnosis needs the interaction of clinical, biochemical (hormonal), genetic, imaging and, sometimes, surgical examinations. The treatment should deal with sex assignment, the possible need for hormone replacement therapy (adrenal if adrenal function is impaired, and with sex steroids from pubertal age if gonadal function is impaired), as well as the need for surgery on genital structures (currently deferred when possible) and/or on gonads (depending on the risk of malignancy), the need of psychosocial support and, finally, an adequate organisation of the transition to adult medical specialties. Patient Support Groups have a fundamental role in the support of families, as well as the interaction with professional and social media. The use of Registries and the collaboration between professionals in Working Groups of national and international medical societies are crucial for improving the diagnostic and therapeutic tools required for the care of patients with DSD.

• #28 Placental Methylation Influences Sex Differences in Neonatal Traits and Adult Disease | Inside Precision Medicine

  https://www.insideprecisionmedicine.com/topics/precision-medicine/placental-methylation-influences-sex-differences-in-neonatal-traits-and-adult-disease/

  It’s been established that sex differences in physiological and disease traits arise during early development, but what causes this is largely unknown. […] We establish that several sex-differentiated genetic effects on placental methylation and gene expression colocalize with birthweight and adult disease genetic associations, facilitating mechanistic insights on early life origins of health and disease outcomes shaped by sex. […] The differences they studied involve the presence or absence of tags on DNA known as methyl groups, which switch genes on or off without changing their structure. […] The study identified 2,497 previously unreported DNA sites that had different methylation patterns for males and females. […] Increases in methylation in male placentas were linked with greater neonatal size, whereas those in females were linked with greater placental size.

• #29 Placental Methylation Influences Sex Differences in Neonatal Traits and Adult Disease | Inside Precision Medicine

  https://www.insideprecisionmedicine.com/topics/precision-medicine/placental-methylation-influences-sex-differences-in-neonatal-traits-and-adult-disease/

  Lower activation of CCDC6 has been linked with preterm birth in previous studies. […] Higher methylation near the FNDC5 gene was associated with lower expression of the gene in male placentas but not in female placentas. […] Genetic factors are known to influence the health differences between males and females from before birth. […] Dysfunction of the placenta underlies many pregnancy complications and is thought to set the stage for male and female health differences that occur later in life. […] The differences in DNA methylation patterns these researchers have uncovered could thus fuel future research on the higher risk for pregnancy complications involving male fetuses, such as stillbirth and prematurity, as well as later life health conditions that occur in adults who were born after a complicated pregnancy.

• #30 Turner syndrome – Symptoms & causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/turner-syndrome/symptoms-causes/syc-20360782

  Turner syndrome, a condition that affects only females, results when one of the X chromosomes (sex chromosomes) is missing or partially missing. […] The genetic changes of Turner syndrome may be one of the following: Monosomy. The complete absence of an X chromosome generally occurs because of an error in the father’s sperm or in the mother’s egg. This results in every cell in the body having only one X chromosome. […] The missing or changed X chromosome of Turner syndrome causes problems during fetal development and other developmental problems after birth for example, short stature, ovarian insufficiency and heart defects.

• #31 Turner Syndrome: What It Is, Causes, Symptoms & Treatment

  https://my.clevelandclinic.org/health/diseases/15200-turner-syndrome

  Turner syndrome leads to a variety of features and symptoms and affects each person differently. But short stature and reduced ovary functioning (primary ovarian insufficiency) are the two most common features. […] Common features of Turner syndrome include short stature, differences in sexual development and certain physical traits. […] Another common feature is differences in sexual development. Most people with TS: Typically dont go through puberty unless they get hormone therapy in late childhood and early adolescence. […] Estrogen can help with breast development and menstruation. Estrogen replacement improves brain development, heart function, liver function and bone health, too.

• #32

  https://scite.ai/reports/mechanism-of-sex-determination-in-kJ0mgJ

  In about 15-20%, the cause of 46,XY GD is a mutation in the SRY gene, which is the master regulator starting the male sex-determining cascade in utero. […] Other autosomal genes involved in gonadal development such as SOX9, NR5A1, GATA4, FOG2, CBX2 MKAP3K1, DMRT1 may determine this condition. […] Recently, analysis of copy number variants by genome-wide human array suggested that dysfunctional pathways of human gonad development may also be related to rearrangements of noncoding sequences disturbing gene regulation. […] However, the cause of 46,XY GD remains unknown in several subjects. […] A 46,XY European woman with 46,XY GD and a novel homozygous DHH pathogenic variant is reported, confirming that this gene plays a key role in male gonadal development. […] Thus, DHH seems not to be involved in the ovarian development pathway or its postpubertal function. Homozygous DHH mutations cause a specific peripheral neuropathy in humans with both 46,XY and 46,XX karyotypes.

• #33 Copy Number Variation in Patients with Disorders of Sex Development Due to 46,XY Gonadal Dysgenesis | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0017793

  Disorders of sex development (DSD), ranging in severity from mild genital abnormalities to complete sex reversal, represent a major concern for patients and their families. DSD are often due to disruption of the genetic programs that regulate gonad development. […] Although some genes have been identified in these developmental pathways, the causative mutations have not been identified in more than 50% 46,XY DSD cases. […] Here we describe three discrete changes in copy number that are the likely cause of the GD. Firstly, we identified a large duplication on the X chromosome that included DAX1 (NR0B1). Secondly, we identified a rearrangement that appears to affect a novel gonad-specific regulatory region in a known testis gene, SOX9. […] Functional analysis of potential SRY binding sites within this deleted region identified five putative enhancers, suggesting that sequences additional to the known SRY-binding TES enhancer influence human testis-specific SOX9 expression. […] These CNV analyses give new insights into the pathways involved in human gonad development and dysfunction, and suggest that rearrangements of non-coding sequences disturbing gene regulation may account for significant proportion of DSD cases.

• #34 Disorders/Differences of Sex Development Presenting in the Newborn With 46,XY Karyotype

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8100517/

  The same molecular diagnosis (compound heterozygosity for SRD5A2 gene variants) was made in adulthood. […] Although there is still an association between the external appearance of the genitalia and the choice of sex assignment, clear temporal trends pointing toward an increased likelihood of infants with 46, XY DSD being raised as boys has been reported. […] The past recommendation for female assignment based on easier surgery has been overcome by improvements in male reconstructive surgical techniques. […] Future studies integrating genetic, endocrine, imaging, surgical, psychologic, and follow-up data will give more objective data to aid sex assignment.

• #35 Gonadal malignancy in patients with differences of sex development – Morin – Translational Andrology and Urology

  https://tau.amegroups.org/article/view/41184/html

  Differences of sexual development (DSD) are known to be associated with an elevated risk of malignant and pre-malignant tumors. […] Some patients with DSD are at an increased risk of developing pre-malignant conditions such as germ cell neoplasia in situ (GCNIS) and gonadoblastoma (Gb), or malignant invasive germ cell tumors (GCT), including seminomas, non-seminomas, and dysgerminomas. […] This review aims to define the pathogenesis of malignancy in this population, review screening methods, and outline various malignancy risks based on the available literature. […] As research has expanded regarding the genes, signaling molecules, and hormones involved with sexual development, insights into how differences in this process may cause certain conditions has emerged. […] These many gene aberrancies demonstrate the complexities of the development of DSD diagnoses and provide evidence for how malignancy predisposition may be associated in this patient population.

• #36 Caring for individuals with a difference of sex development (DSD): a Consensus Statement | Nature Reviews Endocrinology

  https://www.nature.com/articles/s41574-018-0010-8

  The risk of gonadal germ cell cancer in individuals with a 46,XY or 45,X/46,XY DSD is related to the degree of differentiation (or testicularization) of the gonads, which can be derived from histopathological and immunohistochemical characteristics, such as the overall morphological aspect, maturational disturbances of the germ cells, inappropriate presence of pluripotent germ cells and impaired Sertoli or granulosa cell differentiation. […] The various forms of XY and X/XY DSD have a variable risk of developing a gonadal germ cell cancer, which is further modulated by patient age, location of the gonad and, possibly, genetic predisposition.

• #37 Gonadal malignancy in patients with differences of sex development – Morin – Translational Andrology and Urology

  https://tau.amegroups.org/article/view/41184/html

  It is well known that some patients with a DSD are at an increased risk of malignancy. […] Gb is a distinct type of GCNIS occurring in ovarian-type gonads, these entities can be grouped together and thought of similarly as pre-malignant conditions. […] The gonads of patients with DSD are fundamentally altered and given the pathogenesis of the maldevelopment, it is intuitive that these gonads are at an elevated risk of malignancy. […] The best available data right now involve loosely applying what is known about testicular and ovarian cancer in the general population, with the caveat that it is unclear if or how a DSD diagnosis may alter this information. […] Patients with the Y chromosome are generally deemed high or intermediate risk. […] The last time surgical management of patients with DSD was comprehensively updated was 2016, and as previously mentioned, malignancy risk and management were scantily discussed. […] Due to the inherent alteration in gonadal development associated with a diagnosis of DSD, these patients are at an elevated risk of developing gonadal malignancy.

• #38 Differences of Sex Development (DSD) Panel Test – PreventionGenetics

  https://www.preventiongenetics.com/testInfo?val=Differences-of-Sex-Development-%28DSD%29-Panel

  Known etiologies include SRY translocation, and SOX9 or SOX3 gene CNVs. […] DSD are complex conditions caused by a wide range of genetic anomalies. […] To date, more than 60 genes have been showed to be involved in DSD. […] Androgen insensitivity is the most common form of DSD and is caused by a mix of missense, protein truncating variants, and deletions in the AR gene. […] Pathogenic variants in the AR gene have been reported in 9.4% (26/278) of 46,XY DSD patients. […] Beyond the AR gene, pathogenic variants in NR5A1, SRD5A2, ZFPM2, HSD17B3, DHH, MAP3K1, SRY, CYP21A2, SOX9, duplication of NR0B1 and deletion of DMRT1 have also been frequently detected in DSD patients. […] Sex chromosome aneuploidy, structural abnormality and copy number variants (CNVs) are common genetic causes of DSD. […] For this reason, genetic testing to detect large cytogenetic events and CNVs is recommended in the case of a patient with ambiguous genitalia or other suspected disorder of sex development.

• #39 Differences of Sex Development (Intersex) Care | Article | GLOWM

  https://www.glowm.com/article/heading/vol-2–adolescent-gynecology–differences-of-sex-development-intersex-care/id/418293

  Differences of Sex Development (DSD) refers to a diverse group of congenital conditions within which the development of chromosomal, gonadal, or anatomic sex is atypical. […] Genetics’ evaluation plays a key role in evaluating patients with DSD conditions. Genital differences can be seen in hundreds of genetic syndromes, or can be isolated; an examination by a geneticist typically starts by assessing if the anatomic, gonadal or hormonal discordance are more likely an isolated finding or as part of a larger genetic syndrome or sequence. […] A karyotype (+/ FISH for SRY gene) is a key first step and can help determine which category of DSD the patient falls under (46,XX DSD, 46,XY DSD or other chromosomal aneuploidy) and direct further evaluation; this test is typically ordered as soon as possible.

• #40 Differences of Sex Development (Intersex) Care | Article | GLOWM

  https://www.glowm.com/article/heading/vol-2–adolescent-gynecology–differences-of-sex-development-intersex-care/id/418293

  Biochemical markers for evaluation of a suspected DSD condition include LH, FSH, testosterone, dihydrotestosterone (DHT), estradiol, 17-hydroxy progesterone (hormone panel for congenital adrenal hyperplasia if indicated), anti-Mullerian hormone (AMH) and inhibin b. […] Physical examination is central to diagnostic evaluation of individuals with suspected DSD conditions. […] Laboratory investigations play a key role in the diagnostic evaluation of individuals with suspected DSD conditions. Establishing the diagnosis is essential to counseling on the likelihood of endogenous hormone production, physical response to hormones and fertility.

• #41 46, XX Differences of Sex Development outside congenital adrenal hyperplasia: pathogenesis, clinical aspects, puberty, sex hormone replacement therapy and fertility … | Free article summary for Students

  https://aithor.com/paper-summary/46-xx-differences-of-sex-development-outside-congenital-adrenal-hyperplasia-pathogenesis-clinical-aspects-puberty-sex-hormone-replacement-therapy-and-fertility-

  The article discusses the various causes and clinical aspects of 46,XX differences of sex development (DSD) outside congenital adrenal hyperplasia, focusing on the genetic pathways involved in gonadal development, puberty, and fertility outcomes. […] Understanding the physiological development and molecular bases of gonadal and adrenal structures is crucial for determining the diagnosis and best management and treatment for these patients. […] The review focuses on other rare causes of 46,XX DSD, summarizing the most relevant data on genetic, clinical aspects, puberty, and fertility outcomes of these rare diseases.

• #42 The laboratory in the multidisciplinary diagnosis of differences or disorders of sex development (DSD)

  https://www.degruyterbrill.com/document/doi/10.1515/almed-2021-0042/html?lang=en

  Diagnosis of the cause of a DSD is challenging and will depend on the knowledge and skills of each specialist involved, added to the performance of the multidisciplinary team. All protocols emphasize that DSD diagnosis requires the involvement of a multidisciplinary team coordinated by a clinician that includes a Service of Biochemistry (general biochemistry and specific markers or hormones); a Service of Clinical and Molecular Genetics (initial karyotype and interpretation of the results of other studies will guide further studies); a Service of Radiology and Imaging (pelvic ultrasonography to detect internal genital structures and the presence of intraabdominal gonads); and a Service of Anatomic Pathology (when analysis of gonad structure is required). […] The karyotype is essential for DSD categorization into one of the three diagnostic groups based on the sex chromosomes found. The gold-standard method is cytogenetics, although array-complementary genomic hybridization (array-CGH) techniques are increasingly used.

• #43 Disorders/Differences of Sex Development Presenting in the Newborn With 46,XY Karyotype

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8100517/

  The impact of 46,XY DSD in the life of the affected individuals and their families is immense, as these conditions require long-term clinical, endocrinological, and psychological management. […] Early correct diagnosis is a key factor for optimizing quality of life, but true diagnoses based on pathogenetic pathways is still not reached in some individuals, jeopardizing outcome. […] The challenge for health professionals will lie in integrating specific genetic information with better defined clinical and endocrine phenotypes and in terms of long-term evolution. […] The molecular diagnosis will permit more rational sex assignment, recognizing the natural history of the identified 46,XY DSD, the risk of gonadal neoplasia, the possibility for fertility, and mental health. […] New ideas on psycho-sexual development as the result of multifaceted genetic, hormonal, and psychosocial influences have arisen.

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