Materiały źródłowe

• #1 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. […] There are several causes of 46,XY DSD. One possible cause is androgen insensitivity syndrome (AIS), where the body „ignores” androgens or is insensitive to them. […] The cause is not usually clear, but some people with the condition have been found to have genetic material that’s usually seen on the Y chromosome appearing on their X chromosome. […] The cause is not clear, but girls and women with Rokitansky syndrome/MRKH have XX chromosomes. […] The cause is not usually clear, but some people with the condition have been found to have genetic material that’s usually seen on the Y chromosome appearing on their X chromosome.

• #1 Current Diagnostic Approaches in the Genetic Diagnosis of Disorders of Sex Development – Journal of Clinical Research in Pediatric Endocrinology

  https://jcrpe.org/articles/current-diagnostic-approaches-in-the-genetic-diagnosis-of-disorders-of-sex-development/doi/jcrpe.galenos.2024.2024-3-3

  Disorders of sex development (DSD) are a clinically and genetically highly heterogeneous group of congenital disorders. […] DSDs occur as a result of a disorder in one of the stages of sex development, especially in the first trimester due to incompatibility of chromosomes, gonads, or anatomical structure. […] Multiple genetic etiologies, ranging from missense single nucleotide variants (SNVs) to complete chromosome aneuploidies, have been demonstrated among the genetic causes of DSD. […] At least 75 genes have been associated with DSD in humans. […] The first step in cases with suspected DSD is to determine the presence of sex chromosome and the SRY gene. […] Despite the genetic tests performed in current daily practice, the genetic cause is still not elucidated in a significant proportion of cases.

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

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

  Candidates for this test are individuals with symptoms of disorders of sex development including both non-syndromic DSD with ambiguous or abnormal genitalia and syndromic conditions that involve additional congenital anomalies. […] Disorders of sex development (DSD) are congenital conditions with atypical development of chromosomal, gonadal, or anatomic sex (Hughes et al. 2006. PubMed ID: 18947601). This group of disorders are highly heterogeneous and range in severity from hypospadias (1 in 250 boys), ambiguous genitalia (1 in 4,500 live births), to complete XX or XY sex reversal (1 in 20,000 births) (Park et al. 2006; Ohnesorg et al. 2014. PubMed ID: 24504012). […] Three subtypes of DSD are generally recognized: Sex Chromosome DSD, 46,XY DSD, and 46,XX DSD. Sex chromosome DSDs include Turner syndrome (45,X), Klinefelter syndrome (47,XXY), mosaic 45,X/46,XY mixed gonadal dysgenesis, and 46,XX/46/XY ovotesticular DSD.

• #1 Disorders or Differences of Sex Development | SpringerLink

  https://link.springer.com/10.1007/978-3-030-23709-7_1

  Disorders or Differences of sex development (DSD) refer to a diverse group of conditions in which chromosomal, gonadal, or anatomic sex development is atypical. […] DSDs can be classified based on karyotype with further subdivision in disorders of gonadal development and problems of hormone synthesis or action. […] The increased availability of next generation sequencing has allowed for the identification of many new genes involved in DSD and the advent and increased accessibility of this technology has changed the diagnostic approach and refined the molecular genetic diagnosis in many cases.

• #1 Differences of sex development: MedlinePlus Medical EncyclopediaLock

  https://medlineplus.gov/ency/article/001669.htm

  Many chromosome configurations other than simple 46,XX or 46,XY can result in disorders of sex development. […] These disorders do not result in a condition in which there is a discrepancy between internal and external genitalia. However, there may be problems with sex hormone levels and overall sexual development, due to the altered numbers of sex chromosomes.

• #1 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. […] 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. During this stage, genetic mutations can result from endocrine disrupters in the mother’s diet or environmental factors. […] The SRY gene plays an important role in developing the testes of a male individual. Following the development of the testes, hormones synthesized within the testes regulate the differentiation of both internal and external parts of the genitals. The absence of the testicles or the hormones synthesized may lead to irregular differentiation of the genitals. Genetic abnormalities or environmental factors that influence these procedures may lead to the incomplete development of the gonads and the genitals.

• #1 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. […] Etiology: X-linked recessive mutation of the gene encoding the androgen receptor (AR gene). […] Etiology: autosomal recessive mutations in the CYP19A1 gene that encodes the enzyme aromatase.

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

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

  The development of female or male sex characteristics occurs during fetal life, when the genetic, gonadal, and internal and external genital sex is determined (female or male). Any discordance among sex determination and differentiation stages results in differences/disorders of sex development (DSD), which are classified based on the sex chromosomes found on the karyotype. […] The Chicago Consensus categorizes the causes of DSD according to the karyotype. Hence, DSD are categorized into three major groups: 1) Sex chromosome DSD, which occurs when the arrangement of sex chromosomes is different from the XX or XY pair; 2) 46,XX DSD with female karyotype, and 3) 46,XY DSD with male karyotype. Each group is divided into subgroups. In Groups 2 and 3, a broad range of genes are involved, which increase over the years.

• #1 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&srsltid=AfmBOoplEyzyCXQEKqRViEDNkfZiC6OggrCVLQW2ybTPf-vKs-3ae31i

  The development of female or male sex characteristics occurs during fetal life, when the genetic, gonadal, and internal and external genital sex is determined (female or male). Any discordance among sex determination and differentiation stages results in differences/disorders of sex development (DSD), which are classified based on the sex chromosomes found on the karyotype. […] The Chicago Consensus categorizes the causes of DSD according to the karyotype. Hence, DSD are categorized into three major groups: 1) Sex chromosome DSD, which occurs when the arrangement of sex chromosomes is different from the XX or XY pair; 2) 46,XX DSD with female karyotype, and 3) 46,XY DSD with male karyotype. Each group is divided into subgroups. In Groups 2 and 3, a broad range of genes are involved, which increase over the years.

• #1 Differences of sex development: MedlinePlus Medical EncyclopediaLock

  https://medlineplus.gov/ency/article/001669.htm

  Differences of sex development (DSD) is a group of conditions in which there is a discrepancy between the external (outside) genitals (penis, scrotum, vulva, labia) and the internal (inside) genitals (testes, vagina, ovaries). Intersex is an older term for DSD. […] There are many causes of DSD. They can be divided into several categories, discussed in more detail below: […] The cause of DSD may remain undetermined, even with modern diagnostic techniques. […] The person has the XX chromosomes (typically seen in females), the ovaries of a female, but external genitals that appear male. This most often is the result of a female fetus having been exposed to excess male hormones before birth. […] There are several possible causes: Congenital adrenal hyperplasia. This is the most common cause of 46,XX DSD.

• #1 Differences (Disorders) of Sex Development (DSDs): Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/1015520-overview

  Infants born with ambiguous or abnormal genitalia may have indeterminate phenotypic sex. […] DSDs may be caused by virilization of a child with 46,XX or undervirilization of a child with 46,XY. […] Congenital adrenal hyperplasia (CAH) is the most common cause of DSDs. […] The most common cause of CAH is 21-hydroxylase deficiency resulting in virilization of a child with 46,XX. […] 46,XX DSDs can be caused by CAH or maternal androgens. […] Overall, CAH is the most frequent cause of ambiguous genitalia in the newborn, constituting approximately 60% of all DSDs. […] In 90% of patients with CAH, the block is at the 21-hydroxylation enzyme (21-hydroxylase deficiency). […] Common causes of 46,XY DSDs include deficient biosynthesis of testosterone, complete androgen insensitivity syndrome, partial androgen insensitivity syndrome, 5-alpha-reductase deficiency, and isolated MIS deficiency.

• #1 Disorders of Sex Development: Classification, Review, and Impact on Fertility

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7694247/

  Disruption of any of the genes involved in these processes during the course of testicular or ovarian development, or in the subsequent sex differentiation, could lead to ASDs (or DSDs). […] The most common enzymatic defects are those affecting 21-hydroxylase (P450c21), 11-hydroxylase (P450c11), and 3-HSD. […] In the severe and uncompensated blockage, virilization is accompanied by salt loss and shock. […] The degree of virilization depends on the moment of action of the androgenic effect (before or after 12 weeks), the most important effects being those that affect the external genitalia. […] In females, folliculogenesis is arrested, and in males, there is testicular atrophy with interstitial cell hyperplasia and arrested spermatogenesis. […] In summary, in the 21-hydroxylase deficit, there is: (1) adrenal failure; (2) an increase in androgens due to steroidogenetic deviation, leading to growth of a phallus and to fusing of the labioscrotal rims; (3) increased androgens that slow down the ovary; (4) a lack of mineralocorticosteroids that leads to salt loss alterations.

• #1 Frontiers | Diagnosis and management of non-CAH 46,XX disorders/differences in sex development

  https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2024.1354759/full

  Prenatal-onset androgen excess leads to abnormal sexual development in 46,XX individuals. This androgen excess can be caused endogenously by the adrenals or gonads or by exposure to exogenous androgens. The most common cause of 46,XX disorders/differences in sex development (DSD) is congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, comprising >90% of 46,XX DSD cases. Deficiencies of 11β-hydroxylase, 3β-hydroxysteroid dehydrogenase, and P450-oxidoreductase (POR) are rare types of CAH, resulting in 46,XX DSD. In all CAH forms, patients have normal ovarian development. The molecular genetic causes of 46,XX DSD, besides CAH, are uncommon. These etiologies include primary glucocorticoid resistance (PGCR) and aromatase deficiency with normal ovarian development. Additionally, 46,XX gonads can differentiate into testes, causing 46,XX testicular (T) DSD or a coexistence of ovarian and testicular tissue, defined as 46,XX ovotesticular (OT)-DSD. PGCR is caused by inactivating variants in NR3C1, resulting in glucocorticoid insensitivity and the signs of mineralocorticoid and androgen excess. Pathogenic variants in the CYP19A1 gene lead to aromatase deficiency, causing androgen excess. Many genes are involved in the mechanisms of gonadal development, and genes associated with 46,XX T/OT-DSD include translocations of the SRY; copy number variants in NR2F2, NR0B1, SOX3, SOX9, SOX10, and FGF9, and sequence variants in NR5A1, NR2F2, RSPO1, SOX9, WNT2B, WNT4, and WT1. Progress in cytogenetic and molecular genetic techniques has significantly improved our understanding of the etiology of non-CAH 46,XX DSD. Nonetheless, uncertainties about gonadal function and gender outcomes may make the management of these conditions challenging. This review explores the intricate landscape of diagnosing and managing these conditions, shedding light on the unique aspects that distinguish them from other types of DSD.

• #1 Ambiguous genitalia and disorders of sexual development (DSD)

  https://www.utmb.edu/pedi_ed/CoreV2/Endocrine/Endocrine7.html

  Klinefelter Syndrome: Etiology: 47, XXY (classic) vs 46, XY/47, XXY (mosaic). […] Turner Syndrome: Etiology: 45 X (classic) vs Mosaic types (or mixed gonadal dysgenesis) like 45, XO/46, XX; 45, XO/46, XY etc. […] Congenital Adrenal Hyperplasia (CAH): Etiology: Group of autosomal recessive disorders, most common type is due to CYP21A2 gene mutations resulting in 21-hydroxylase deficiency. […] Androgen insensitivity syndrome: Etiology: 46, XY/ X-linked recessive/ Androgen Receptor (AR) gene mutation. […] Cryptorchidism mean that the testis is not in the scrotum and is not descended by 4 months old.

• #1 Frontiers | Diagnosis and management of non-CAH 46,XX disorders/differences in sex development

  https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2024.1354759/full

  Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is the most common etiology of 46,XX DSD, and other rare forms of CAH causing 46,XX DSD include 11β-hydroxylase, 3β-hydroxysteroid dehydrogenase, and P450-oxidoreductase (POR) deficiency. […] Non-CAH 46,XX DSD are categorized as follows: (1) disorders with excessive amounts of endogenous androgens, such as primary glucocorticoid resistance (PGCR) and aromatase deficiency; (2) increased exogenous androgen exposure, such as gestational hyperandrogenism; (3) disorders/differences of gonadal differentiation [testicular (T)/ovotesticular (OT)-DSD, ovarian dysgenesis (OD)]; (4) others, classified as Mayer–Rokitansky–Küster–Hauser syndrome (MRKHS) (types I and II) and variants—complex syndromic disorders like cloacal exstrophy.

• #1 Differences of sex development: MedlinePlus Medical EncyclopediaLock

  https://medlineplus.gov/ency/article/001669.htm

  Male hormones (such as testosterone) taken or encountered by the mother during pregnancy. […] Male hormone-producing tumors in the mother. These are most often ovarian tumors. […] Aromatase deficiency. This may not be noticeable until puberty. […] The person has the XY chromosomes (typically seen in males), but the external genitals are incompletely formed, ambiguous (ambiguous genitalia), or clearly female. […] Internally, testes may be normal, malformed, or absent. This condition is also called 46,XY with undervirilization. […] 46,XY DSD has many possible causes: Problems with the testes. […] Problems with testosterone formation. […] Problems with using testosterone. […] The person has both ovarian and testicular tissue. […] In most people with ovotesticular DSD, the underlying cause is unknown.

• #1 46,XY Differences of Sexual Development – Endotext – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK279170/

  The 46,XY differences of sex development (46,XY DSD) can result either from decreased synthesis of testosterone and/or DHT or from impairment of androgen action. […] 46,XY DSD can result either from decreased synthesis of testosterone or DHT or from impairment of androgen action. […] Dosage imbalances in genes involved in DSD (deletions or duplication) have also been identified as a cause of these developmental differences. […] The term differences of sex development (DSD) include congenital conditions in which development of chromosomal, or gonadal or anatomical sex is atypical. […] The proposed changes in terminology aim to integrate upcoming advances in molecular genetics in the most recent DSD classification. […] The diagnostic evaluation of DSD includes hormone measurements, imaging, cytogenetic, and molecular studies.

• #1 Causes of differences of sex development – UpToDate

  https://www.uptodate.com/contents/causes-of-disorders-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. […] The causes of XX differences of sex development include adrenal overproduction of androgens, gonadal overproduction of androgens, and gestational hyperandrogenism. […] The causes of XY differences of sex development include global defects in testicular function and conditions affecting androgen synthesis or response.

• #1 Differences (Disorders) of Sex Development (DSDs): Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/1015520-overview

  Production of testosterone from cholesterol involves five enzymatic steps, and defects have been identified at each step. […] Complete androgen insensitivity syndrome involves a failure of the end organs in a 46,XY gonadal male fetus to respond to appropriately produced levels of dihydrotestosterone (DHT).

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

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

  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. […] Hyperpigmented genitalia points to cortisol deficiency due to CAH and result from melanocyte stimulating hormone excess, which is cosecreted with adrenocorticotropic hormone (ACTH) due to a lack of feedback inhibition. […] The most common DSD to present in concert with primary amenorrhea is the sex chromosome DSD, Turner syndrome. […] 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.

• #1 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

  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. […] Unfortunately, a great number of cases do not have an identifiable cause, particularly among 46XY DSD, which highlights the importance of an experienced team with multidisciplinary focus.

• #1 FloridaHealthFinder | Differences of sex development | Health Encyclopedia | FloridaHealthFinder

  https://quality.healthfinder.fl.gov/health-encyclopedia/HIE/1/001669

  Male hormones (such as testosterone) taken or encountered by the mother during pregnancy. […] Male hormone-producing tumors in the mother. These are most often ovarian tumors. […] Aromatase deficiency. This may not be noticeable until puberty. […] The person has the chromosomes of a man, but the external genitals are incompletely formed, ambiguous (ambiguous genitalia), or clearly female. […] Internally, testes may be normal, malformed, or absent. […] Formation of normal male external genitals depends on the appropriate balance between male and female hormones. […] 46, XY DSD has many possible causes: Problems with the testes. […] Problems with testosterone formation. […] Problems with using testosterone. […] AIS is the most common cause of 46, XY DSD. […] The person has both ovarian and testicular tissue.

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

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

  Etiology: rare autosomal recessive loss-of-function mutation of the SRD5A2 gene on chromosome 2. […] Etiology: usually due to nondisjunction of sex chromosomes during meiosis. […] Etiology: paternal meiotic nondisjunction. […] Etiology: SRY gene translocation from the Y to the X chromosome (rarely to other chromosomes). […] Etiology: mutations of genes involved in male sex development after the 8th embryonic week. […] Etiology: underlying etiology is unknown, but several gene mutations (esp. of the BMP15 and NR5A1 genes), have been implicated. […] Etiology: insufficient anti-Mullerian hormone (AMH) or insensitivity to AMH due to AMH gene or AMHR2 gene mutation. […] Etiology: autosomal recessive mutation of the HSD17B3 gene, which encodes for the enzyme 17-hydroxysteroid dehydrogenase 3.

• #1 Disorders of gender development | Radiology Reference Article | Radiopaedia.org

  https://radiopaedia.org/articles/disorders-of-gender-development?lang=us

  Disorder of gender development refers to the spectrum of rare congenital conditions where there is an atypical development of chromosomal, gonadal, or anatomic sex. […] They can be classified broadly into four categories on the basis of gonadal histologic features which include: female pseudohermaphroditism: 46XX with two ovaries, male pseudohermaphroditism: 46XY with two testes, true hermaphroditism: both ovarian and testicular tissues, 46XX and 46XY mosaic, gonadal dysgenesis. […] Mixed gonadal dysgenesis (MGD): a testis and a streak gonad, 45XO/46XY, pure gonadal dysgenesis (PGD): bilateral streak gonads, 46XO/46XX/46XY, complete gonadal dysgenesis (CGD).

• #1

  https://www.nicklauschildrens.org/conditions/disorders-of-sexual-differentiation

  Disorders of sexual differentiation can refer to a wide range of different medical conditions that all impact the normal development of the babys sexual organs. […] The most common DSDs are congenital adrenal hyperplasia and mixed gonadal dysgenesis; others include Androgen insensitivity syndrome (AIS), and Impaired testicular development. Most of these disorders are caused by genetic/ chromosomal abnormalities, though some may be idiopathic, where no cause can be found. […] Mixed gonadal dysgenesis is a sex developmental disorder where the gonads are abnormal from there being some cells with XY chromosomes and some with just a single X, known as chromosome Y mosaicism.

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

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

  DSD are complex conditions caused by a wide range of genetic anomalies. They can be inherited in an autosomal dominant (AD), autosomal recessive (AR), X-linked (XL), and Y-linked (YL) manner, or arise de novo depending on the gene involved. To date, more than 60 genes have been showed to be involved in DSD (Baxter et al. 2015. PubMed ID: 25383892; Eggers et al. 2016. PubMed ID: 27899157). These genes are implicated in sex determination, sex differentiation and hypogonadism. […] 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 (Baxter et al. 2015. PubMed ID: 25383892; Eggers. et al. 2016. PubMed ID: 27899157).

• #1 Disorders of Sexual Development (DSDs)

  https://my.clevelandclinic.org/health/diseases/disorders-of-sexual-development

  Disorders of sexual development (DSDs) are a range of conditions in which a person has characteristics of both sexes. These characteristics can happen due to chromosomal, gonadal (ovaries or testes) or genital differences and they can appear at birth, during puberty or later in adulthood. […] There are many reasons why a person might be born with a DSD. Possible causes are: […] Genetic mutations (changes). These include inherited mutations (passed from biological parent to child) and spontaneous mutations (changes that occur for no known reason). […] Developmental issues during fetal development. This can happen when organs dont form correctly. […] Hormone insufficiency. This is when a baby either doesnt make enough hormones or doesnt respond to them as expected. It can also occur when another factor prevents hormone production (like a lack of blood flow to the testes or ovaries). […] Exposure to certain hormones or medications during pregnancy. This may include things like testosterone blockers.

• #1 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&srsltid=AfmBOoplEyzyCXQEKqRViEDNkfZiC6OggrCVLQW2ybTPf-vKs-3ae31i

  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 most frequent monogenic causes of DSD were identified in the late 20th century with the cloning of the genes codifying proteins that were known to be altered in the clinical and biochemical phenotype. This was especially useful for determination of enzyme deficiencies in adrenal and gonadal steroidogenesis, both in 46,XX and 46,XY DSD, and in complete androgen insensitivity. In contrast, the genes involved in the differentiation and development of male and female gonads are being progressively detected on the basis of family studies, animal models and functional studies in vitro. A large number of genes involved in the development of DSD encode the regulatory transcription factors of other genes.

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

  https://www.degruyter.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; a Service of Clinical and Molecular Genetics; a Service of Radiology and Imaging; and a Service of Anatomic Pathology. […] The most frequent monogenic causes of DSD were identified in the late 20th century with the cloning of the genes codifying proteins that were known to be altered in the clinical and biochemical phenotype. This was especially useful for determination of enzyme deficiencies in adrenal and gonadal steroidogenesis, both in 46,XX and 46,XY DSD, and in complete androgen insensitivity. In contrast, the genes involved in the differentiation and development of male and female gonads are being progressively detected on the basis of family studies, animal models and functional studies in vitro. A large number of genes involved in the development of DSD encode the regulatory transcription factors of other genes. […] The list is progressively enriched over time, especially in relation to the causes of dysgenetic gonadal development.

• #1 Breakthrough in diagnosing disorders of sex development – Hudson Institute of Medical Research

  https://www.hudson.org.au/news/breakthrough-in-diagnosing-sex-development-disorders/

  Disorders/differences of sex development (DSD) are difficult to diagnose because of the multiple phenotypes and genes involved, but a new technique developed at Hudson Institute of Medical Research is set to change all that. […] This research has identified important genetic targets to advance the understanding of how genetic mutations contribute to DSDs, paving the way for more accurate diagnoses and potential treatments. […] Until now diagnosing the cause of many DSDs has been hampered because the events that determine sex development occur at around week nine of gestation and only in a small number of cells of the gonads of the developing fetus. […] Prof Harley explains: Sertoli cells are relevant because they act like an organising centre of embryonic gonadal development and many DSDs arise when these developmental processes go awry.

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

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

  Sex chromosome aneuploidy, structural abnormality and copy number variants (CNVs) are common genetic causes of DSD. Deletions or duplications have been reported in SOX3, LHCGR, SRY, NR0B1, DMRT1, NR5A1, GATA4, WT1, WNT4, and FGFR2 genes in DSD patients. 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. Our CNV analysis enables these large cytogenetic abnormalities as well as exon level CNVs to be identified from NGS data.

• #1 Prevalence of differences of sex development in children and adolescents in Switzerland from 2000-2019 | medRxiv

  https://www.medrxiv.org/content/10.1101/2024.03.11.24304115v2.full-text

  Over the 20-year study period, we identified 561 individuals with DSD. […] Causes for 46,XY DSD were disturbed androgen synthesis or action (37/177, 21%), atypical gonadal development (28/177, 16%), or other causes (112/177, 63%). Causes for 46,XX DSD were androgen excess (99/118, 84%), atypical gonadal development (8/118, 7%), or other causes (11/118, 9%). […] Most DSDs are congenital due to their genetic origins. […] The term DSD has first been introduced with the Chicago Consensus Statement in 2006 that defined DSD as „congenital conditions in which the development of chromosomal, gonadal, anatomic sex is atypical”. […] The accurate incidence and prevalence of DSD are still unknown. […] We aimed to calculate prevalence and trends of DSD diagnostic groups according to the Chicago Consensus Classification in children and adolescents born population based from 2000-2019 in Switzerland.

• #1 Prevalence of differences of sex development in children and adolescents in Switzerland from 2000-2019 | medRxiv

  https://www.medrxiv.org/content/10.1101/2024.03.11.24304115v2.full-text

  We report prevalence for different DSD diagnoses according to the Chicago Consensus Classification in a population-based cohort between 2000-2019 in Switzerland. […] Prevalence of DSD treated by pediatric endocrinologist was 37 per 100000 (1 of 2735) newborns including sex chromosome, 46,XY and 46,XX DSD. Overall, DSD prevalence decreased from 2000-2019, which was driven by a strong decrease in prevalence of sex chromosome DSD. Prevalence of 46,XY DSD tended to increase and prevalence of 46,XX DSD to decrease over time. […] We assume almost complete coverage of rare and complex subgroups of non-chromosomal DSD with atypical genitalia. […] We calculated prevalence of DSD based on live birth rates in Switzerland. […] Our overall prevalences are lower than published data for sex chromosome DSD.

• #1 46,XY Differences of Sex Development (DSD)/Complete Gonadal Dysgenesis Panel | The University of Chicago Genetic Services

  https://dnatesting.uchicago.edu/tests/46xy-differences-sex-development-dsdcomplete-gonadal-dysgenesis-panel

  Differences of sex development (DSDs) occur when sex development does not follow the course of typical male or female patterning. DSDs can be caused by a wide range of genetic abnormalities. […] Determining the etiology of a DSD in an individual can assist in identifying potential health problems such as adrenal crisis or gonadoblastoma. […] DSDs may also be referred to as Disorders of Sex Development, Variations in Sex Characteristics (VSC), or Diverse Sex Development.

• #1 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

  Intersex activists have encouraged legislative bodies worldwide to ban elective, irreversible genital surgery without the individuals informed consent. […] In the absence of long-term outcome data that support or disfavour deferring genital surgery, there is currently little evidence that surgical practice has dramatically changed in recent years. […] 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. […] The risk is much higher in men and women with gonadal dysgenesis, especially forms that arise from early gonadal differentiation defects, than in individuals with ovotesticular DSD or with hormone synthesis or action disorders. […] The underlying pathogenic mechanisms and proposed management were reviewed elsewhere.

• #1 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 standardization of somatic assessments is crucial to secure the validity of cross-centre data pooling with the aim of revealing hitherto unrecognized health consequences and outcomes. […] Individuals who have a sex chromosome DSD are at increased risk of autoimmune disorders, metabolic disturbances and type 2 diabetes mellitus. […] The prevalence of these conditions in men and women with 46,XY DSD is poorly documented. […] Individuals who receive HRT might be vulnerable to metabolic disturbances, and clinicians should screen these patients accordingly. […] The developmental origin of DSD conditions and the effect they can have on the functioning of several organ systems warrant extensive somatic assessment of all individuals presenting with a DSD, irrespective of age. […] The creation of multidisciplinary teams dedicated to the management of DSD conditions worldwide poses its own challenges.

• #1 Differences in sex development — Knowledge Hub

  https://www.genomicseducation.hee.nhs.uk/genotes/knowledge-hub/differences-in-sex-development/

  Differences in sex development are a group of rare conditions where chromosomal, gonadal or anatomic sex is atypical. […] Differences in sex development (DSD), sometimes called disorders of sex development, refer to a group of congenital conditions where chromosomal, gonadal or anatomic sex is atypical. […] There are a number of genetic and chromosomal causes for DSD that include (though are not limited to) the following: […] Conditions associated with androgen synthesis/action, including: […] Conditions associated with testicular development (complete or partial gonadal dysgenesis), including: […] Conditions associated with fetal androgen excess, including: […] Conditions associated with ovarian development, including: […] Genomic counselling for individuals with a DSD will vary depending on the specific condition or associated gene. […] Assessment, investigation and management of DSDs should be delivered via a multidisciplinary team, including endocrinologists, urologists, gynaecologists, psychologists and geneticists.

• #1 Prevalence of differences of sex development in children and adolescents in Switzerland from 2000-2019 | medRxiv

  https://www.medrxiv.org/content/10.1101/2024.03.11.24304115v2.full-text

  We found a prevalence of 24-29 per 100000 newborn girls for Turner syndrome and variants during 2000-2009, which decreased to 9 per 100000 during 2015-2019. […] Our cohort included individuals with DSD who were born from 2000-2019, thus a large proportion of individuals were too young to have received a Turner syndrome or Klinefelter syndrome diagnosis. […] We also assume underreporting of 46,XX disorders of gonadal development and other 46,XX DSD for the earliest interval from 2000-2004 due to the retrospective study design and lack of consensus on diagnostic nomenclature. […] Information of population-based cohorts are important to yield reliable estimates on DSD prevalence, and to provide evidence-based data for topics such as sex reassignment, genital surgery, hormonal treatments and other needs of DSD care.

• #1 Differences of Sex Development 101: it’s complicated

  https://www.hudson.org.au/news/differences-of-sex-development-101-its-complicated/

  Boy or girl? Its not always as simple as that. […] Intersex traits can vary considerably and have a complex range of causes. Most are random but some are inherited. […] Differences of sex development or DSDs are genetic conditions where a persons X or Y sex chromosomes or their gonads or genitals are not typical, sometimes making it unclear if a newborn baby is a boy or girl. DSDs are complex genetically and clinically, with potentially hundreds of different causes. […] Some DSDs result in medical issues such as problems making or regulating hormones, development issues during puberty and possibly increased cancer risk due to undeveloped tissue. […] My team has classified 48 different forms of DSD among children born with ambiguous genitalia, as well as 12 new genes which have improved the rate of successful genetic testing from 15 to 50 per cent. Based on these findings, they have developed a tool in the form of a decision tree to help inform the decision-making of DSD clinicians and families faced with newborns with ambiguous genitalia.

• #1 Disorders of Sex Development: Classification, Review, and Impact on Fertility

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7694247/

  In this review, the elements included in both sex determination and sex differentiation are briefly analyzed, exposing the pathophysiological and clinical classification of disorders or anomalies of sex development. […] Disorders of sex development (DSDs) were defined as congenital conditions within which the development of chromosomal, gonadal, and anatomic sex is atypical at the Chicago Consensus Meeting in 2005, which was then published as a Consensus Statement in 2006. […] We believe that the origin of abnormal sex development situations or ASDs must be: (1) in the chromosomes and SRY gene (and other sex-determining (SD) genes located in the autosomes) that may therefore be carried into the formation of the gonad; (2) in the hormone-producing glands involved in sex development (i.e., gonads, adrenals, and pituitary), as well as in the metabolization of these hormones, in their action on the target organs or in the content of receptors.

• #1 Differences of Sex Development (DSD) | Ambiguous Genitalia | Duke Health

  https://www.dukehealth.org/pediatric-treatments/pediatric-endocrinology/disorders-of-sex-development

  Children born with differences of sex development may have sex-specific traits that aren’t clearly male or female. This may be referred to as ambiguous genitalia. Some of the more common differences of sex development (DSD) are Turner syndrome, Klinefelter syndrome, congenital adrenal hyperplasia, and androgen insensitivity. These can be caused by several different factors. […] Chromosomal disorders can result from an abnormal number of sex chromosomes or a specific gene mutation. […] Hormonal imbalances can include congenital adrenal hyperplasia (CAH), a genetic disorder that affects hormone production in the adrenal glands. In females, CAH can cause an enlarged clitoris and fused labia. Androgen insensitivity can also be the result of a hormone imbalance. Androgen insensitivity results from the body’s inability to carry out the signals from the hormones. […] Genital abnormalities include abnormal growth of the penis, scrotum, vagina, uterus, ovaries, or clitoris; impaired testicle development; or an absent or atypical vagina.

• #2 Differences (Disorders) of Sex Development (DSDs): Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/1015520-overview

  Infants born with ambiguous or abnormal genitalia may have indeterminate phenotypic sex. […] DSDs may be caused by virilization of a child with 46,XX or undervirilization of a child with 46,XY. […] Congenital adrenal hyperplasia (CAH) is the most common cause of DSDs. […] The most common cause of CAH is 21-hydroxylase deficiency resulting in virilization of a child with 46,XX. […] 46,XX DSDs can be caused by CAH or maternal androgens. […] Overall, CAH is the most frequent cause of ambiguous genitalia in the newborn, constituting approximately 60% of all DSDs. […] In 90% of patients with CAH, the block is at the 21-hydroxylation enzyme (21-hydroxylase deficiency). […] Common causes of 46,XY DSDs include deficient biosynthesis of testosterone, complete androgen insensitivity syndrome, partial androgen insensitivity syndrome, 5-alpha-reductase deficiency, and isolated MIS deficiency.

• #2 Differences of Sex Development (DSD) | Causes, Diagnosis & Care

  https://www.cincinnatichildrens.org/health/d/differences-sexual-development

  Differences of sex development (DSD) describes a group of conditions that occur early in pregnancy in which sex development is not typical. […] There are two main factors that decide whether a baby develops as male or female: genetic factors and sex hormones. The reproductive body parts may develop differently if there is a change in any of the factors needed for sex development. This results in DSD. […] Changes in some genes or chromosome patterns may explain why some peoples bodies develop differently. […] The reasons for people to be born with one of these conditions may be a change that involves any of the following: Sex chromosomes or genes, Sex glands (such as testes or ovaries), Sex hormones.

• #2 46,XY Differences of Sexual Development – Endotext – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK279170/

  The 46,XY differences of sex development (46,XY DSD) can result either from decreased synthesis of testosterone and/or DHT or from impairment of androgen action. […] 46,XY DSD can result either from decreased synthesis of testosterone or DHT or from impairment of androgen action. […] Dosage imbalances in genes involved in DSD (deletions or duplication) have also been identified as a cause of these developmental differences. […] The term differences of sex development (DSD) include congenital conditions in which development of chromosomal, or gonadal or anatomical sex is atypical. […] The proposed changes in terminology aim to integrate upcoming advances in molecular genetics in the most recent DSD classification. […] The diagnostic evaluation of DSD includes hormone measurements, imaging, cytogenetic, and molecular studies.

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

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

  Multidisciplinary teams are unable to establish the aetiology of DSDs in 40% to 50% of cases, especially in patients with a 46,XY karyotype. Considering the diversity and complexity of DSDs and the need to investigate further unknown causes, health professionals need to share their knowledge, or, in other words, record information in registers.

• #2 FloridaHealthFinder | Differences of sex development | Health Encyclopedia | FloridaHealthFinder

  https://quality.healthfinder.fl.gov/health-encyclopedia/HIE/1/001669

  In most people with ovotesticular DSD, the underlying cause is unknown. […] Many chromosome configurations other than simple 46, XX or 46, XY can result in disorders of sex development. […] These disorders do not result in a condition in which there is a discrepancy between internal and external genitalia. […] The prognosis depends on the specific cause of DSD.

• #2 Prevalence of differences of sex development in children and adolescents in Switzerland from 2000-2019 | medRxiv

  https://www.medrxiv.org/content/10.1101/2024.03.11.24304115v2.full-text

  Over the 20-year study period, we identified 561 individuals with DSD. […] Causes for 46,XY DSD were disturbed androgen synthesis or action (37/177, 21%), atypical gonadal development (28/177, 16%), or other causes (112/177, 63%). Causes for 46,XX DSD were androgen excess (99/118, 84%), atypical gonadal development (8/118, 7%), or other causes (11/118, 9%). […] Most DSDs are congenital due to their genetic origins. […] The term DSD has first been introduced with the Chicago Consensus Statement in 2006 that defined DSD as „congenital conditions in which the development of chromosomal, gonadal, anatomic sex is atypical”. […] The accurate incidence and prevalence of DSD are still unknown. […] We aimed to calculate prevalence and trends of DSD diagnostic groups according to the Chicago Consensus Classification in children and adolescents born population based from 2000-2019 in Switzerland.

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

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

  Etiology: rare autosomal recessive loss-of-function mutation of the SRD5A2 gene on chromosome 2. […] Etiology: usually due to nondisjunction of sex chromosomes during meiosis. […] Etiology: paternal meiotic nondisjunction. […] Etiology: SRY gene translocation from the Y to the X chromosome (rarely to other chromosomes). […] Etiology: mutations of genes involved in male sex development after the 8th embryonic week. […] Etiology: underlying etiology is unknown, but several gene mutations (esp. of the BMP15 and NR5A1 genes), have been implicated. […] Etiology: insufficient anti-Mullerian hormone (AMH) or insensitivity to AMH due to AMH gene or AMHR2 gene mutation. […] Etiology: autosomal recessive mutation of the HSD17B3 gene, which encodes for the enzyme 17-hydroxysteroid dehydrogenase 3.

• #2 Causes of differences of sex development – UpToDate

  https://www.uptodate.com/contents/causes-of-disorders-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. […] The causes of XX differences of sex development include adrenal overproduction of androgens, gonadal overproduction of androgens, and gestational hyperandrogenism. […] The causes of XY differences of sex development include global defects in testicular function and conditions affecting androgen synthesis or response.

• #2 FloridaHealthFinder | Differences of sex development | Health Encyclopedia | FloridaHealthFinder

  https://quality.healthfinder.fl.gov/health-encyclopedia/HIE/1/001669

  Differences of sex development (DSD) is a group of conditions in which there is a discrepancy between the external (outside) genitals (penis, scrotum, vulva, labia) and the internal (inside) genitals (testes, vagina, ovaries). Intersex is an older term for DSD. […] There are many causes of DSD. They can be divided into several categories, discussed in more detail below: […] The cause of DSD may remain undetermined, even with modern diagnostic techniques. […] The person has the chromosomes of a female, the ovaries of a female, but external genitals that appear male. This most often is the result of a female fetus having been exposed to excess male hormones before birth. […] There are several possible causes: Congenital adrenal hyperplasia. This is the most common cause of 46, XX DSD.

• #2 Differences in Sexual Development | Endocrine Society

  https://www.endocrine.org/patient-engagement/endocrine-library/differences-in-sexual-development

  Differences of sexual development are a group of conditions where the biological sex (being male or female) of a baby does not match the genital appearance. […] There are many causes of DSD: […] 46, XX DSD occurs when the fetus is exposed to excess male hormones at the time that the genitals form. The most common cause is congenital adrenal hyperplasia (CAH). […] 46, XY DSD occurs in the fetus when: […] In certain cases, DSD occurs when there is an atypical number or combination of sex chromosomes. […] DSD may occur as part of a genetic syndrome. […] The cause of your child’s condition (if the cause can be found) and likely gender identity […] Hormone Therapy: Many children with DSD do not go into puberty on their own and would need sex hormone therapy (i.e. estrogen for those raised as girls or testosterone therapy for those raised as boys), to start and maintain puberty. […] Removal of gonads in case of increased risk of cancer is done in certain cases.

• #2 Disorders of Sex Development: Classification, Review, and Impact on Fertility

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7694247/

  Disruption of any of the genes involved in these processes during the course of testicular or ovarian development, or in the subsequent sex differentiation, could lead to ASDs (or DSDs). […] The most common enzymatic defects are those affecting 21-hydroxylase (P450c21), 11-hydroxylase (P450c11), and 3-HSD. […] In the severe and uncompensated blockage, virilization is accompanied by salt loss and shock. […] The degree of virilization depends on the moment of action of the androgenic effect (before or after 12 weeks), the most important effects being those that affect the external genitalia. […] In females, folliculogenesis is arrested, and in males, there is testicular atrophy with interstitial cell hyperplasia and arrested spermatogenesis. […] In summary, in the 21-hydroxylase deficit, there is: (1) adrenal failure; (2) an increase in androgens due to steroidogenetic deviation, leading to growth of a phallus and to fusing of the labioscrotal rims; (3) increased androgens that slow down the ovary; (4) a lack of mineralocorticosteroids that leads to salt loss alterations.

• #2 Frontiers | Diagnosis and management of non-CAH 46,XX disorders/differences in sex development

  https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2024.1354759/full

  Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is the most common etiology of 46,XX DSD, and other rare forms of CAH causing 46,XX DSD include 11β-hydroxylase, 3β-hydroxysteroid dehydrogenase, and P450-oxidoreductase (POR) deficiency. […] Non-CAH 46,XX DSD are categorized as follows: (1) disorders with excessive amounts of endogenous androgens, such as primary glucocorticoid resistance (PGCR) and aromatase deficiency; (2) increased exogenous androgen exposure, such as gestational hyperandrogenism; (3) disorders/differences of gonadal differentiation [testicular (T)/ovotesticular (OT)-DSD, ovarian dysgenesis (OD)]; (4) others, classified as Mayer–Rokitansky–Küster–Hauser syndrome (MRKHS) (types I and II) and variants—complex syndromic disorders like cloacal exstrophy.

• #2 FloridaHealthFinder | Differences of sex development | Health Encyclopedia | FloridaHealthFinder

  https://quality.healthfinder.fl.gov/health-encyclopedia/HIE/1/001669

  Male hormones (such as testosterone) taken or encountered by the mother during pregnancy. […] Male hormone-producing tumors in the mother. These are most often ovarian tumors. […] Aromatase deficiency. This may not be noticeable until puberty. […] The person has the chromosomes of a man, but the external genitals are incompletely formed, ambiguous (ambiguous genitalia), or clearly female. […] Internally, testes may be normal, malformed, or absent. […] Formation of normal male external genitals depends on the appropriate balance between male and female hormones. […] 46, XY DSD has many possible causes: Problems with the testes. […] Problems with testosterone formation. […] Problems with using testosterone. […] AIS is the most common cause of 46, XY DSD. […] The person has both ovarian and testicular tissue.

• #2 Pediatric Differences in Sex Development – Conditions and Treatments | Children’s National Hospital

  https://www.childrensnational.org/get-care/health-library/differences-in-sex-development

  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. […] Making a correct determination of gender is important for treatment. But it’s also important for the child’s emotional well-being.

• #2 Genetic cause of difference in sexual development uncovered | Crick

  https://www.crick.ac.uk/news/2020-06-03_genetic-cause-of-difference-in-sexual-development-uncovered

  Researchers at the Francis Crick Institute, the Institut Pasteur and their clinical collaborators have identified a cause of testicular tissue developing in people with female chromosomes. […] Differences in sexual development (DSD) are genetic conditions in which there is a mismatch between the chromosomal sex, XY or XX, which are typically of males and females, and some aspect of their anatomy, for example, an XY individual born as female or XX individual born as male. In many of the cases the genetic cause is unknown. […] By analysing the DNA of 78 children with this condition, they found that 9% had mutations affecting a specific part of another gene called Wilms Tumor 1 (WT1), that is located not on a sex chromosome, but on one of the other 22 chromosome pairs. […] Using human cell cultures, they found that these changes interfere with the delicate balance between the promotion of either the formation of male testis or female ovaries. This imbalance suppresses a protein (-CATENIN) which is important to the development of ovaries, resulting in the balance shifting to favour the development of testicular tissue.

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

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

  46,XY DSD include complete and partial gonadal dysgenesis (CGD) and result from incomplete intrauterine virilization. It is characterized by a 46,XY karyotype, ambiguous or female external genitalia, variable gonadal dysgenesis, hypospadias, azoospermia, and mullerian structures that range from absence to presence of a uterus and fallopian tubes (Mohnach et al. 2016. PubMed ID: 20301714). The main cause is pathogenic variants or deletions of SRY, which have been identified in 15% of individuals with 46,XY CGD. […] 46,XX DSD relate to excess androgen and are characterized by ambiguous or male external genitalia, mullerian aplasia, hyperandrogenism and primary amenorrhea (Knarston et al. 2016. PubMed ID: 26846580). These include 46,XX testicular and ovotesticular DSD, as well as 46,XX gonadal dysgenesis. Known etiologies include SRY translocation, and SOX9 or SOX3 gene CNVs.

• #2 Differences in Sex Development – UCI Pediatric Urology

  https://ucipediatricurology.com/specialties/differences-in-sex-development/

  Some babies are born with genitals that aren’t clearly male or female. This type of ambiguous development is referred to as differences in sex development (DSD). […] Children born with DSD may develop this issue because of an abnormal mixture of sex chromosomes. A baby with DSD sometimes has chromosomes with both ovarian and testicular tissue. There may also be male and female internal organs present. Its also possible for high levels of male hormones to enter the placenta via the mother, as may happen if a woman is given progesterone to prevent a miscarriage. DSD can also be the result of androgen insensitivity syndrome, which means that a childs body does not respond to androgens (testosterone). If there is some type of partial response to androgens, its referred to as partial androgen insensitivity. In some situations, DSD is caused by a problem with the adrenal gland that results in excess production of male hormones.

• #2 Pediatric Differences in Sex Development – Conditions and Treatments | Children’s National Hospital

  https://www.childrensnational.org/get-care/health-library/differences-in-sex-development

  When a child’s gender is not clear at birth, the child has atypical genitalia (ambiguous genitalia). […] Many genetic and environmental factors can affect the developing baby and lead to atypical genitalia. […] Atypical genitalia can have a number of different causes. In many cases, healthcare providers dont know the cause. It seems to occur by chance. […] The two primary causes of male pseudohermaphroditism are androgen insensitivity syndrome and 5-alpha reductase deficiency. […] This is called androgen insensitivity syndrome because male babies dont respond to testosterone (androgens). This syndrome is inherited. It’s caused by a problem with a gene on the X chromosome. […] Children with this condition lack an enzyme (5-alpha reductase). This enzyme is needed to help the male sex organs complete their development. This condition is inherited. It’s caused by an autosomal recessive gene.

• #2 Differences of sex development

  https://www.rch.org.au/endo/differences-of-sex-development/

  Differences in genital appearance can happen for a number of reasons that may be to do with differences in the development of the gonads (testes or ovaries), or hormonal signals that are responsible for the development of the genitalia during pregnancy, or may be a chance development. […] For some, genetic testing (either on a research basis or through an accredited clinical lab if available) may help to further explore underlying causes. […] Differences of sex development include diagnoses such as: Congenital adrenal hyperplasia, Androgen insensitivity syndrome (complete or partial), Gonadal dysgenesis (complete, partial or mixed) including Swyer syndrome, Hypospadias, Klinefelter Syndrome and other X Y chromosomal variations (Triple X syndrome, XXYY syndrome etc), Turner syndrome, Premature ovarian insufficiency, Mayer Rokitansky Kuster Hauser Syndrome (MRKH) including Vaginal or Uterine agenesis, Cloacal anomalies Bladder Exstrophy, 5-alpha reductase deficiency 17 Beta-HSD deficiency, Other XY DSD, Other XX DSD, Ovotesticular DSD, Anorchidism.

• #2 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

  Dozens of genes are involved in 46, XY differences in sex development (DSD). Notably, about 3/4 of patients cannot make a clear etiology diagnosis and single gene variant identified cannot fully explain the clinical heterogeneity of 46, XY DSD. […] Genetic analysis can quickly and accurately detect the etiology of DSD, but with high cost and low penetration rate about 3/4 of 46, XY DSD cannot make an unambiguous etiology diagnosis. […] 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. […] In addition to the NR5A1 gene, DSD can also be caused by mutations in other genes, such as the MAP3K1 gene. […] 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.

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

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

  Disorders of sex development (DSDs) are a genetically and clinically heterogeneous group of congenital conditions of the urogenital tract and reproductive system. […] These conditions may be caused by numerical or structural variations in sex chromosomes as well as autosomes, variations in genes involved in gonadal and/or genital development, and changes in gonadal and/or adrenal steroidogenesis. […] Endogenous or exogenous (maternal) and possibly endocrine disruptors may also interfere with genital development. […] Differences in sex development result from predominantly genetic pathogenic variants, but DSDs do not always manifest at birth and may be detected at different developmental stages of the life cycle. […] The initial diagnosis and management of patients with ambiguous genitalia are challenging.

• #2 Differences (Disorders) of Sex Development (DSDs) Workup: Laboratory Studies, Imaging Studies, Other Tests

  https://emedicine.medscape.com/article/1015520-workup

  Routine workup in infants born with ambiguous genitalia should include genetic testing and endocrine screening. […] The diagnosis is evident if a difference (disorder) of sex development (DSD) is caused by chromosomal abnormalities. […] Molecular cytogenetic examinations can detect specific structural rearrangements. […] Hormonal diagnostics and serum electrolytes/chemistry levels are essential right after birth. […] In the absence of palpable testes, markedly elevated luteinizing hormone (LH) levels or lack of testosterone elevation in response to human chorionic gonadotropin (hCG) stimulation can indicate the absence of normally functioning testicular tissue in patients with nonpalpable gonads. […] The hCG stimulation test can also help to diagnose 5-alpha-reductase deficiency and distinguish impaired testosterone synthesis from androgen insensitivity.

• #2 Differences in sex development — Knowledge Hub

  https://www.genomicseducation.hee.nhs.uk/genotes/knowledge-hub/differences-in-sex-development/

  Differences in sex development are a group of rare conditions where chromosomal, gonadal or anatomic sex is atypical. […] Differences in sex development (DSD), sometimes called disorders of sex development, refer to a group of congenital conditions where chromosomal, gonadal or anatomic sex is atypical. […] There are a number of genetic and chromosomal causes for DSD that include (though are not limited to) the following: […] Conditions associated with androgen synthesis/action, including: […] Conditions associated with testicular development (complete or partial gonadal dysgenesis), including: […] Conditions associated with fetal androgen excess, including: […] Conditions associated with ovarian development, including: […] Genomic counselling for individuals with a DSD will vary depending on the specific condition or associated gene. […] Assessment, investigation and management of DSDs should be delivered via a multidisciplinary team, including endocrinologists, urologists, gynaecologists, psychologists and geneticists.

• #2 Current Diagnostic Approaches in the Genetic Diagnosis of Disorders of Sex Development – Journal of Clinical Research in Pediatric Endocrinology

  https://jcrpe.org/articles/current-diagnostic-approaches-in-the-genetic-diagnosis-of-disorders-of-sex-development/doi/jcrpe.galenos.2024.2024-3-3

  Disorders of sex development (DSD) are a clinically and genetically highly heterogeneous group of congenital disorders. […] DSDs occur as a result of a disorder in one of the stages of sex development, especially in the first trimester due to incompatibility of chromosomes, gonads, or anatomical structure. […] Multiple genetic etiologies, ranging from missense single nucleotide variants (SNVs) to complete chromosome aneuploidies, have been demonstrated among the genetic causes of DSD. […] At least 75 genes have been associated with DSD in humans. […] The first step in cases with suspected DSD is to determine the presence of sex chromosome and the SRY gene. […] Despite the genetic tests performed in current daily practice, the genetic cause is still not elucidated in a significant proportion of cases.

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

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

  However, due to the large number of candidate genes that may be involved in DSDs, many laboratories use next generation sequencing (NGS) techniques that allow the simultaneous sequencing of a variable number of genes; these methods can be used to find the genetic cause quicker and at lower cost. […] In Spain, there are two DSD registers that are currently active and accessible. One is a Spanish register, and the other an international one.

• #2 Breakthrough in diagnosing disorders of sex development – Hudson Institute of Medical Research

  https://www.hudson.org.au/news/breakthrough-in-diagnosing-sex-development-disorders/

  Our new model will help Identify new causes and mechanisms of DSD in children. […] A different but related research paper in Frontiers in Cell and Developmental Biology showed a new target for mutations in and around the SOX9 gene which is likely to contribute to DSDs. […] These studies advance our understanding of basic biological mechanisms, and the perturbations that lead to sex development disorders including intersex conditions.

• #2 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

  Differences of sex development (DSDs; also known as disorders of sex development) refer to a heterogeneous group of congenital conditions affecting human sex determination and differentiation. […] Our knowledge of DSDs has greatly evolved in the past decade owing to cutting-edge research on mammalian sex development and the genetic mechanisms underlying DSDs. […] The lack of conclusive outcome data for patients with DSDs has triggered large-scale collaborative research that initially focused on basic science projects and since 2012 began addressing clinically oriented issues and outcomes. […] The development of international registries was crucial in the development of collaborative research projects. […] Standardizing the longitudinal assessment of individuals with a DSD across centres might also provide evidence for or against controversial procedures such as surgical management of genitalia with an atypical appearance.

• #2 Prevalence of differences of sex development in children and adolescents in Switzerland from 2000-2019 | medRxiv

  https://www.medrxiv.org/content/10.1101/2024.03.11.24304115v2.full-text

  We report prevalence for different DSD diagnoses according to the Chicago Consensus Classification in a population-based cohort between 2000-2019 in Switzerland. […] Prevalence of DSD treated by pediatric endocrinologist was 37 per 100000 (1 of 2735) newborns including sex chromosome, 46,XY and 46,XX DSD. Overall, DSD prevalence decreased from 2000-2019, which was driven by a strong decrease in prevalence of sex chromosome DSD. Prevalence of 46,XY DSD tended to increase and prevalence of 46,XX DSD to decrease over time. […] We assume almost complete coverage of rare and complex subgroups of non-chromosomal DSD with atypical genitalia. […] We calculated prevalence of DSD based on live birth rates in Switzerland. […] Our overall prevalences are lower than published data for sex chromosome DSD.

• #2 Differences of Sex Development – Clinical Tree

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

  DSD can result from anomalies in any of the processes described above. They can present as an isolated urogenital atypia but can also be part of a large number of multiorgan syndromes, underscoring the need for an accurate molecular diagnosis to seek and manage associated comorbidities. […] Conditions associated with dysgenetic gonads result from events affecting sex determination, while conditions that can cause ambiguous genitalia but are not associated with dysgenetic gonads, such as androgen insensitivity syndrome (AIS) or congenital adrenal hyperplasia (CAH), are considered differences in sexual differentiation. […] The major concern in the treatment of patients with XY GD is the risk of gonadoblastoma, a mixed germ-cell, sex-cord tumor. The risk of gonadoblastoma formation in XY GD increases with age and has been estimated to be as high as 30% by 30 years of age.

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

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

  DSD are complex conditions caused by a wide range of genetic anomalies. They can be inherited in an autosomal dominant (AD), autosomal recessive (AR), X-linked (XL), and Y-linked (YL) manner, or arise de novo depending on the gene involved. To date, more than 60 genes have been showed to be involved in DSD (Baxter et al. 2015. PubMed ID: 25383892; Eggers et al. 2016. PubMed ID: 27899157). These genes are implicated in sex determination, sex differentiation and hypogonadism. […] 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 (Baxter et al. 2015. PubMed ID: 25383892; Eggers. et al. 2016. PubMed ID: 27899157).

• #2 Disorders of Sexual Differentiation | UCSF Department of Urology

  https://urology.ucsf.edu/patient-care/children/genital-anomalies/disorders-of-sex-development

  Disorders of sex development (DSDs) are conditions in which the reproductive organs and genitals do not develop normally. […] DSDs occur because of variations in the genes that control sexual development or because a person has an underlying condition that affects how the body responds to sex hormones. […] For example, people with a DSD caused by congenital adrenal hyperplasia (CAH), do not produce an enzyme required to make two hormones, cortisol and aldosterone. As a result the body produces too much androgen (male sex hormone), resulting in male sex characteristics. If the DSD is caused by androgen insensitivity syndrome, the body does not process androgen in a normal way.

• #2

  https://www.healthychildren.org/English/health-issues/conditions/genitourinary-tract/Pages/Explaining-Disorders-of-Sex-Development-Intersexuality.aspx

  A DSD is a mismatch between a child’s chromosomes, or genetic material, and the appearance of the child’s genitals. A child may present with a DSD in infancy, childhood or adolescence. […] What Causes DSDs? A genetic change that may or may not be inherited from a parent. Unknown exposure to certain medications or hormones during pregnancy. A developmental problem in the baby during pregnancy that prevents the production of enough of his or her own hormones (e.g. lack of blood flow to the ovaries or testes). A developmental problem that causes the bladder or lower abdomen to not form properly (e.g. cloacal exstrophy). […] The medical community used to think that gender identity (the feeling that a person is a boy or a girl), was learned or taught. However, we now know it is influenced by genetics, exposure to hormones while still in the mother’s uterus and other factors that are not known yet.

• #3

  https://journals.lww.com/adhb/fulltext/2022/12020/current_status_of_disorders_of_sexual_development.20.aspx

  Disorders of Sex Development (DSD) rise challenges in various aspects of life due to the abnormalities in the patients’ sex chromosomes, gonads or reproductive organs. Its causes are often due to genetic and environmental factors. […] Genetic, hormonal and environmental factors during prenatal and postnatal development are likely responsible for DSD manifestations. […] The incidence of DSD is estimated to be 1 in every 4500-5500 births. […] The management of children with DSD is determined by the discord between chromosomal, gonadal, and phenotypic sex. […] There are limited options for medical and surgical management for patients with DSD in Indonesia. […] The examination effort to establish the diagnosis of DSD according to its classification includes giving hormone therapy. […] Hormonal therapy can start when patients with DSD reach the age of puberty.

• #3 Disorders of Sex Development: Classification, Review, and Impact on Fertility

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7694247/

  In this review, the elements included in both sex determination and sex differentiation are briefly analyzed, exposing the pathophysiological and clinical classification of disorders or anomalies of sex development. […] Disorders of sex development (DSDs) were defined as congenital conditions within which the development of chromosomal, gonadal, and anatomic sex is atypical at the Chicago Consensus Meeting in 2005, which was then published as a Consensus Statement in 2006. […] We believe that the origin of abnormal sex development situations or ASDs must be: (1) in the chromosomes and SRY gene (and other sex-determining (SD) genes located in the autosomes) that may therefore be carried into the formation of the gonad; (2) in the hormone-producing glands involved in sex development (i.e., gonads, adrenals, and pituitary), as well as in the metabolization of these hormones, in their action on the target organs or in the content of receptors.

• #3 Disorders of sex development: a genetic study of patients in a multidisciplinary clinic in: Endocrine Connections Volume 3 Issue 4 (2014)

  https://ec.bioscientifica.com/view/journals/ec/3/4/180.xml

  Sex development is a process under genetic control directing both the bi-potential gonads to become either a testis or an ovary, and the consequent differentiation of internal ducts and external genitalia. This complex series of events can be altered by a large number of genetic and non-genetic factors. Disorders of sex development (DSD) are all the medical conditions characterized by an atypical chromosomal, gonadal, or phenotypical sex. […] Incomplete knowledge of the genetic mechanisms involved in sex development results in a low probability of determining the molecular definition of the genetic defect in many of the patients. […] In conclusion, our results highlight the fact that each category of DSD is related to a large number of different DNA alterations, thus requiring multiple genetic studies to achieve a precise etiological diagnosis for each patient.

• #3 Disorders of sex development: a genetic study of patients in a multidisciplinary clinic in: Endocrine Connections Volume 3 Issue 4 (2014)

  https://ec.bioscientifica.com/view/journals/ec/3/4/180.xml

  Current understanding of the genetic control of sex development is still incomplete, resulting a low probability of determining the molecular definition of the causal defect in many of the patients with DSD. […] Our results highlight that each category of DSD is related to a large number of different DNA alterations, thus requiring multiple genetic studies to possibly achieve a precise etiological diagnosis in every patient.

• #3 Prevalence of differences of sex development in children and adolescents in Switzerland from 2000-2019 | medRxiv

  https://www.medrxiv.org/content/10.1101/2024.03.11.24304115v2.full-text

  We report prevalence for different DSD diagnoses according to the Chicago Consensus Classification in a population-based cohort between 2000-2019 in Switzerland. […] Prevalence of DSD treated by pediatric endocrinologist was 37 per 100000 (1 of 2735) newborns including sex chromosome, 46,XY and 46,XX DSD. Overall, DSD prevalence decreased from 2000-2019, which was driven by a strong decrease in prevalence of sex chromosome DSD. Prevalence of 46,XY DSD tended to increase and prevalence of 46,XX DSD to decrease over time. […] We assume almost complete coverage of rare and complex subgroups of non-chromosomal DSD with atypical genitalia. […] We calculated prevalence of DSD based on live birth rates in Switzerland. […] Our overall prevalences are lower than published data for sex chromosome DSD.

• #3 Frontiers | Diagnosis and management of non-CAH 46,XX disorders/differences in sex development

  https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2024.1354759/full

  Prenatal-onset androgen excess leads to abnormal sexual development in 46,XX individuals. This androgen excess can be caused endogenously by the adrenals or gonads or by exposure to exogenous androgens. The most common cause of 46,XX disorders/differences in sex development (DSD) is congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, comprising >90% of 46,XX DSD cases. Deficiencies of 11β-hydroxylase, 3β-hydroxysteroid dehydrogenase, and P450-oxidoreductase (POR) are rare types of CAH, resulting in 46,XX DSD. In all CAH forms, patients have normal ovarian development. The molecular genetic causes of 46,XX DSD, besides CAH, are uncommon. These etiologies include primary glucocorticoid resistance (PGCR) and aromatase deficiency with normal ovarian development. Additionally, 46,XX gonads can differentiate into testes, causing 46,XX testicular (T) DSD or a coexistence of ovarian and testicular tissue, defined as 46,XX ovotesticular (OT)-DSD. PGCR is caused by inactivating variants in NR3C1, resulting in glucocorticoid insensitivity and the signs of mineralocorticoid and androgen excess. Pathogenic variants in the CYP19A1 gene lead to aromatase deficiency, causing androgen excess. Many genes are involved in the mechanisms of gonadal development, and genes associated with 46,XX T/OT-DSD include translocations of the SRY; copy number variants in NR2F2, NR0B1, SOX3, SOX9, SOX10, and FGF9, and sequence variants in NR5A1, NR2F2, RSPO1, SOX9, WNT2B, WNT4, and WT1. Progress in cytogenetic and molecular genetic techniques has significantly improved our understanding of the etiology of non-CAH 46,XX DSD. Nonetheless, uncertainties about gonadal function and gender outcomes may make the management of these conditions challenging. This review explores the intricate landscape of diagnosing and managing these conditions, shedding light on the unique aspects that distinguish them from other types of DSD.

• #3 Disorders of Sex Development

  http://library.oumedicine.com/Wellness/BackandNeck/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.

• #3 Pediatric Differences in Sex Development – Conditions and Treatments | Children’s National Hospital

  https://www.childrensnational.org/get-care/health-library/differences-in-sex-development

  When a child’s gender is not clear at birth, the child has atypical genitalia (ambiguous genitalia). […] Many genetic and environmental factors can affect the developing baby and lead to atypical genitalia. […] Atypical genitalia can have a number of different causes. In many cases, healthcare providers dont know the cause. It seems to occur by chance. […] The two primary causes of male pseudohermaphroditism are androgen insensitivity syndrome and 5-alpha reductase deficiency. […] This is called androgen insensitivity syndrome because male babies dont respond to testosterone (androgens). This syndrome is inherited. It’s caused by a problem with a gene on the X chromosome. […] Children with this condition lack an enzyme (5-alpha reductase). This enzyme is needed to help the male sex organs complete their development. This condition is inherited. It’s caused by an autosomal recessive gene.

• #3 Ovotesticular Difference of Sexual Development | Lurie Children’s

  https://www.luriechildrens.org/en/specialties-conditions/ovotesticular-difference-of-sexual-development/

  Ovotesticular Difference of Sexual Development (DSD) is a condition in which an individual is born with both ovarian and testicular tissue in their body. […] While specific genetic causes can sometimes be identified, the exact cause of ovotesticular DSD remains uncertain in many cases.

• #3 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. […] 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). […] An aetiological diagnosis needs the interaction of clinical, biochemical (hormonal), genetic, imaging and, sometimes, surgical examinations. […] The different molecular studies are used to assess for a variety of genetic disorders: Detection of pathogenic changes in the sequence of a gene: the classic Sanger sequencing technique is used when there is a clear candidate gene.

• #3 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

  Intersex activists have encouraged legislative bodies worldwide to ban elective, irreversible genital surgery without the individuals informed consent. […] In the absence of long-term outcome data that support or disfavour deferring genital surgery, there is currently little evidence that surgical practice has dramatically changed in recent years. […] 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. […] The risk is much higher in men and women with gonadal dysgenesis, especially forms that arise from early gonadal differentiation defects, than in individuals with ovotesticular DSD or with hormone synthesis or action disorders. […] The underlying pathogenic mechanisms and proposed management were reviewed elsewhere.

• #3 46,XY Differences of Sexual Development – Endotext – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK279170/

  The 46,XY differences of sex development (46,XY DSD) can result either from decreased synthesis of testosterone and/or DHT or from impairment of androgen action. […] 46,XY DSD can result either from decreased synthesis of testosterone or DHT or from impairment of androgen action. […] Dosage imbalances in genes involved in DSD (deletions or duplication) have also been identified as a cause of these developmental differences. […] The term differences of sex development (DSD) include congenital conditions in which development of chromosomal, or gonadal or anatomical sex is atypical. […] The proposed changes in terminology aim to integrate upcoming advances in molecular genetics in the most recent DSD classification. […] The diagnostic evaluation of DSD includes hormone measurements, imaging, cytogenetic, and molecular studies.

• #3 FloridaHealthFinder | Differences of sex development | Health Encyclopedia | FloridaHealthFinder

  https://quality.healthfinder.fl.gov/health-encyclopedia/HIE/1/001669

  Male hormones (such as testosterone) taken or encountered by the mother during pregnancy. […] Male hormone-producing tumors in the mother. These are most often ovarian tumors. […] Aromatase deficiency. This may not be noticeable until puberty. […] The person has the chromosomes of a man, but the external genitals are incompletely formed, ambiguous (ambiguous genitalia), or clearly female. […] Internally, testes may be normal, malformed, or absent. […] Formation of normal male external genitals depends on the appropriate balance between male and female hormones. […] 46, XY DSD has many possible causes: Problems with the testes. […] Problems with testosterone formation. […] Problems with using testosterone. […] AIS is the most common cause of 46, XY DSD. […] The person has both ovarian and testicular tissue.

• #3 Atypical genitalia – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/atypical-genitalia/symptoms-causes/syc-20369273

  Atypical genitalia is not a disease; it’s a difference of sex development. […] Atypical genitalia usually happen when hormone changes during pregnancy stop or disturb an unborn baby’s developing sex organs. […] A change in the steps that influence fetal sex development can result in a mismatch between the appearance of a baby’s external genitals and the baby’s internal sex organs or genetic sex, typically XX or XY. […] If a genetic male fetus doesn’t make hormones called androgens or doesn’t have enough of these hormones, it can cause atypical genitalia. Exposure to androgens during development in a genetic female fetus results in atypical external genitalia. […] Changes in certain genes can affect fetal sex development and cause atypical genitalia. […] Atypical genitalia also can be a feature of certain rare or complex syndromes that affect many organs. These syndromes can include chromosome changes such as a missing sex chromosome or an extra one.

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