{{Short description|Medical conditions involving the development of the reproductive system}} {{Redirect|Sex anomaly|other conditions|Sexual disorder}} {{Infobox medical condition (new) | name = Disorders of sex development | synonyms = Disorders of sex differentiation, variations of sex characteristics<ref name="hawaii.edu">{{cite journal | vauthors = Diamond M, Beh HG | title = Changes in the management of children with intersex conditions | journal = Nature Clinical Practice. Endocrinology & Metabolism | volume = 4 | issue = 1 | pages = 4–5 | date = January 2008 | pmid = 17984980 | doi = 10.1038/ncpendmet0694 | hdl-access = free | s2cid = 13382948 | hdl = 10125/66380 | author-link1 = Milton Diamond }}</ref> | caption = | pronounce = | field = Medical genetics | symptoms = | complications = | onset = | duration = | types = | causes = | risks = | diagnosis = | differential = | prevention = | treatment = | medication = | prognosis = | frequency = | deaths = }} '''Disorders of sex development''' ('''DSDs'''), also known as '''differences in sex development''', '''variations in sex characteristics''' ('''VSC'''),<ref name="NHS">{{cite web|url=https://www.nhs.uk/conditions/differences-in-sex-development/|title=Differences in sex development|date=2017-10-18| work = U.K. National Health Service (NHS) |language=en|access-date=2020-04-10}}</ref><ref>{{Cite web |title=Information about the standard for gender, sex, and variations of sex characteristics {{!}} Stats NZ |url=https://www.stats.govt.nz/methods/information-about-the-standard-for-gender-sex-and-variations-of-sex-characteristics |access-date=2024-03-12 |website=www.stats.govt.nz}}</ref> '''sexual anomalies''', or '''sexual abnormalities''', are congenital conditions affecting the reproductive system, in which development of chromosomal, gonadal, or anatomical sex is atypical.<ref name="lee">{{cite journal | vauthors = Lee PA, Houk CP, Ahmed SF, Hughes IA | title = Consensus statement on management of intersex disorders. International Consensus Conference on Intersex | journal = Pediatrics | volume = 118 | issue = 2 | pages = e488-500 | date = August 2006 | pmid = 16882788 | pmc = 2082839 | doi = 10.1542/peds.2006-0738 }}</ref><ref>{{Cite book|date=2017-01-01|title=Disorders of Sex Development Loci|chapter=Disorders of Sex Development Loci☆ |publisher=Elsevier |chapter-url=https://www.sciencedirect.com/science/article/pii/B9780128096338065523|language=en|doi=10.1016/B978-0-12-809633-8.06552-3|isbn=978-0-12-809633-8 |last1=Sreenivasan |first1=R. |last2=Alankarage |first2=D. |last3=Harley |first3=V. }}</ref>
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.<ref>{{Citation |last1=Domenice |first1=Sorahia |title=46,XY Differences of Sexual Development |date=2000 |url=https://www.ncbi.nlm.nih.gov/books/NBK279170/ |work=Endotext |editor-last=Feingold |editor-first=Kenneth R. |place=South Dartmouth (MA) |publisher=MDText.com, Inc. |pmid=25905393 |access-date=2023-01-20 |last2=Batista |first2=Rafael Loch |last3=Arnhold |first3=Ivo J. |last4=Sircili |first4=Maria Helena |last5=Costa |first5=Elaine M. F. |last6=Mendonca |first6=Berenice Bilharinho |editor2-last=Anawalt |editor2-first=Bradley |editor3-last=Boyce |editor3-first=Alison |editor4-last=Chrousos |editor4-first=George}}</ref>
In the cases when a baby is born with an atypical anatomical sex, families often experience confusion and distress. Sexual and psychological development are influenced by numerous factors that include, but are not limited to, gender differences in brain structure, genes associated with sexual development, prenatal androgen exposure, interactions with family, and cultural and societal factors.<ref>{{Citation|last1=Achermann|first1=John C.|title=Pediatric Disorders of Sex Development|date=2016|url=https://linkinghub.elsevier.com/retrieve/pii/B978032329738700023X|work=Williams Textbook of Endocrinology|pages=893–963|publisher=Elsevier|language=en|doi=10.1016/b978-0-323-29738-7.00023-x|isbn=978-0-323-29738-7|access-date=2021-04-01|last2=Hughes|first2=Ieuan A.|url-access=subscription}}</ref> Because of the complex and multifaceted factors involved, communication and psychosexual support are important.
A team of experts, or patient support groups, are usually recommended for cases related to sexual anomalies. This team of experts are usually derived from a variety of disciplines including pediatricians, neonatologists, pediatric urologists, pediatric general surgeons, endocrinologists, geneticists, radiologists, psychologists and social workers.<ref name=":332">{{Cite journal|last1=Guerrero-Fernández|first1=Julio|last2=Azcona San Julián|first2=Cristina|last3=Barreiro Conde|first3=Jesús|last4=Bermúdez de la Vega|first4=José Antonio|last5=Carcavilla Urquí|first5=Atilano|last6=Castaño González|first6=Luis Antonio|last7=Martos Tello|first7=José María|last8=Rodríguez Estévez|first8=Amaya|last9=Yeste Fernández|first9=Diego|last10=Martínez Martínez|first10=Leopoldo|last11=Martínez-Urrutia|first11=María José|date=2018|title=Management guidelines for disorders/different sex development (DSD)|journal=Anales de Pediatría (English Edition)|language=en|volume=89|issue=5|pages=315.e1–315.e19|doi=10.1016/j.anpede.2018.06.006|pmid=30033107 |doi-access=free}}</ref><ref>{{Cite web|title=Ambiguous genitalia - Diagnosis and treatment - Mayo Clinic|url=https://www.mayoclinic.org/diseases-conditions/ambiguous-genitalia/diagnosis-treatment/drc-20369278|access-date=2021-04-01|website=www.mayoclinic.org}}</ref><ref name=":432">{{Cite book|date=2020|editor-last=Deligdisch-Schor|editor-first=Liane|editor2-last=Mareş Miceli|editor2-first=Angelica|title=Hormonal Pathology of the Uterus|series=Advances in Experimental Medicine and Biology|volume=1242 |language=en-gb|page=133|doi=10.1007/978-3-030-38474-6|isbn=978-3-030-38473-9 |s2cid=218624824 |issn=0065-2598 }}</ref> These professionals are capable of providing first line (prenatal) and second line diagnostic (postnatal) tests to examine and diagnose sexual anomalies.
==Overview== DSDs are defined as "any problem noted at birth where the genitalia are atypical in relation to the chromosomes or gonads".<ref name="Hughes20008">{{cite journal |last1=Hughes |first1=Ieuan A. |title=Disorders of sex development: a new definition and classification |journal=Best Practice & Research Clinical Endocrinology & Metabolism |date=February 2008 |volume=22 |issue=1 |pages=119–134 |doi=10.1016/j.beem.2007.11.001 |pmid=18279784 |quote=In its place, a consensus statement recommends the term 'disorder of sex development' (DSD), a generic definition encompassing any problem noted at birth where the genitalia are atypical in relation to the chromosomes or gonads.}}</ref> There are several types of DSDs, and their effect on the external and internal reproductive organs varies greatly.
A frequently used, casual social adjective for people with DSDs is "intersex". Urologists were concerned that terms like intersex, hermaphrodite, and pseudohermaphrodite were confusing and pejorative with respect to humans. This led to the Chicago Consensus, recommending a new terminology based on the umbrella term ''disorders of sex development.''<ref name="Disorders of sex development">{{cite journal | vauthors = Kim KS, Kim J | title = Disorders of sex development | journal = Korean Journal of Urology | volume = 53 | issue = 1 | pages = 1–8 | date = January 2012 | pmid = 22323966 | pmc = 3272549 | doi = 10.4111/kju.2012.53.1.1 }}</ref><ref>{{Cite journal |last=Hughes |first=Ieuan |date=February 2008 |title=Disorders of sex development: a new definition and classification |url=https://www.sciencedirect.com/science/article/abs/pii/S1521690X07001054 |journal= Best Practice & Research Clinical Endocrinology & Metabolism|volume=22 |issue=1 |pages=119–134 |doi=10.1016/j.beem.2007.11.001 |pmid=18279784 |via=Science Direct|url-access=subscription }}</ref> However, intersex people have continued to prefer the term "intersex" over "DSD" by large margins.<ref name="jones2016">{{Cite book|publisher=Open Book Publishers |isbn=978-1-78374-208-0 |last1=Jones |first1=Tiffany |last2=Hart |first2=Bonnie |last3=Carpenter |first3=Morgan |last4=Ansara |first4=Gavi |last5=Leonard |first5=William |last6=Lucke |first6=Jayne |title=Intersex: Stories and Statistics from Australia |location=Cambridge, UK |date=2016 |access-date=2 February 2016 |url=http://oii.org.au/wp-content/uploads/key/Intersex-Stories-Statistics-Australia.pdf |archive-url=https://web.archive.org/web/20160914152729/http://oii.org.au/wp-content/uploads/key/Intersex-Stories-Statistics-Australia.pdf |archive-date=14 September 2016 }}</ref> Other than disorders of sex development, another term is congenital conditions of sex development (CCSD). Since 2006, people who were previously incorrectly categorized as hermaphrodites are now labelled as having ovotesticular syndrome.
DSDs are divided into the following categories, emphasizing the karyotype's role in diagnosis:<ref name="pmid29503125">{{cite journal | vauthors = Witchel SF | title = Disorders of sex development | journal = Best Practice & Research. Clinical Obstetrics & Gynaecology | volume = 48 | issue = | pages = 90–102 | date = April 2018 | pmid = 29503125 | pmc = 5866176 | doi = 10.1016/j.bpobgyn.2017.11.005 }}</ref><ref>{{cite journal |last1=Hughes |first1=Ieuan A. |title=Disorders of sex development: a new definition and classification |journal=Best Practice & Research Clinical Endocrinology & Metabolism |date=February 2008 |volume=22 |issue=1 |pages=119–134 |doi=10.1016/j.beem.2007.11.001 |pmid=18279784 |quote=Adding some diagnostic specificity to the generic DSD definition utilizes knowledge of the karyotype. This is based on recognizing the central role of karyotype analysis in the investigation of most cases of DSD, and knowledge in general about sex chromosomes.}}</ref> * 46,XX DSD: Genetic Female Sex Chromosomes. Mainly virilized females as a result of congenital adrenal hyperplasia (CAH) and girls with aberrant ovarian development. * 46,XY DSD: Genetic Male Sex Chromosomes. Individuals with abnormal testicular differentiation, defects in testosterone biosynthesis, and impaired testosterone action. * Sex chromosome DSD: patients with sex chromosome aneuploidy or mosaic sex karyotypes. This includes patients with Turner Syndrome (45,X or 45,X0) and Klinefelter Syndrome (47,XXY) even though they do not generally present with atypical genitals. * XX, Sex reversal: consist of two groups of patients with male phenotypes, the first with translocated Sex-determining region Y protein (SRY) and the second with no SRY gene. * Ovotesticular disorder: patients having both ovarian and testicular tissue. In some cases the ovarian tissue is functional. * XY, Sex reversal: patients with female phenotypes where duplication in the Xp21.2 region of the X chromosome that contains the ''NR0B1'' (''DAX1'') gene is associated with XY sex reversal.
=== Genital anatomy === [[File:Quigley scale for androgen insensitivity syndrome.jpg|thumb|class=skin-invert-image|The Quigley scale is a method for describing genital development in AIS.]]
The penis (males) and clitoris (females) have a common origin, both arising from an embryonic structure called the primordial phallus. In typical males, the urethra is located at the tip of the penis, while in typical females the urethra is located below the base of the clitoris.<ref>{{Cite journal |last1=Baskin |first1=Laurence |last2=Shen |first2=Joel |last3=Sinclair |first3=Adriane |last4=Cao |first4=Mei |last5=Liu |first5=Xin |last6=Liu |first6=Ge |last7=Isaacson |first7=Dylan |last8=Overland |first8=Maya |last9=Li |first9=Yi |last10=Cunha |first10=Gerald R. |date=2018 |title=Development of the human penis and clitoris |journal=Differentiation |volume=103 |pages=74–85 |doi=10.1016/j.diff.2018.08.001 |issn=1432-0436 |pmc=6234061 |pmid=30249413}}</ref> It is also possible to have a urethral opening located along the shaft; this condition is known as hypospadias.<ref>{{Cite journal |last1=Baskin |first1=Laurence |last2=Shen |first2=Joel |last3=Sinclair |first3=Adriane |last4=Cao |first4=Mei |last5=Liu |first5=Xin |last6=Liu |first6=Ge |last7=Isaacson |first7=Dylan |last8=Overland |first8=Maya |last9=Li |first9=Yi |last10=Cunha |first10=Gerald R. |date=2018-09-01 |title=Development of the human penis and clitoris |journal=Differentiation |language=en |volume=103 |pages=74–85 |doi=10.1016/j.diff.2018.08.001 |pmid=30249413 |pmc=6234061 |issn=0301-4681}}</ref>
=== Management of DSDs === Due to the significant and life-long impacts that DSDs can have on patients and their families,<ref>{{Cite journal|last=Wisniewski|first=Amy B.|date=January 2017|title=Psychosocial implications of disorders of sex development treatment for parents|journal=Current Opinion in Urology|language=en|volume=27|issue=1|pages=11–13|doi=10.1097/MOU.0000000000000344|issn=0963-0643|pmc=5283739|pmid=27584026}}</ref> it is widely accepted that children with DSDs should be managed by an experienced multidisciplinary team.<ref>{{cite book | vauthors = O'Connell MA, Hutson GM, Grover SR | chapter = Medical management of DSD | veditors = Hutson JM, Grover SR, O'Connell MA, Bouty A, Hanna C | chapter-url= https://books.google.com/books?id=c-jqDwAAQBAJ&pg=PA204 |title=Disorders{{!}}Differences of Sex Development: An Integrated Approach to Management |date=2020-06-10|publisher=Springer Nature|isbn=978-981-13-7864-5|page=204|language=en}}</ref> Health care providers generally agree that children with DSDs should be notified early.<ref>{{cite journal | vauthors = Cools M, Nordenström A, Robeva R, Hall J, Westerveld P, Flück C, Köhler B, Berra M, Springer A, Schweizer K, Pasterski V | display-authors = 6 | title = Caring for individuals with a difference of sex development (DSD): a Consensus Statement | journal = Nature Reviews. Endocrinology | volume = 14 | issue = 7 | pages = 415–429 | date = July 2018 | pmid = 29769693 | doi = 10.1038/s41574-018-0010-8 | pmc = 7136158 }}</ref>
Appropriate and conservative medical intervention and age-appropriate child involvement in the treatment plan contribute greatly to successful outcomes for the entire range of DSDs.<ref>{{Cite journal |last1=Bhandari |first1=Nita |last2=Mazumder |first2=Sarmila |last3=Bahl |first3=Rajiv |last4=Martines |first4=Jose |last5=Black |first5=Robert E. |last6=Bhan |first6=Maharaj K. |date=2004-09-01 |title=An educational intervention to promote appropriate complementary feeding practices and physical growth in infants and young children in rural Haryana, India |journal=The Journal of Nutrition |volume=134 |issue=9 |pages=2342–2348 |doi=10.1093/jn/134.9.2342 |issn=0022-3166 |pmid=15333726|doi-access=free }}</ref><ref>{{Cite journal |last1=Bender |first1=Melinda S. |last2=Nader |first2=Philip R. |last3=Kennedy |first3=Christine |last4=Gahagan |first4=Sheila |date=2013-04-05 |title=A culturally appropriate intervention to improve health behaviors in Hispanic mother-child dyads |journal=Childhood Obesity (Print) |volume=9 |issue=2 |pages=157–163 |doi=10.1089/chi.2012.0118 |issn=2153-2176 |pmc=3621339 |pmid=23514697}}</ref>
== Key hormones == thumb|class=skin-invert-image|'''Chemical structure of testosterone'''
In the normal prenatal stages of fetal development, the fetus is exposed to testosterone - albeit more in male fetuses than female ones. Upon the presence of the 5α-reductase enzyme, testosterone is converted to dihydrotestosterone (i.e. DHT). If DHT is present, the male external genitalia will develop.
Development of male external genitalia: * Genital tubercle forms the penis<ref name=":1">{{Cite journal|last1=Kinter|first1=Kevin|last2=Anekar|first2=Aabha|date=2021-03-13|title=Biochemistry, Dihydrotestosterone|url=https://www.statpearls.com/ArticleLibrary/viewarticle/20527|journal=StatPearls|language=en}}</ref> * Urethral folds form the penile raphe<ref>{{cite book|last1=Hodges|first1=Frederick Mansfield S.|last2=Denniston|first2=George C.|last3=Milos|first3=Marilyn Fayre|publisher=Springer US|year= 2007|title=Male and Female Circumcision: Medical, Legal, and Ethical Considerations in Pediatric Practice|page=10|access-date=November 24, 2023|isbn=978-0-58539-937-9|url=https://books.google.com/books?id=U0EyBwAAQBAJ&pg=PA10}}</ref><ref>{{cite book|last1=Martin|first1=Richard J.|last2=Fanaroff|first2=Avory A.|last3=Walsh| first3=Michele C.|publisher=Elsevier Health Sciences|year=2014|title=Fanaroff and Martin's Neonatal-Perinatal Medicine E-Book: Diseases of the Fetus and Infant|page=1522|access-date=November 24, 2023|isbn=978-0-32329-537-6|url=https://books.google.com/books?id=AnVYBAAAQBAJ&pg=PA1522}}</ref> * Genital swellings form the scrotum<ref name=":1" />
On the other hand, if maternal placenta estrogen is present without DHT, then the development of female external genitalia occurs.<ref>{{cite book |last1=Flück |first1=Christa E. |last2=Güran |first2=Tülay |editor-last1=Feingold |editor-first1=Kenneth R. |editor-last2=Anawalt |editor-first2=Bradley |editor-last3=Blackman |editor-first3=Marc R |editor-last4=Boyce |editor-first4=Allison |display-editors=3 |date=November 13, 2023 |title=Endotext |chapter=Ambiguous Genitalia in the Newborn |url=https://www.ncbi.nlm.nih.gov/books/NBK278943/ |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK279168/ |location=South Dartmouth, MA |publisher=MDText.com, Inc. |pmid=25905160 }}</ref>
Development of female external genitalia (the vulva): * Genital tubercle forms the clitoris<ref name=":0a">{{Cite journal|last1=A|first1=Aatsha P.|last2=Krishan|first2=Kewal|date=2020-05-30|title=Embryology, Sexual Development|url=https://www.statpearls.com/ArticleLibrary/viewarticle/28946|journal=StatPearls|language=en}}</ref> * Urethral folds form the labia minora<ref name=":0a" /> * Genital swellings form the labia majora<ref name=":0a" />
thumb|class=skin-invert-image|'''Chemical structure of dihydrotestosterone (DHT)'''
However, in abnormal cases, sexual anomalies occur due to a variety of factors that lead to an excess of androgens in the fetus. The effects of excessive androgens differ in fetuses with XX chromosome (female) and XY chromosomes (male).
In XX chromosome fetuses, excess androgens result in ambiguous genitalia. This makes identification of external genitalia as male or female difficult.<ref name=":0" /> Additionally, the individual may have clitoromegaly, a shallow vagina, early and rapid growth of pubic hair in childhood, delayed puberty, hirsutism, virilisation, irregular menstrual cycle in adolescence and infertility due to anovulation.<ref name="Momodu">{{Cite journal|last1=Momodu|first1=Ifeanyi|last2=Lee|first2=Brian|last3=Singh|first3=Gurdeep|date=2021-02-05|title=Congenital Adrenal Hyperplasia|url=https://www.statpearls.com/ArticleLibrary/viewarticle/17229|journal=StatPearls|language=en}}</ref>
In XY chromosome fetuses, excess androgens result in a functional and average-sized penis with extreme virilisation, but the inability for sperm production.<ref>{{Cite journal|last=Witchel|first=Selma Feldman|date=April 2018|title=Disorders of sex development|journal=Best Practice & Research Clinical Obstetrics & Gynaecology|language=en|volume=48|pages=90–102|doi=10.1016/j.bpobgyn.2017.11.005|pmc=5866176|pmid=29503125}}</ref> Additionally, the individual will also experience early and rapid growth of pubic hair during childhood and precocious puberty stages.<ref name="Momodu"/>
==Causes== 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.<ref>{{Cite web|last=Rogers|first=Kara|date=2016-12-05|title=Endocrine disruptor {{!}} biochemistry|url=https://www.britannica.com/science/endocrine-disruptor|access-date=2021-04-13|website=Encyclopedia Britannica|language=en}}</ref> The general causes of sexual anomalies can not be outlined due to the high variability of each individual's situations. Thus, the cause of each specific anomaly has to be studied independently.
Sexual differentiation occurs through various processes during the prenatal development period of the fetus. These processes are initiated and regulated by biological metabolites such as DNA, hormones and proteins. 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.<ref>{{Cite journal|last1=Peinkofer|first1=Gabriel|last2=Burkert|first2=Karsten|last3=Urban|first3=Katja|last4=Krausgrill|first4=Benjamin|last5=Hescheler|first5=Jürgen|last6=Saric|first6=Tomo|last7=Halbach|first7=Marcel|date=2016|title=From Early Embryonic to Adult Stage: Comparative Study of Action Potentials of Native and Pluripotent Stem Cell-Derived Cardiomyocytes|url=https://www.liebertpub.com/doi/10.1089/scd.2016.0073|journal=Stem Cells and Development|language=en|volume=25|issue=19|pages=1397–1406|doi=10.1089/scd.2016.0073|pmid=27484788 |issn=1547-3287|url-access=subscription}}</ref> Differentiation of the gonads begins after the 6th week, which is determined by the sex-determining region Y (SRY) gene in the Y chromosome.<ref name=":0a"/>
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. These malformations can occur any time during the development or the birth of the embryo, manifesting as ambiguous genitals or dissonance within the genotypic and phenotypic sex of the individual, leading to a late onset of puberty, amenorrhea, a lack of or excess virilization, or later in life, infertility or early occurrence of menopause.<ref>{{Cite journal|last1=Pal|first1=AsokeK|last2=Ambulkar|first2=PrafullaS|last3=Sontakke|first3=BharatR|last4=Talhar|first4=ShwetaS|last5=Bokariya|first5=Pradeep|last6=Gujar|first6=VijayK|date=2019|title=A study on chromosomal analysis of patients with primary amenorrhea|journal=Journal of Human Reproductive Sciences|language=en|volume=12|issue=1|pages=29–34|doi=10.4103/jhrs.JHRS_125_17|issn=0974-1208|pmc=6472206|pmid=31007464 |doi-access=free }}</ref>
=== Chromosomal variation === [[File:Klinefelter's_syndrome.jpg|thumb|'''The symptoms of Klinefelter's syndrome in a human male.''']] DSDs caused by chromosomal variation generally do not present with genital ambiguity. This includes sex chromosome DSDs such as Klinefelter syndrome, Turner syndrome and 45,X or 46,XY gonadal dysgenesis.<ref name="Witchel 2018 90–102">{{Cite journal|last=Witchel|first=Selma Feldman|date=2018|title=Disorders of sex development|journal=Best Practice & Research Clinical Obstetrics & Gynaecology|language=en|volume=48|pages=90–102|doi=10.1016/j.bpobgyn.2017.11.005|pmc=5866176|pmid=29503125}}</ref>
Males with Klinefelter syndrome usually have a karyotype of 47,XXY as a result of having two or more X chromosomes.<ref name=":132">{{Cite web|title=Klinefelter syndrome - Symptoms and causes|url=https://www.mayoclinic.org/diseases-conditions/klinefelter-syndrome/symptoms-causes/syc-20353949|access-date=2021-04-01|website=Mayo Clinic|language=en}}</ref> Affected patients generally have normal genital development, yet are infertile and have small, poor functioning testes, breast growth and delayed puberty.<ref name=":132" /> The incidence for 47,XXY is 1 in 500 males, but severe and rare cases of Klinefelter syndrome presents as three or more X chromosomes.<ref name=":132" />
Turner syndrome is classified as aneuploidy or structural rearrangement of the X chromosome. Signs and symptoms of affected females vary among them, such as low birth weight, low-set ears, short stature, short neck and delayed puberty.<ref>{{Cite journal|last1=Gravholt|first1=Claus H|last2=Andersen|first2=Niels H|last3=Conway|first3=Gerard S|last4=Dekkers|first4=Olaf M|last5=Geffner|first5=Mitchell E|last6=Klein|first6=Karen O|last7=Lin|first7=Angela E|last8=Mauras|first8=Nelly|last9=Quigley|first9=Charmian A|last10=Rubin|first10=Karen|last11=Sandberg|first11=David E|date=2017|title=Clinical practice guidelines for the care of girls and women with Turner syndrome: proceedings from the 2016 Cincinnati International Turner Syndrome Meeting|url=https://eje.bioscientifica.com/view/journals/eje/177/3/EJE-17-0430.xml|journal=European Journal of Endocrinology|volume=177|issue=3|pages=G1–G70|doi=10.1530/EJE-17-0430|pmid=28705803 |issn=0804-4643|doi-access=free}}</ref> The incidence is 1 in 2,500 live-born females, while most patients do not survive for more than one year after birth.<ref name="Witchel 2018 90–102"/>
=== Gonadal development disorders === Gonadal development disorders form a wide spectrum, classified by their cytogenetic and histopathological features. However, unsolved diagnosis and malignancy still represent difficulties in the sex determination of these patients.<ref>{{Cite journal|last1=Wolffenbuttel|first1=K. P.|last2=Hersmus|first2=R.|last3=Stoop|first3=H.|last4=Biermann|first4=K.|last5=Hoebeke|first5=P.|last6=Cools|first6=M.|last7=Looijenga|first7=L. H. J.|date=2016-12-12|title=Gonadal dysgenesis in disorders of sex development: Diagnosis and surgical management|journal=Journal of Pediatric Urology|volume=12|issue=6|pages=411–416|doi=10.1016/j.jpurol.2016.08.015|issn=1873-4898|pmid=27769830}}</ref> Such disorders include partial or complete gonadal dysgenesis, ovotesticular DSD, testicular DSD and sex reversal.<ref name=":332" />
=== Abnormal genital development === Genital abnormality can occur in the penis, scrotum or testes in males; and vagina and labia in females.<ref name=":332" /> Sometimes, ambiguous genitalia could occur, where the clear distinction of external genitalia is absent in both male and female. Hence, examination (typically at birth) is carried out where the sex of the patient will be determined through imaging and blood tests.<ref name=":332" /> Abnormal genital development includes disorders of fetal origin, disorders in androgen synthesis or action, disorders in anti-Müllerian hormone synthesis or action.<ref name=":332" />
=== Others === In addition to the aforementioned sexual anomalies, there are other unclassified sexual anomalies. In males, this includes severe early-onset intrauterine growth restriction, isolated hypospadias, congenital hypogonadotropic hypogonadism, hypogonadism and cryptorchidism. In females, this includes Malformation syndromes, Müllerian agenesis/hypoplasia, uterine anomalies, vaginal atresia and labial adhesions.<ref name=":332" />
== Conditions == * 5α-reductase deficiency (5-ARD) – an autosomal recessive condition caused by a mutation of the 5-alpha reductase type 2 gene. It only affects people with Y chromosomes, namely genetic males. People with this condition are fertile, with the ability to father children, but may be raised as females due to ambiguous or feminized genitalia.<ref>{{Citation |last1=Kumar |first1=Gopi |title=5 Alpha Reductase Deficiency |date=2022 |url=https://www.ncbi.nlm.nih.gov/books/NBK539904/ |work=StatPearls |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=30969726 |access-date=2023-01-20 |last2=Barboza-Meca |first2=Joshuan J.}}</ref><ref>{{Citation |last1=Taplin |first1=Craig E. |title=Chapter 42 - Disorders of Sexual Differentiation |date=2009-01-01 |url=https://www.sciencedirect.com/science/article/pii/B9780323058858000428 |work=Endocrine Secrets (Fifth Edition) |pages=351–361 |editor-last=McDermott |editor-first=Michael T. |place=Philadelphia |publisher=Mosby |language=en |isbn=978-0-323-05885-8 |access-date=2023-01-20 |last2=Slover |first2=Robert H.}}</ref> * 17β-Hydroxysteroid dehydrogenase deficiency – a condition characterized by impaired androgen and estrogen synthesis in males and females, respectively. Results in pseudohermaphroditism/undervirilization in males.<ref>{{Cite journal |last1=Faienza |first1=M. F. |last2=Baldinotti |first2=F. |last3=Marrocco |first3=G. |last4=TyuTyusheva |first4=N. |last5=Peroni |first5=D. |last6=Baroncelli |first6=G. I. |last7=Bertelloni |first7=S. |year=2020 |title=17β-hydroxysteroid dehydrogenase type 3 deficiency: female sex assignment and follow-up |journal=Journal of Endocrinological Investigation |volume=43 |issue=12 |pages=1711–1716 |doi=10.1007/s40618-020-01248-y |issn=1720-8386 |pmid=32297288|s2cid=215775031 }}</ref><ref>{{Cite journal |last1=Yang |first1=Zuwei |last2=Ye |first2=Lei |last3=Wang |first3=Wei |last4=Zhao |first4=Yu |last5=Wang |first5=Wencui |last6=Jia |first6=Huiying |last7=Dong |first7=Zhiya |last8=Chen |first8=Yuhong |last9=Wang |first9=Weiqing |last10=Ning |first10=Guang |last11=Sun |first11=Shouyue |date=2017-10-29 |title=17β-Hydroxysteroid dehydrogenase 3 deficiency: Three case reports and a systematic review |journal=The Journal of Steroid Biochemistry and Molecular Biology |volume=174 |pages=141–145 |doi=10.1016/j.jsbmb.2017.08.012 |issn=1879-1220 |pmid=28847746|s2cid=33621139 }}</ref> * 46,XX/46,XY – a chimeric condition where the person shows variable karyotype in the 23rd chromosome pair, resulting from embryonic merging.<ref>{{Cite journal|vauthors=Kawamura, R, Kato, T, Miyai, S, et al.|date=2020|title=A case of a parthenogenetic 46,XX/46,XY chimera presenting ambiguous genitalia|journal=J Hum Genet|volume=65|issue=8 |pages=705–709|doi=10.1038/s10038-020-0748-4|pmid=32277176 |pmc=7324356}}</ref> It can vary in presentation from phenotypically normal, to ambiguous.<ref>{{Cite journal|last1=Schoenle|first1=E|last2=Schmid|first2=W|last3=Schinzel|first3=A|last4=Mahler|first4=M|last5=Ritter|first5=M|last6=Schenker|first6=T|last7=Metaxas|first7=M|last8=Froesch|first8=P|last9=Froesch|first9=ER|date=1983|title=46,XX/46,XY chimerism in a phenotypically normal man|journal=Hum Genet|volume=64|issue=1|pages=86–9|doi=10.1007/BF00289485|pmid=6575956}}</ref> * Androgen insensitivity syndrome (AIS) – a condition which affects a genetic male's virilization. A person with androgen insensitivity syndrome produces androgens and testosterone but their body does not recognize it, either partially or completely. Mild androgen insensitivity syndrome generally causes no developmental issues and people with this form are raised as males.<ref>{{Cite web |title=Partial androgen insensitivity syndrome - NIH Genetic Testing Registry (GTR) - NCBI |url=https://www.ncbi.nlm.nih.gov/gtr/conditions/C0268301/ |access-date=2023-01-20 |website=ncbi.nlm.nih.gov}}</ref> Partial androgen insensitivity syndrome results in ambiguous genitalia and there is no consensus regarding whether to raise a child with this form as male or female. Complete androgen insensitivity syndrome causes a genetic male to have a vagina (often incompletely developed, nearly always blind-ending), breasts, and a clitoris; people with this form are raised as females.<ref>{{Cite journal |last=Mazur |first=Tom |year=2005 |title=Gender dysphoria and gender change in androgen insensitivity or micropenis |journal=Archives of Sexual Behavior |volume=34 |issue=4 |pages=411–421 |doi=10.1007/s10508-005-4341-x |issn=0004-0002 |pmid=16010464|s2cid=26471278 |citeseerx=10.1.1.586.7462 }}</ref> * Aphallia – a rare condition where a XY male is born without a penis. As of 2017, only 100 cases have been reported in literature.<ref>{{cite book| vauthors = Legato MJ |url=https://books.google.com/books?id=khATDgAAQBAJ&pg=PA38 |title=Principles of Gender-Specific Medicine: Gender in the Genomic Era|date=2017-05-15|publisher=Academic Press|isbn=978-0-12-803542-9|page=38|language=en|author-link=Marianne Legato}}</ref> * Aromatase deficiency – a disorder which, in females, is characterized by androgen excess and estrogen deficiency, and can result in inappropriate virilization, though without pseudohermaphroditism (i.e., genitals are phenotypically appropriate) (with the exception of the possible incidence of clitoromegaly). Aromatase deficiency can also be caused by mutations in P450 oxidoreductase gene.<ref>{{cite journal | vauthors = Parween S, Fernández-Cancio M, Benito-Sanz S, Camats N, Rojas Velazquez MN, López-Siguero JP, Udhane SS, Kagawa N, Flück CE, Audí L, Pandey AV | display-authors = 6 | title = Molecular Basis of CYP19A1 Deficiency in a 46,XX Patient With R550W Mutation in POR: Expanding the PORD Phenotype | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 105 | issue = 4 | pages = e1272–e1290 | date = April 2020 | pmid = 32060549 | doi = 10.1210/clinem/dgaa076 | doi-access = free | hdl = 10668/15112 | hdl-access = free }}</ref> * Aromatase excess syndrome (familial hyperestrogenism) - a condition that causes excessive estrogen production, resulting in feminization without pseudohermaphroditism (i.e., male genitalia at birth and female secondary sexual characteristics at puberty) in males and hyperfeminization in females.<ref>{{Cite journal |last=Styne |first=Dennis M. |title=Physiology and Disorders of Puberty |journal=Williams Textbook of Endocrinology |volume=25 |issue=1}}</ref> * Campomelic dysplasia – a condition caused by ''de novo'' autosomal dominant mutations in the SOX9 gene, causing bowing of the limbs, sex reversal in around two thirds of 46,XY males (but not in 46,XX females), and respiratory insufficiency. While in roughly 95% of cases, death occurs in the neonatal period due to respiratory distress, those that live past infancy typically survive to become adults.<ref>{{Citation |last1=Unger |first1=Sheila |title=Campomelic Dysplasia |date=1993 |url=https://www.ncbi.nlm.nih.gov/books/NBK1760/ |work=GeneReviews® |editor-last=Adam |editor-first=Margaret P. |place=Seattle (WA) |publisher=University of Washington, Seattle |pmid=20301724 |access-date=2023-01-20 |last2=Scherer |first2=Gerd |last3=Superti-Furga |first3=Andrea |editor2-last=Everman |editor2-first=David B. |editor3-last=Mirzaa |editor3-first=Ghayda M. |editor4-last=Pagon |editor4-first=Roberta A.}}</ref> * Clitoromegaly – a clitoris that is considered larger than average. While clitoromegaly may be a symptom of an intersex condition, it may also be considered a normal variation in clitoris size. Clitoromegaly causes no health issues. Surgical reduction of the clitoris or its complete removal may be performed to normalize the appearance of the genitalia. While female genital mutilation is outlawed in many countries, reduction or the removal of the clitoris in cases of clitoromegaly are generally exempt, despite the fact that it is a nontherapeutic and sexually damaging surgery. Clitoromegaly may also be caused by females using testosterone or anabolic steroids for purposes related to female to male gender transition or bodybuilding. * Combined 17α-hydroxylase/17,20-lyase deficiency – a condition which presents as a combination of the symptoms of congenital adrenal hyperplasia and isolated 17,20-lyase deficiency. See those two conditions for more information.<ref>{{Cite journal |last1=Ma |first1=Lizhen |last2=Peng |first2=Fengying |last3=Yu |first3=Lingying |last4=Chen |first4=Jun |last5=Ji |first5=Weiqin |last6=Zhang |first6=Chu |last7=Zhang |first7=Xianfeng |date=2016 |title=Combined 17α-hydroxylase/17,20-lyase deficiency with short stature: case study |journal=Gynecological Endocrinology|volume=32 |issue=4 |pages=264–266 |doi=10.3109/09513590.2015.1116506 |issn=1473-0766 |pmid=26607998|s2cid=29440749 }}</ref> * Complete androgen insensitivity syndrome (CAIS) – a condition which completely affects a genetic male's ability to recognize androgens. It is considered a form of androgen insensitivity syndrome and is the most severe form. People with complete androgen insensitivity are raised as females and usually do not discover they are genetic males until they experience amenorrhoea in their late teens or they need medical intervention due to a hernia caused by their undescended testes.<ref>{{Cite journal |last1=Gîngu |first1=Constantin |last2=Dick |first2=Alexandru |last3=Pătrăşcoiu |first3=Sorin |last4=Domnişor |first4=Liliana |last5=Mihai |first5=Mihaela |last6=Hârza |first6=Mihai |last7=Sinescu |first7=Ioanel |date=2014 |title=Testicular feminization: complete androgen insensitivity syndrome. Discussions based on a case report |journal=Romanian Journal of Morphology and Embryology = Revue Roumaine de Morphologie et Embryologie |volume=55 |issue=1 |pages=177–181 |issn=2066-8279 |pmid=24715185}}</ref><ref>{{Cite web |title=Complete androgen insensitivity syndrome - About the Disease - Genetic and Rare Diseases Information Center |url=https://rarediseases.info.nih.gov/diseases/10597/complete-androgen-insensitivity-syndrome |access-date=2023-01-20 |website=rarediseases.info.nih.gov |language=en}}</ref> Complete androgen insensitivity syndrome results in a genetic male having a vagina, clitoris, and breasts which are capable of breastfeeding. However, they will not have ovaries or a uterus. Because they do not have ovaries or sufficiently developed testicles, people with complete androgen insensitivity syndrome are infertile.<ref>{{Citation |last1=Gottlieb |first1=Bruce |title=Androgen Insensitivity Syndrome |date=1993 |url=https://www.ncbi.nlm.nih.gov/books/NBK1429/ |work=GeneReviews® |editor-last=Adam |editor-first=Margaret P. |place=Seattle (WA) |publisher=University of Washington, Seattle |pmid=20301602 |access-date=2023-01-20 |last2=Trifiro |first2=Mark A. |editor2-last=Everman |editor2-first=David B. |editor3-last=Mirzaa |editor3-first=Ghayda M. |editor4-last=Pagon |editor4-first=Roberta A.}}</ref> * Congenital adrenal hyperplasia (CAH) – a condition that causes excessive androgen production, which causes excessive virilization. It is most problematic in genetic females, where severe virilization can result in fusion of the labia and an enlarged clitoris.<ref>{{Citation |last1=Momodu |first1=Ifeanyi I. |title=Congenital Adrenal Hyperplasia |date=2022 |url=https://www.ncbi.nlm.nih.gov/books/NBK448098/ |work=StatPearls |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=28846271 |access-date=2023-01-20 |last2=Lee |first2=Brian |last3=Singh |first3=Gurdeep}}</ref><ref>{{Cite journal |last1=Pignatelli |first1=Duarte |last2=Pereira |first2=Sofia S. |last3=Pasquali |first3=Renato |date=2019 |title=Androgens in Congenital Adrenal Hyperplasia |journal=Frontiers of Hormone Research |volume=53 |pages=65–76 |doi=10.1159/000494903 |issn=1662-3762 |pmid=31499506|isbn=978-3-318-06470-4 |s2cid=202412336 }}</ref> Females with this condition are usually fertile, with the ability to become pregnant and give birth. The salt-wasting variety of this condition is fatal in infants if left untreated.<ref>{{Cite journal |last1=Claahsen-van der Grinten |first1=H. L. |last2=Stikkelbroeck |first2=N. M. M. L. |last3=Sweep |first3=C. G. J. |last4=Hermus |first4=A. R. M. M. |last5=Otten |first5=B. J. |date=2006-05-01 |title=Fertility in patients with congenital adrenal hyperplasia |journal=Journal of Pediatric Endocrinology & Metabolism |volume=19 |issue=5 |pages=677–685 |doi=10.1515/jpem.2006.19.5.677 |issn=0334-018X |pmid=16789634|hdl=2066/49346 |s2cid=14683441 |hdl-access=free }}</ref> * Denys–Drash syndrome and the related Frasier syndrome – similar rare conditions arising from ''de novo'' autosomal dominant mutations in the WT1 gene, causing symptoms ranging from undervirilization to complete sex reversal with persistent Müllerian ducts in affected 46,XY males (but not in 46,XX females).<ref>{{Citation |last1=Lin |first1=Fangming |title=Chapter 27 - Renal Dysgenesis |date=2009-01-01 |url=https://www.sciencedirect.com/science/article/pii/B9780124498518000279 |work=Genetic Diseases of the Kidney |pages=463–493 |editor-last=Lifton |editor-first=Richard P. |place=San Diego |publisher=Academic Press |language=en |isbn=978-0-12-449851-8 |access-date=2023-01-20 |last2=Patel |first2=Vishal |last3=Igarashi |first3=Peter |editor2-last=Somlo |editor2-first=Stefan |editor3-last=Giebisch |editor3-first=Gerhard H. |editor4-last=Seldin |editor4-first=Donald W.}}</ref> The disorders are invariably fatal before the age of 15, causing kidney failure due to nephrotic syndrome.<ref>{{Cite journal |last=Donohoue |first=Patricia A. |year=2022 |title=Disorders of Sex Development |journal=Nelson Textbook of Pediatrics |volume=21 |issue=1 |pages=3008–3019}}</ref> * Estrogen insensitivity syndrome (EIS) – the estrogen counterpart to androgen insensitivity syndrome. Extremely rare, with only one verified case having been reported; a biological male presented with tall stature, a heightened risk of osteoporosis, and sterility.<ref>{{Cite journal |last1=Li |first1=Yin |last2=Hamilton |first2=Katherine J. |last3=Perera |first3=Lalith |last4=Wang |first4=Tianyuan |last5=Gruzdev |first5=Artiom |last6=Jefferson |first6=Tanner B. |last7=Zhang |first7=Austin X. |last8=Mathura |first8=Emilie |last9=Gerrish |first9=Kevin E. |last10=Wharey |first10=Laura |last11=Martin |first11=Negin P. |last12=Li |first12=Jian-Liang |last13=Korach |first13=Kenneth S. |date=2020-06-01 |title=ESR1 Mutations Associated With Estrogen Insensitivity Syndrome Change Conformation of Ligand-Receptor Complex and Altered Transcriptome Profile |journal=Endocrinology |volume=161 |issue=6 |article-number=bqaa050 |doi=10.1210/endocr/bqaa050 |issn=1945-7170 |pmc=7947601 |pmid=32242619}}</ref> * Gartner's duct cyst – persistent Wolffian Ducts in XX females. * Gonadal dysgenesis – any congenital developmental disorder of the reproductive system characterized by a progressive loss of primordial germ cells on the developing gonads of an embryo. * Herlyn-Werner-Wunderlich syndrome – a disorder where the Müllerian ducts fail to fuse during embryonic development, leading to the presence of 2 vaginas, 2 uteruses, and a single kidney. Can also affect the spleen, bladder and other urogenital structures.<ref>{{Cite journal |last1=Hayat |first1=Abdul Malik |last2=Yousaf |first2=Khalid Rehman |last3=Chaudhary |first3=Saman |last4=Amjad |first4=Sohaib |date=2022-03-02 |title=The Herlyn-Werner-Wunderlich (HWW) syndrome - A case report with radiological review |journal=Radiology Case Reports |volume=17 |issue=5 |pages=1435–1439 |doi=10.1016/j.radcr.2022.02.017 |issn=1930-0433 |pmc=8899131 |pmid=35265236}}</ref><ref>{{Cite journal |last1=Horst |first1=Wagner |last2=de Melo |first2=Rafael Cardoso |last3=Theilacker |first3=Giulia |last4=Schmitt |first4=Betina |date=2021-03-04 |title=Herlyn-Werner-Wunderlich syndrome: clinical considerations and management |journal=BMJ Case Reports |volume=14 |issue=3 |article-number=e239160 |doi=10.1136/bcr-2020-239160 |issn=1757-790X |pmc=7934712 |pmid=33664029}}</ref> * Isolated 17,20-lyase deficiency – a condition that is characterized by either partial or complete inability to produce androgens and estrogens.<ref name="Miller_2012">{{cite journal | vauthors = Miller WL | title = The syndrome of 17,20 lyase deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 97 | issue = 1 | pages = 59–67 | date = January 2012 | pmid = 22072737 | pmc = 3251937 | doi = 10.1210/jc.2011-2161 }}</ref> Results in partial or complete feminization and undervirilization in males and in a delayed, reduced, or absent puberty in both sexes, in turn causing sexual infantilism and infertility, among other symptoms.<ref>{{Cite journal |last1=Bjerke |first1=D. L. |last2=Brown |first2=T. J. |last3=MacLusky |first3=N. J. |last4=Hochberg |first4=R. B. |last5=Peterson |first5=R. E. |date=2002-05-25 |title=Partial demasculinization and feminization of sex behavior in male rats by in utero and lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin is not associated with alterations in estrogen receptor binding or volumes of sexually differentiated brain nuclei |journal=Toxicology and Applied Pharmacology |volume=127 |issue=2 |pages=258–267 |doi=10.1006/taap.1994.1160 |issn=0041-008X |pmid=8048069|doi-access=free }}</ref> * Klinefelter syndrome (47,XXY and XXY syndrome) – a condition that describes a male born with at least one extra X chromosome. Though the most common variation is 47,XXY, a man may also be 48,XXXY or 49,XXXXY. It is a common occurrence, affecting 1 in 500 to 1,000 men.<ref name="The Focus Foundation">{{cite web | work = The Focus Foundation. | title = X & Y Variations | url = http://www.thefocusfoundation.org/FF/XYvariations.php | archive-url = https://archive.today/20130113082846/http://www.thefocusfoundation.org/FF/XYvariations.php| archive-date= 13 January 2013 }}</ref> About 1 in 50,000 men are affected by variant 48,XXXY (Two extra X) and 1 in 100,000 men affected by variant 49,XXXXY (Three extra X).<ref>{{Cite web |date=2016-12-01 |title=How many people are affected by or at risk for Klinefelter syndrome (KS)? {{!}} NICHD - Eunice Kennedy Shriver National Institute of Child Health and Human Development |url=https://www.nichd.nih.gov/health/topics/klinefelter/conditioninfo/risk |access-date=2023-07-17 |website=www.nichd.nih.gov |language=en}}</ref> While some men may have no issues related to the syndrome, some may experience gynecomastia, micropenis, cognitive difficulties, hypogonadism, reduced fertility/infertility, and/or little or no facial hair. Testosterone therapy may be pursued by men who desire a more masculine appearance and those with gynecomastia may opt to undergo a reduction mammoplasty. Men who wish to father children may be able to do so with the help of IVF.<ref>{{cite journal | vauthors = Fullerton G, Hamilton M, Maheshwari A | title = Should non-mosaic Klinefelter syndrome men be labelled as infertile in 2009? | journal = Human Reproduction | volume = 25 | issue = 3 | pages = 588–97 | date = March 2010 | pmid = 20085911 | doi = 10.1093/humrep/dep431 | doi-access = free }}</ref><ref name="lee" /><ref name="2016dsd" /> * Leydig cell hypoplasia – a condition solely affecting biological males which is characterized by partial or complete inactivation of the luteinizing hormone receptor, resulting in stymied androgen production. Patients may present at birth with a fully female phenotype, ambiguous genitalia, or only mild genital defects such as micropenis and hypospadias. Upon puberty, sexual development is either impaired or fully absent.<ref>{{Citation |last=Kolon |first=Thomas F. |title=CHAPTER 25 - Disorders of Sexual Development |date=2007-01-01 |url=https://www.sciencedirect.com/science/article/pii/B9781416038481100257 |work=Penn Clinical Manual of Urology |pages=827–852 |editor-last=Hanno |editor-first=Philip M. |place=Philadelphia |publisher=W.B. Saunders |language=en |isbn=978-1-4160-3848-1 |access-date=2023-01-20 |editor2-last=Malkowicz |editor2-first=S. Bruce |editor3-last=Wein |editor3-first=Alan J.}}</ref><ref>{{Cite journal |last1=Jahan |first1=Sharmin |last2=Abul Hasanat |first2=Muhammad |last3=Alam |first3=Fakhrul |last4=Fariduddin |first4=Mohammad |last5=Tofail |first5=Tania |title=Leydig Cell Hypoplasia: A Unique Paradox in the Diagnosis of 46,XY Disorders of Sex Development |date=2020 |journal=AACE Clinical Case Reports |volume=6 |issue=3 |pages=e117–e122 |doi=10.4158/ACCR-2019-0152 |issn=2376-0605 |pmc=7282282 |pmid=32524024}}</ref> * Lipoid congenital adrenal hyperplasia – an endocrine disorder that arises from defects in the earliest stages of steroid hormone synthesis: the transport of cholesterol into the mitochondria and the conversion of cholesterol to pregnenolone—the first step in the synthesis of all steroid hormones.<ref>{{Cite journal |last=Kim |first=Chan Jong |date=2014-12-31 |title=Congenital lipoid adrenal hyperplasia |journal=Annals of Pediatric Endocrinology & Metabolism |volume=19 |issue=4 |pages=179–183 |doi=10.6065/apem.2014.19.4.179 |issn=2287-1012 |pmc=4316413 |pmid=25654062}}</ref><ref>{{Cite journal |last1=Chen |first1=Hong |last2=Zhang |first2=Qianru |last3=Chen |first3=Ruimin |last4=Yuan |first4=Xin |last5=Lin |first5=Xiangquan |last6=Yang |first6=Xiaohong |last7=Zhang |first7=Ying |date=2020-03-12 |title=Lipoid congenital adrenal hyperplasia due to steroid acute regulatory protein (STAR) variants in Three Chinese patients |journal=The Journal of Steroid Biochemistry and Molecular Biology |volume=200 |article-number=105635 |doi=10.1016/j.jsbmb.2020.105635 |issn=1879-1220 |pmid=32068072|s2cid=211116603 }}</ref> * Mild androgen insensitivity syndrome (MAIS) – a condition which mildly affects a genetic male's ability to recognize androgens. It is considered a form of androgen insensitivity syndrome and is considered the least severe form. While men generally do not need any specialized medical care related to this form, mild androgen insensitivity syndrome may result in gynecomastia and hypospadias. Neither gynecomastia nor hypospadias require surgical intervention or adversely affect a man's health though some men may opt to undergo surgery to remove their breasts and/or repair their hypospadias. Men with mild androgen insensitivity syndrome may have reduced fertility. * Mixed gonadal dysgenesis – a condition of unusual and asymmetrical gonadal development leading to an unassigned sex differentiation. A number of differences have been reported in the karyotype, most commonly a mosaicism 45,X/ 46,XY.<ref>{{Cite journal |last1=Ostrow |first1=Vlady |last2=De Luca |first2=Francesco |year=2009 |title=Long term follow-up of a child with ambiguous genitalia, mixed gonadal dysgenesis, and unusual mosaicism |journal=Journal of Pediatric Endocrinology & Metabolism |volume=22 |issue=9 |pages=863–866 |doi=10.1515/jpem.2009.22.9.863 |issn=0334-018X |pmid=19960897|s2cid=11040976 }}</ref> * Ovotesticular disorder (also called true hermaphroditism) – a rare condition where an individual has both ovarian and testicular tissue.<ref name=":0">{{cite book| vauthors = Nistal M, González-Peramato P, Serrano Á |url=https://books.google.com/books?id=Xi9IDgAAQBAJ&q=Ovotesticular+disorder+disorders+of+sex+development |title=Clues in the Diagnosis of Non-tumoral Testicular Pathology|date=2017-03-07|publisher=Springer|isbn=978-3-319-49364-0|page=33|language=en}}</ref> It is the rarest DSD with at least 500 cases being reported in literature.<ref>{{cite web|title=Ovotesticular Disorder of Sex Development|url=https://rarediseases.org/rare-diseases/ovotesticular-disorder-of-sex-development/|access-date=2021-08-01 | work = Rare Disease Database | publisher = National Organization for Rare Disorders (NORD) |language=en-US}}</ref> * Partial androgen insensitivity syndrome (PAIS) – a condition which partially affects a genetic male's ability to recognize androgens. It is considered a form of androgen insensitivity syndrome and while it is not as severe as complete androgen insensitivity syndrome, it is more severe than mild androgen insensitivity syndrome.<ref>{{Cite journal |last1=Vaidyanathan |first1=Priya |last2=Kaplowitz |first2=Paul |date=2018 |title=Partial androgen insensitivity syndrome presenting as pubertal gynecomastia: clinical and hormonal findings and a novel mutation in the androgen receptor gene |journal=Endocrinology, Diabetes & Metabolism Case Reports |volume=2018 |pages=18–0128, EDM180128 |doi=10.1530/EDM-18-0128 |issn=2052-0573 |pmc=6311465 |pmid=30601762}}</ref> Partial androgen insensitivity syndrome causes major problems with gender assignment because it causes ambiguous genitalia such as a micropenis or clitoromegaly in addition to breast development. People with partial androgen insensitivity syndrome who are assigned as males may undergo testosterone therapy to virilize their body while those who are assigned as females may undergo a surgical reduction of the clitoris and/ or estrogen therapy.<ref>{{Cite journal |last1=Hellmann |first1=Philip |last2=Christiansen |first2=Peter |last3=Johannsen |first3=Trine Holm |last4=Main |first4=Katharina M. |last5=Duno |first5=Morten |last6=Juul |first6=Anders |date=2012-04-22 |title=Male patients with partial androgen insensitivity syndrome: a longitudinal follow-up of growth, reproductive hormones and the development of gynaecomastia |journal=Archives of Disease in Childhood |volume=97 |issue=5 |pages=403–409 |doi=10.1136/archdischild-2011-300584 |issn=1468-2044 |pmid=22412043|s2cid=6532237 }}</ref> * Penoscrotal transposition (PST) – a group of congenital defects involving an abnormal spatial arrangement of penis and scrotum. * Persistent Müllerian duct syndrome – a condition where fallopian tubes, uterus, or the upper part of the vagina are present in an otherwise normal male.<ref>{{Citation |last=Al-Salem |first=Ahmed H. |title=Persistent Müllerian Duct Syndrome (Hernia Uteri Inguinalis) |date=2020 |work=Atlas of Pediatric Surgery: Principles and Treatment |pages=773–776 |editor-last=Al-Salem |editor-first=Ahmed H. |place=Cham |publisher=Springer International Publishing |language=en |doi=10.1007/978-3-030-29211-9_74 |isbn=978-3-030-29211-9 |s2cid=213274311 }}</ref> * Pseudovaginal perineoscrotal hypospadias (PPSH) – a form of ambiguous genitalia which results in a phallic structure that is smaller than a penis but larger than a clitoris, a chordee, hypospadias, and a shallow vagina.<ref>{{Cite journal |last1=Simpson |first1=J. L. |last2=New |first2=M. |last3=Peterson |first3=R. E. |last4=German |first4=J. |year=1971 |title=Pseudovaginal perineoscrotal hypospadias (PPSH) in sibs |journal=Birth Defects Original Article Series |volume=7 |issue=6 |pages=140–144 |issn=0547-6844 |pmid=5173156}}</ref> * Swyer syndrome (Pure Gonadal Dysgenesis or XY gonadal dysgenesis) – a type of hypogonadism in a person whose karyotype is 46,XY. The person is externally female with streak gonads, and left untreated, will not experience puberty. Such gonads are typically surgically removed (as they have a significant risk of developing tumors) and a typical medical treatment would include hormone replacement therapy with female hormones.<ref>{{Cite web |title=Pure gonadal dysgenesis 46,XY - NIH Genetic Testing Registry (GTR) - NCBI |url=https://www.ncbi.nlm.nih.gov/gtr/conditions/C2936694/ |access-date=2023-01-20 |website=www.ncbi.nlm.nih.gov}}</ref><ref>{{Cite journal |last1=Malhotra |first1=Neena |last2=Dadhwal |first2=Vatsla |last3=Sharma |first3=Kandala Aparna |last4=Gupta |first4=Deepika |last5=Agarwal |first5=Sumita |last6=Deka |first6=Dipika |date=2015 |title=The laparoscopic management of Swyer syndrome: Case series |journal=Journal of the Turkish German Gynecological Association |volume=16 |issue=4 |pages=252–256 |doi=10.5152/jtgga.2015.15061 |issn=1309-0399 |pmc=4664218 |pmid=26692777}}</ref> * Turner syndrome (Ullrich-Turner syndrome and gonadal dysgenesis) – a condition that describes a female born with only one X chromosome or with an abnormal X chromosome, making her karotype 45,X0. It occurs in 1 in 2,000 to 5,000 females.<ref>{{Cite journal |last1=Ranke |first1=M. B. |last2=Saenger |first2=P. |date=2001-07-28 |title=Turner's syndrome |journal=Lancet |volume=358 |issue=9278 |pages=309–314 |doi=10.1016/S0140-6736(01)05487-3 |issn=0140-6736 |pmid=11498234|s2cid=42096888 }}</ref> Turner syndrome can cause numerous health and development problems, including but not limited to short stature, lymphedema, infertility, webbed neck, coarctation of the aorta, ADHD, amenorrhoea, and obesity.<ref>{{Cite journal |last1=Gravholt |first1=Claus H. |last2=Viuff |first2=Mette H. |last3=Brun |first3=Sara |last4=Stochholm |first4=Kirstine |last5=Andersen |first5=Niels H. |date=2019-05-23 |title=Turner syndrome: mechanisms and management |journal=Nature Reviews. Endocrinology |volume=15 |issue=10 |pages=601–614 |doi=10.1038/s41574-019-0224-4 |issn=1759-5037 |pmid=31213699|s2cid=190653543 }}</ref> * Müllerian agenesis (Mayer-Rokitansky-Küster-Hauser syndrome or vaginal agenesis) – a condition that causes the uterus and other reproductive organs in a 46,XX female to be small or absent, as well as the vaginal canal itself. It affects 1 out of 4,500 to 5,000 females and can also come with skeletal or endocrine system issues at conception.<ref>{{Cite journal |last=Committee on Adolescent Health Care |year=2018 |title=ACOG Committee Opinion No. 728: Müllerian Agenesis: Diagnosis, Management, And Treatment |journal=Obstetrics and Gynecology |volume=131 |issue=1 |pages=e35–e42 |doi=10.1097/AOG.0000000000002458 |issn=1873-233X |pmid=29266078|s2cid=40007152 }}</ref><ref>{{Cite journal |last1=Herlin |first1=Morten Krogh |last2=Petersen |first2=Michael Bjørn |last3=Brännström |first3=Mats |date=2020-08-20 |title=Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: a comprehensive update |journal=Orphanet Journal of Rare Diseases |volume=15 |issue=1 |page=214 |doi=10.1186/s13023-020-01491-9 |issn=1750-1172 |pmc=7439721 |pmid=32819397 |doi-access=free }}</ref> * XX testicular DSD – a condition where an individual with an XX karyotype has a male appearance. Genitalia can range from normal to ambiguous genitalia.<ref>{{cite web|title=46,XX testicular disorder of sex development|url=https://rarediseases.org/gard-rare-disease/46xx-testicular-disorder-of-sex-development/|access-date=2021-08-04| work = Rare Disease Database | publisher = National Organization for Rare Disorders (NORD) |language=en-US}}</ref> It is estimated to occur in 1 in 20,000 males.<ref>{{Citation |last1=Délot |first1=Emmanuèle C. |title=Nonsyndromic 46,XX Testicular Disorders/Differences of Sex Development |date=1993 |url=https://www.ncbi.nlm.nih.gov/books/NBK1416/ |work=GeneReviews® |editor-last=Adam |editor-first=Margaret P. |place=Seattle (WA) |publisher=University of Washington, Seattle |pmid=20301589 |access-date=2023-01-20 |last2=Vilain |first2=Eric J. |editor2-last=Everman |editor2-first=David B. |editor3-last=Mirzaa |editor3-first=Ghayda M. |editor4-last=Pagon |editor4-first=Roberta A.}}</ref>
== Diagnosis and symptoms == === First line diagnostic tests (prenatal) === thumb|236x236px|class=skin-invert-image|'''Human male karyotype'''
==== Family history ==== * Symptoms such as infertility, early menopause, amenorrhea or sudden infant death syndrome (SIDS) could be a sign. Hence, an early check-up should be conducted.<ref name=":332" />
==== Analysis of karyotype ==== * Peripheral blood is collected for karyotyping. This helps classify the patient in one of the three main categories of DSD: chromosomal variation, gonadal development disorders and abnormal genital development.<ref name=":332" />
==== Abdominal ultrasounds ==== * The presence of gonads, uterus and vagina should be monitored. This can be done through abdominal ultrasounds. However, the absence of these sex organs will lead to difficulties in gender identification.<ref name=":332" />
=== Second line diagnostic tests (postnatal) === ==== Physical examination ==== # Inspection of the genitalia with care and palpation must be conducted with the following points in mind.<ref name=":332" /> #* Determining the degree of virilization or masculinisation: #** In a female fetus, the Prader scale should be used to assess the extent of the virilisation if the karyotyping results are not out yet.<ref name=":332" /> #** In males, the external masculinization score should be used.<ref name=":332" /> # Palpation of gonads from the labioscrotal fold to the abdomen (inguinal canal).<ref name=":332" /> # Hydration and blood pressure assessment should be conducted.<ref name=":332" /> # Additional dysmorphic features should be ruled out because genitalia malformations would occur if the patient has multiple malformation syndromes.<ref name=":332" />
==== Evaluation of hormones 48 hours after birth ==== * 17-Hydroxyprogesterone can be used to screen for congenital adrenal hyperplasia (CAH). This is commonly found in patients with 46, XX DSD.<ref name=":332" /><ref name=":532">{{Cite journal|last1=Juniarto|first1=A. Zulfa|last2=van der Zwan|first2=Yvonne G.|last3=Santosa|first3=Ardy|last4=Ariani|first4=Mahayu Dewi|last5=Eggers|first5=Stefanie|last6=Hersmus|first6=Remko|last7=Themmen|first7=Axel P.N.|last8=Bruggenwirth|first8=Hennie T.|last9=Wolffenbuttel|first9=Katja P.|last10=Sinclair|first10=Andrew|last11=White|first11=Stefan J.|date=2016|title=Hormonal evaluation in relation to phenotype and genotype in 286 patients with a disorder of sex development from Indonesia|url=http://doi.wiley.com/10.1111/cen.13051|journal=Clinical Endocrinology|language=en|volume=85|issue=2|pages=247–257|doi=10.1111/cen.13051|pmid=26935236 |hdl=11343/291143 |s2cid=20604226 |hdl-access=free}}</ref> * Dehydroepiandrosterone (DHEA) in addition to progesterone allows for the diagnosis of more uncommon forms of CAH and other inherited disorders.<ref name=":332" /> * Base testosterone, follicle stimulating hormone (FSH) and luteinising hormone (LH) levels are precursors in individuals with 46,XX DSD. These tests are conducted within the timeframe of thirty hours post-birth to anywhere between fifteen and ninety days post-birth. This data collected within time frame can be used to gauge the growth of the fetus when it reaches six months of age.<ref name=":332" /><ref name=":532" /> * Basal cortisol levels and adrenocorticotropic hormone (ACTH) is essential in diagnosing panhypopituitarism and enzymatic disorders affecting adrenal steroidogenesis.<ref name=":332" /> * The anti-Müllerian hormone is used for evaluating the function of Sertoli cells.<ref name=":332" /> * A urinary steroid profile shows the ratio of precursor metabolites within measured urine concentrations and the resultant products produced indicates the enzyme is the cause of a sexual defect. This is a more specific procedure in the detection of the defect in comparison to analysing blood.<ref name=":332" />
== Treatment and management == {{main|Intersex healthcare}} The treatment and/or management of DSDs with atypical genitalia will vary from person to person. This may include gender affirmation surgery, medical treatment and surgical treatment.
=== Gender affirmation surgery === {{main|Gender affirmation surgery}}
Gender affirmation plays a critical role in the management of sexual anomaly cases. Ultimately, the parents and a multidisciplinary team are responsible for assigning the sex that is affirmative the gender of the concerned person. The current guidelines of gender affirmation include the psychosocial effects in adults with etiological diagnosis, the potential for fertility, surgical opportunities and hormone replacement therapy in the course of puberty.<ref>{{Citation |last=Mareş Miceli |first=Angelica |title=Replacement Hormone Therapy for Gender Dysphoria and Congenital Sexual Anomalies |date=2020 |work=Hormonal Pathology of the Uterus |pages=121–143 |editor-last=Deligdisch-Schor |editor-first=Liane |series=Advances in Experimental Medicine and Biology |volume=1242 |place=Cham |publisher=Springer International Publishing |language=en |doi=10.1007/978-3-030-38474-6_7 |pmid=32406031 |isbn=978-3-030-38474-6 |editor2-last=Mareş Miceli |editor2-first=Angelica}}</ref><ref name=":432" />
There are other factors considered during this process. This may include cultural and religious factors as well as the implications it has on the individual in later life. It is regulated by reference centers with groups specialised in managing cases of sexual anomalies.<ref name=":432" />
=== Medical treatment === Hormonal treatment is an accepted and standardised approach to treat different congenital sexual anomalies. Patients that are deficient in hormones produced by the adrenal glands require immediate medical attention. They are given a hormone called hydrocortisone, a form of hormone replacement therapy, with the objective to induce puberty.<ref name=":432" />
Utilizing sex steroids as hormonal therapy is deemed controversial with concerns of its duration of initiation, dosage and regimen.<ref name=":432" /> However, it is agreed amongst most clinicians that low doses of hormonal treatment should begin around the age of 11 to 12 years old and should be increased progressively.<ref name=":432" />
=== Surgical treatment === Surgical procedures are an alternative to hormonal treatment available for patients to address genital anomalies and improve the body's sexual functions. However, a common dilemma in these procedures is that they are often derived from the patient's expectation of 'normal' genitals from an aesthetic and functional standpoint. Oftentimes, this leads to extensive surgical interventions.<ref name=":632">{{Cite web|date=2020-10-22|title=Klinefelter Syndrome|url=https://www.physio-pedia.com/index.php?title=Klinefelter_Syndrome&oldid=256970|access-date=2021-04-11|website=Physiopedia|language=en}}</ref>
In most cases, surgical procedures result in permanent changes to the appearance and function of the patient's body. Therefore, the decision to proceed with this arrangement must be a joint agreement between the family and the multidisciplinary team. The most ideal situation would be to include the patient as part of the decision-making process. However, cases where surgical treatments were performed at an early age are recognised as mutilation of the body. Subsequently, it has become increasingly common to defer surgical treatments until the patient is of appropriate age to be involved in the decision-making process.<ref name=":432" />
== Organizations == === Clinical networks and organizations === ==== DSD-TRN ==== The Differences of Sex Development-Translational Research Network (DSD-TRN) is based in the United States and aims to improve DSD care across the United States.<ref>{{cite web|title=Disorders/Differences of Sex Development (DSD) - Translational Research Network | work = NIH RePORTER | publisher = National Institutes of Health, U.S. Department of Health and Human Services |url=https://reporter.nih.gov/project-details/9912798|access-date=2021-01-18 }}</ref>
==== I-DSD ==== The International-Differences of Sex Development (I-DSD) is a research organization in Europe. This organization connects medical and research centers internationally in an effort to improve clinical practice, research, and general understanding of differences of sex development.<ref>{{cite web|title=I-DSD/I-CAH/I-TS Registries|url=https://home.i-dsd.org/|access-date=2021-01-18|website=home.i-dsd.org|language=en|archive-date=2021-03-03|archive-url=https://web.archive.org/web/20210303112936/https://home.i-dsd.org/}}</ref> I-DSD regularly hosts a symposium to provide updates on current care in DSD internationally, facilitate networking for those in DSD Care, and promote high quality DSD research.<ref>{{cite news|date=2018-08-29|title=7th I-DSD Symposium 2019|url=https://home.i-cah.org/i-dsd-symposium-2019/|archive-url=https://web.archive.org/web/20200924122143/https://home.i-cah.org/i-dsd-symposium-2019/|archive-date=September 24, 2020|access-date=2021-01-18|website=I-CAH|language=en}}</ref>
=== Patient support and advocacy organizations === {{Main|Intersex civil society organizations}}
{{transcluded section|Intersex civil society organizations}} Notable patient support and advocacy organizations include: {{#section:Intersex civil society organizations|bycountry}}
==Controversy== Even though the term disorder of sex development (DSD) is widely accepted by the medical community, its suitability and adequacy to represent these individuals are criticised by many support and advocacy groups. Firstly, the word 'disorder' carries negative connotations. Secondly, with current nomenclature, DSD is an overly generalised term for conditions that do not have differences in genital appearance or gender identity (e.g. Klinefelter syndrome and Turner syndrome). Thirdly, the term 'DSD' lacks specificity and clarity; and therefore unhelpful in the diagnosis process. Hence, many support groups and advocates believe that the medical community should discontinue the use of 'DSD' as a designation tool.<ref>{{Cite web|last1=Houk|first1=Christopher P|last2=Baskin|first2=Laurence S|last3=Levitsky|first3=Lynne L|date=Jan 9, 2021|editor-last=Geffner|editor-first=Mitchell E|editor2-last=Hoppin|editor2-first=Alison G|title=Management of the infant with atypical genitalia (disorder of sex development)|url=https://www.uptodate.com/contents/management-of-the-infant-with-atypical-genitalia-disorder-of-sex-development|access-date=April 9, 2021|website=UpToDate}}</ref>
Furthermore, people who live with conditions regarding sexual abnormalities may encounter various mental and physical health problems. This may include traumatic experience with their own bodies, dissatisfaction with body image, low-self esteem, anxiety, depression, bipolar disorders, eating disorders, personality disorders, schizophrenia disorders, trauma and stress-related disorders, etc.<ref>{{Cite web|date=2019-09-24|title=Supporting yourself - Intersex people|url=https://headtohealth.gov.au/supporting-yourself/support-for/intersex|access-date=2021-04-01|website=headtohealth.gov.au|language=en}}</ref>
Many intersex people are engaged in activism to stop hormonal treatments, citing the extreme and harmful nature of many of the treatments, further arguing that many of the treatments serve no medical purpose.<ref>{{Cite web |date=2025-01-01 |title={{!}} I want to be like nature made me {{!}} |url=https://www.hrw.org/report/2017/07/25/i-want-be-nature-made-me/medically-unnecessary-surgeries-intersex-children-us|access-date=2025-01-01 |website=www.hrw.org|language=en}}</ref>
=== Terminology === The term ''disorders of sex development'' has generally been accepted by the medical community, as well as being a popular term in academic literature.<ref>{{cite book |url=https://books.google.com/books?id=cNHHDwAAQBAJ&pg=PA862 |title=Atlas of Pediatric Surgery: Principles and Treatment |vauthors=Al-Salem AH |date=2020-01-02 |publisher=Springer Nature |isbn=978-3-030-29211-9 |page=863 |language=en}}</ref> However, the term is not universal among patients or support groups.<ref>{{cite journal |display-authors=6 |vauthors=Lee PA, Nordenström A, Houk CP, Ahmed SF, Auchus R, Baratz A, Baratz Dalke K, Liao LM, Lin-Su K, Looijenga LH, Mazur T, Meyer-Bahlburg HF, Mouriquand P, Quigley CA, Sandberg DE, Vilain E, Witchel S |date=2016 |title=Global Disorders of Sex Development Update since 2006: Perceptions, Approach and Care |journal=Hormone Research in Paediatrics |language=english |volume=85 |issue=3 |pages=158–80 |doi=10.1159/000442975 |pmid=26820577 |doi-access=free}}</ref> One study stated that it can affect individuals covered by the description in a negative way, and that the terminology might impact choice and utilization of health care providers.<ref name="johnson2017" /> Another study found that most affected individuals did not find the term offensive.<ref name=":2">{{cite journal |display-authors=6 |vauthors=Bennecke E, Köhler B, Röhle R, Thyen U, Gehrmann K, Lee P, Nordenström A, Cohen-Kettenis P, Bouvattier C, Wiesemann C |date=May 2021 |title=Disorders or Differences of Sex Development? Views of Affected Individuals on DSD Terminology |url=https://www.researchgate.net/publication/338844558 |url-status=live |journal=Journal of Sex Research |volume=58 |issue=4 |pages=522–531 |doi=10.1080/00224499.2019.1703130 |pmid=31985272 |archive-url=https://web.archive.org/web/20200829030135/https://www.researchgate.net/publication/338844558_Disorders_or_Differences_of_Sex_Development_Views_of_Affected_Individuals_on_DSD_Terminology |archive-date=29 August 2020 |access-date=4 July 2020 |s2cid=210923829}}</ref> The ICD-11, which is the World Health Organization's international guide to medical coding (effective as of January 1, 2022), references DSDs as intersex traits or conditions, as do some medical journals.<ref name="bmj.g2926">{{cite journal |author1-link=Rebecca Jordan-Young |author3-link=Katrina Karkazis |vauthors=Jordan-Young RM, Sönksen PH, Karkazis K |date=April 2014 |title=Sex, health, and athletes |journal=BMJ |volume=348 |article-number=g2926 |doi=10.1136/bmj.g2926 |pmid=24776640 |s2cid=2198650}}</ref> The Council of Europe<ref name="coe" /> and Inter-American Commission on Human Rights<ref name="iachr" /> have called for a review of medical classifications that unnecessarily medicalize intersex traits.<ref name="coe" /><ref name="iachr" /><ref name="fra" />
The DSD as a model was advocated for by intersex advocates to include all variation of atypical sexual development. Specifically the DSD exists as replacement for the "optimum gender rearing model," which was the standard model for individuals with atypical sexual development. This model stated goal was to assign a gender binary, usually female via non-consensual medicalization, often via the falsification of medical records. After the publication of individuals who had undergone the OGR model and had gone through serious physiological distress, (such as David Reimer), the model was discredited. The term "disorders of sexual development" was chosen to reflect the variation of sexual development over differences which effects all individuals, this however has been controversial, with many instead opting for "differentiation" or "variation."<ref>{{cite web|title=''Progress and Politics in the intersex rights movement, Feminist theory in action''|url=https://www.aisia.org/wp-content/uploads/2016/11/Dreger__Herndon_2009.pdf|author1=Alice D. Dreger |author2=April M. Herndon}}</ref>
Sociological research in Australia on 272 "people born with atypical sex characteristics," published in 2016, found that 3% of respondents used the term "disorders of sex development" or "DSD" to define their sex characteristics, while 21% use the term when accessing medical services. In contrast, 60% used the term "intersex" in some form to self-describe their sex characteristics.<ref name="Jones_2016" /> U.S. research by the Lurie Children's Hospital, Chicago, and the AIS-DSD Support Group (now InterConnect Support Group) published in 2017 found that "disorders of sex development" terminology may negatively affect care, give offense, and result in lower attendance at medical clinics.<ref name="lurie20172">{{cite news |author=Ann and Robert H. Lurie Children's Hospital of Chicago |date=11 May 2017 |title=Term "Disorders of Sex Development" May Have Negative Impact |work=Newswise |url=http://www.newswise.com/articles/term-disorders-of-sex-development-may-have-negative-impact |url-status=live |access-date=2017-05-11 |archive-url=https://web.archive.org/web/20170515104842/http://www.newswise.com/articles/term-disorders-of-sex-development-may-have-negative-impact |archive-date=15 May 2017 |df=dmy-all}}</ref><ref name="johnson20173">{{cite journal |author9-link=Georgiann Davis |display-authors=6 |vauthors=Johnson EK, Rosoklija I, Finlayson C, Chen D, Yerkes EB, Madonna MB, Holl JL, Baratz AB, Davis G, Cheng EY |date=December 2017 |title=Attitudes towards "disorders of sex development" nomenclature among affected individuals |journal=Journal of Pediatric Urology |volume=13 |issue=6 |pages=608.e1–608.e8 |doi=10.1016/j.jpurol.2017.03.035 |pmid=28545802 |df=dmy-all}}</ref>
A "dsd-LIFE" study in 2020 found that around 69% of 1,040 participants reported that DSD applied to their condition or that they felt neutral about the term, with most participants preferring terms that were specific to their somatic condition.<ref name=":2" />
===Human rights and community concerns=== {{further|Intersex human rights|Intersex medical interventions}} {{Intersex sidebar|medicine}}{{Duplication|date=September 2025|dupe=Terminology|section=y|othersections=y}} The term DSD (and particularly its association with medical ''disorders'') has been controversial. The argument over terminology reflects a deeper disagreement over the extent to which intersex conditions require medical intervention, the appropriateness of certain interventions, and whether physicians and parents should make irreversible treatment decisions on behalf of young children if the condition is not life-threatening. * Use of the term disorder of sex development (DSD) is controversial among many activists and community organizations due to the label "disorders".<ref name="tiger">{{cite web|url=http://wewhofeeldifferently.info/interview.php?interview=108 |title=An Interview with Dr. Tiger Howard Devore PhD|work=We Who Feel Differently|date=February 7, 2011}}</ref><ref>{{cite web| last = interACT| author-link = Interact Advocates for Intersex Youth | title = interACT Statement on Intersex Terminology| work = Interact Advocates for Intersex Youth| access-date = 30 May 2016| date = May 2016 | url = https://interactadvocates.org/interact-statement-on-intersex-terminology/}}</ref><ref>{{cite web | vauthors = Briffa T | author-link = Tony Briffa (politician) | title = Disorders of Sex Development | date = 8 May 2014 | url = http://oii.org.au/26808/tony-briffa-on-dsd/ | publisher = Organisation Intersex International Australia }}</ref><ref>{{cite web | url = http://www.ukia.co.uk/ukia/dsd.html | title = Why Not "Disorders of Sex Development"? | work = UK Intersex Association | access-date = 30 May 2016 | archive-date = 5 May 2019 | archive-url = https://web.archive.org/web/20190505180543/http://www.ukia.co.uk/ukia/dsd.html }}</ref> Many governments and international institutions use the term 'intersex' in preference to 'DSD', or have called for the review of medical classifications.<ref name="coe" /><ref name="iachr" /> In May 2019, more than 50 intersex-led organizations signed a multilingual joint statement condemning the introduction of "disorders of sex development" language into the International Classification of Diseases, stating that this causes "harm" and facilitates human rights violations, calling on the World Health Organization to publish clear policy to ensure that intersex medical interventions are "fully compatible with human rights norms".<ref>{{cite web | last = Intersex Human Rights Australia| author-link = Intersex Human Rights Australia | title = Joint statement on the International Classification of Diseases 11 | date = 2019-05-23| url = https://ihra.org.au/35299/joint-statement-icd-11/}}</ref><ref>{{cite news| vauthors = Crittenton A| title = World Health Organization condemned for classifying intersex as 'disorder'| work = Gay Star News| access-date = 2019-06-02| date = 2019-05-24| url = https://www.gaystarnews.com/article/world-health-organization-condemned-classifying-intersex-disorder/| archive-date = 2020-02-20| archive-url = https://web.archive.org/web/20200220103216/https://www.gaystarnews.com/article/world-health-organization-condemned-classifying-intersex-disorder/}}</ref><ref>{{cite news| vauthors = Leighton-Dore S | title = World Health Organisation drops transgender from list of mental health disorders| work = SBS| access-date = 2019-06-02| date = 2019-05-28| url = https://www.sbs.com.au/topics/sexuality/agenda/article/2019/05/28/world-health-organisation-drops-transgender-list-mental-health-0}}</ref><ref>{{cite news| vauthors = Barr S | title = Transgender no longer classified as 'mental disorder' by WHO| work = The Independent| access-date = 2019-06-02| date = 2019-05-28| url = https://www.independent.co.uk/life-style/transgender-world-health-organisation-mental-disorder-who-gender-icd11-update-a8932786.html}}</ref><ref>{{cite news| vauthors = Wills E | title = Campaigners hail changes to WHO classification of trans health issues| work = Evening Standard| access-date = 2019-06-02| date = 2019-05-29| url = https://www.standard.co.uk/news/world/human-rights-campaigners-hail-major-change-by-who-as-transgender-no-longer-recognised-as-mental-a4154421.html}}</ref> * Lee et al. in a 2006 ''Consensus statement on management of intersex disorders'' proposed a system of nomenclature based on "disorders of sex development" for clinical use, suggesting that "terms such as intersex, pseudohermaphroditism, hermaphroditism, sex reversal, and gender based diagnostic labels are particularly controversial," may be perceived as pejorative, and are confusing to practitioners and parents alike.<ref name="lee" /> However, research by the Lurie Children's Hospital, Chicago, and the AIS-DSD Support Group published in 2017 found that affected persons, and care givers, object to the term, and that this may impact choice, access, and utilization of health care providers.<ref name="johnson2017">{{cite journal | vauthors = Johnson EK, Rosoklija I, Finlayson C, Chen D, Yerkes EB, Madonna MB, Holl JL, Baratz AB, Davis G, Cheng EY | display-authors = 6 | title = Attitudes towards "disorders of sex development" nomenclature among affected individuals | journal = Journal of Pediatric Urology | volume = 13 | issue = 6 | pages = 608.e1–608.e8 | date = December 2017 | pmid = 28545802 | doi = 10.1016/j.jpurol.2017.03.035 | author9-link = Georgiann Davis }}</ref> Australian sociological research on people born with atypical sex characteristics, published in 2016, found that 3% of respondents choose the term "disorders of sex development" or "DSD" to define their sex characteristics, while 21% use the term when accessing medical services. In contrast, 60% used the term "intersex" in some form to self-describe their sex characteristics.<ref name="Jones_2016">{{cite book| publisher = Open Book Publishers| isbn = 978-1-78374-208-0| vauthors = Jones T, Hart B, Carpenter M, Ansara G, Leonard W, Lucke J | title = Intersex: Stories and Statistics from Australia| location = Cambridge, UK| date = 2016| access-date = 2 February 2016| url = http://oii.org.au/wp-content/uploads/key/Intersex-Stories-Statistics-Australia.pdf| archive-url = https://web.archive.org/web/20160914152729/http://oii.org.au/wp-content/uploads/key/Intersex-Stories-Statistics-Australia.pdf| archive-date = 14 September 2016}}</ref> * A committee of the Senate of Australia found that labelling intersex as "pejorative" appeared to be a post-hoc rationalisation in the 2006 ''Consensus statement''. It recommended a review of clinical use of the term.<ref name="SenateOnSterilisation">{{cite web|url=https://www.aph.gov.au/Parliamentary_Business/Committees/Senate/Community_Affairs/Involuntary_Sterilisation/Sec_Report/index | work = Senate Community Affairs Committee|title=Involuntary or coerced sterilisation of intersex people in Australia|date=October 2013}}</ref> * Alternative terms have been offered: Milton Diamond has suggested the use of "variation"<ref>{{cite journal | vauthors = Beh H, Diamond M |year=2006 |author-link2= Milton Diamond |title=Variations of Sex Development Instead of Disorders of Sex Development |journal=Archives of Disease in Childhood |issue=26 July 2006|url=https://www.hawaii.edu/PCSS/biblio/articles/2005to2009/2006-variations.html}}</ref><ref>{{cite journal | vauthors = Tamar-Mattis A, Diamond M | title = Managing variation in sex development | journal = Journal of Pediatric Endocrinology & Metabolism | volume = 20 | issue = 4 | pages = 552–3 | date = April 2007 | pmid = 17550222 | url = https://www.hawaii.edu/PCSS/biblio/articles/2005to2009/2007-managing-variation.html | author-link2 = Milton Diamond | author-link1 = Anne Tamar-Mattis }}</ref> or of "difference",<ref name="hawaii.edu"/> Elizabeth Reis has suggested "divergence";<ref>{{cite journal | vauthors = Reis E | title = Divergence or disorder?: the politics of naming intersex | journal = Perspectives in Biology and Medicine | volume = 50 | issue = 4 | pages = 535–43 | year = 2007 | pmid = 17951887 | doi = 10.1353/pbm.2007.0054 | s2cid = 17398380 }}</ref> Liao and Simmonds suggest "diverse sex development".<ref name="Liao2013">{{cite journal| doi = 10.1080/19419899.2013.831217| issn = 1941-9899| volume = 5| issue = 1| pages = 83–101| vauthors = Liao LM, Simmonds M| title = A values-driven and evidence-based health care psychology for diverse sex development| journal = Psychology & Sexuality| date = 2013| s2cid = 36307047| doi-access = free}}</ref> The latter suggestions would retain the initial D in DSD. * The 2006 ''Consensus statement on management of intersex disorders'' stated that evidence for early surgery for cosmetic reasons is lacking, outcomes include "decreased sexual sensitivity" and long term outcome data is absent.<ref name="lee" /> A 2016 ''Global Disorders of Sex Development Update since 2006'' states that there is "still no consensual attitude regarding indications, timing, procedure and evaluation of outcome of DSD surgery" and "no evidence regarding the impact of surgically treated or non-treated DSDs during childhood for the individual, the parents, society or the risk of stigmatization".<ref name="2016dsd">{{cite journal | vauthors = Lee PA, Nordenström A, Houk CP, Ahmed SF, Auchus R, Baratz A, Baratz Dalke K, Liao LM, Lin-Su K, Looijenga LH, Mazur T, Meyer-Bahlburg HF, Mouriquand P, Quigley CA, Sandberg DE, Vilain E, Witchel S | display-authors = 6 | title = Global Disorders of Sex Development Update since 2006: Perceptions, Approach and Care | journal = Hormone Research in Paediatrics | volume = 85 | issue = 3 | pages = 158–80 | date = January 28, 2016 | pmid = 26820577 | doi = 10.1159/000442975 | author-link12 = Heino Meyer-Bahlburg | doi-access = free }}</ref> * In 2013, Juan E. Méndez, the United Nations Special Rapporteur on torture and other cruel, inhuman or degrading treatment or punishment, condemned "irreversible sex assignment, involuntary sterilization, involuntary genital normalizing surgery, performed without their informed consent, or that of their parents, 'in an attempt to fix their sex'" stating that "members of sexual minorities are disproportionately subjected to torture and other forms of ill-treatment because they fail to conform to socially constructed gender expectations".<ref name="Mendez2013">{{cite conference| vauthors = Méndez J | author-link= Juan E. Méndez| title = Report of the Special Rapporteur on torture and other cruel, inhuman or degrading treatment or punishment, A.HRC.22.53| date = February 2013| url = http://www.ohchr.org/Documents/HRBodies/HRCouncil/Regularsession/Session22/A.HRC.22.53_English.pdf}}</ref> * In May 2014, the World Health Organization issued a joint statement on ''Eliminating forced, coercive and otherwise involuntary sterilization, An interagency statement'' with the OHCHR, UN Women, UNAIDS, UNDP, UNFPA and UNICEF. Referencing the involuntary surgical "sex-normalising or other procedures" on "intersex persons", the report recommends a range of guiding principles for medical treatment, including ensuring patient autonomy in decision-making, ensuring non-discrimination, accountability and access to remedies.<ref>{{cite web|url=https://www.who.int/reproductivehealth/publications/gender_rights/eliminating-forced-sterilization/en/ |title=Eliminating forced, coercive and otherwise involuntary sterilization, An interagency statement|work= World Health Organization|date=May 2014}}</ref> * During 2015, the Council of Europe<ref name="coe" /> and Inter-American Commission on Human Rights<ref name="iachr" /> called for a review of medical classifications that may unnecessarily medicalize intersex traits,<ref name="coe">{{Citation| last1 = Council of Europe| last2 = Commissioner for Human Rights| author-link2= Commissioner for Human Rights |title = Human rights and intersex people, Issue Paper | date = April 2015 | url = https://wcd.coe.int/ViewDoc.jsp?Ref=CommDH/IssuePaper(2015)1&Language=lanEnglish&Ver=original}}</ref><ref name="iachr">{{Citation| last = Comisión Interamericana de Derechos Humanos| author-link = Inter-American Commission on Human Rights| title = Violencia contra Personas Lesbianas, Gays, Bisexuales, Trans e Intersex en América| date = November 12, 2015| url = http://www.oas.org/es/cidh/informes/pdfs/ViolenciaPersonasLGBTI.pdf|language=es}}</ref><ref name="fra">{{Citation| last = European Union Agency for Fundamental Rights| author-link = Fundamental Rights Agency|title = The fundamental rights situation of intersex people| date = April 2015| url = https://fra.europa.eu/sites/default/files/fra-2015-focus-04-intersex.pdf}}</ref> an end to medical interventions without consent, and improved disclosure. The Council of Europe's Human Rights Commissioner recommended: {{blockquote|National and international medical classifications which pathologise variations in sex characteristics should be reviewed with a view to eliminating obstacles to the effective enjoyment, by intersex persons, of human rights, including the right to the highest attainable standard of health.<ref name="coe" />}} * The European Union Agency for Fundamental Rights<ref name="fra" /> and UN Treaty Bodies have called for informed consent by individuals subjected to medical treatment, improved disclosure, and access to redress.<ref name="crpd">{{Citation| publisher = United Nations| last1 = United Nations| last2 = Committee on the Rights of Persons with Disabilities| title = Concluding observations on the initial report of Germany (advance unedited version)| location = Geneva| date = April 17, 2015 | url = http://tbinternet.ohchr.org/_layouts/treatybodyexternal/Download.aspx?symbolno=CRPD%2FC%2FDEU%2FCO%2F1&Lang=en}}</ref><ref name="crc-ch">{{Citation| publisher = United Nations| last1 = United Nations| last2 = Committee on the Rights of Child| title = Concluding observations on the combined second to fourth periodic reports of Switzerland| location = Geneva| date = February 26, 2015 | url = http://tbinternet.ohchr.org/_layouts/treatybodyexternal/Download.aspx?symbolno=CRC%2fC%2fCHE%2fCO%2f2-4&Lang=en}}</ref>
===Clinical disagreements about the term=== While the 2006 clinical consensus statement that introduced the term,<ref name="lee" /> its 2016 update,<ref name="2016dsd" /> included some sex chromosome anomalies within the term DSD, the inclusion of those conditions is opposed by some clinicians.{{citation needed|date=April 2021}} Medical historian David Griffiths has identified continued controversy about the relationship between sex chromosome variations and intersex/DSD classifications.<ref>{{cite journal | vauthors = Griffiths DA | title = Shifting syndromes: Sex chromosome variations and intersex classifications | journal = Social Studies of Science | volume = 48 | issue = 1 | pages = 125–148 | date = February 2018 | pmid = 29424285 | pmc = 5808814 | doi = 10.1177/0306312718757081 }}</ref>
Similarly, some clinicians have proposed that congenital adrenal hyperplasia be excluded.<ref>{{cite journal | vauthors = González R, Ludwikowski BM | title = Should CAH in Females Be Classified as DSD? | journal = Frontiers in Pediatrics | volume = 4 | page = 48 | date = 2016 | pmid = 27242977 | doi = 10.3389/fped.2016.00048 | pmc = 4865481 | s2cid = 16478320 | doi-access = free }}</ref> Human rights advocate Morgan Carpenter has remarked that this proposal appears motivated by support for contentious medical interventions.<ref>{{cite journal | vauthors = Carpenter M | title = Intersex human rights, sexual orientation, gender identity, sex characteristics and the Yogyakarta Principles plus 10 | journal = Culture, Health & Sexuality | volume = 23 | issue = 4 | pages = 516–532 | date = April 2021 | pmid = 32679003 | doi = 10.1080/13691058.2020.1781262 | s2cid = 220631036 }}</ref>
A member of the legal committee for the World Professional Association for Transgender Health and co-founder of the Australian and New Zealand Professional Association for Transgender Health has described "transsexualism" as "an intersex condition and a disorder of sexual development therapeutically medically treated by hormonal therapy and Genital Reassignment Surgery".<ref>{{cite book| publisher = Intersentia| isbn = 978-1-78068-196-2| doi = 10.1017/9781780685588.022 | pages = 457–526| vauthors = Wallbank R | title = The legal status of transsexual and transgender persons| chapter = The Legal Status of People who Experience Difference in Sexual Formation and Gender Expression in Australia| location = Cambridge, United Kingdom| date = 2015}}</ref> Such views are contested.<ref>{{cite book| publisher = Palgrave Macmillan US| isbn = 978-1-137-54352-3 | pages = 83–113| vauthors = Costello CG | author-link = Cary Gabriel Costello | title = Transgender and Intersex: Theoretical, Practical, and Artistic Perspectives| chapter = Intersex and Trans* Communities: Commonalities and Tensions| location = New York| date = 2016| doi = 10.1057/978-1-349-71325-7_4}}</ref>
=== People with DSDs competing in sporting events === There is particular contention around female-presenting athletes with DSDs (which can cause an elevated level of testosterone) competing in female-only sports events.<ref>{{Cite journal |last1=Pielke |first1=Roger |last2=Tucker |first2=Ross |last3=Boye |first3=Erik |date=September 2019 |title=Scientific integrity and the IAAF testosterone regulations |journal=The International Sports Law Journal |language=en |volume=19 |issue=1–2 |pages=18–26 |doi=10.1007/s40318-019-00143-w |issn=1567-7559 |doi-access=free}}</ref> World Athletics claimed that while 46 XY DSD occurs in roughly 1 in 20,000 people in the general population, it is found in about 7 in 1,000 elite female athletes (with a prevalence 140 times higher), arguing that this offers significant performance advantage. Within the scientific community, there is ongoing debate over whether any physiological advantage in fact exists.<ref>{{Cite web |url=https://www.bbc.com/sport/olympics/articles/c0l8gxzw6n4o |title=The key questions for sport after boxing eligibility row |website=BBC|date=11 August 2024 }}</ref>
== See also == * Intersex medical interventions * Intersex healthcare * Patient support group * Sex chromosome anomalies
== References == {{Reflist}}
== Further reading == {{refbegin}} * {{cite journal | vauthors = Lee PA, Houk CP, Ahmed SF, Hughes IA | title = Consensus statement on management of intersex disorders. International Consensus Conference on Intersex | journal = Pediatrics | volume = 118 | issue = 2 | pages = e488-500 | date = August 2006 | pmid = 16882788 | pmc = 2082839 | doi = 10.1542/peds.2006-0738 }} * {{cite journal | vauthors = Lee PA, Nordenström A, Houk CP, Ahmed SF, Auchus R, Baratz A, Baratz Dalke K, Liao LM, Lin-Su K, Looijenga LH, Mazur T, Meyer-Bahlburg HF, Mouriquand P, Quigley CA, Sandberg DE, Vilain E, Witchel S | display-authors = 6 | title = Global Disorders of Sex Development Update since 2006: Perceptions, Approach and Care | journal = Hormone Research in Paediatrics | volume = 85 | issue = 3 | pages = 158–80 | date = January 28, 2016 | pmid = 26820577 | doi = 10.1159/000442975 | doi-access = free }} {{refend}}
== External links == {{Medical resources | DiseasesDB = | ICD10 = | ICD9 = | ICDO = | OMIM = | MedlinePlus = | eMedicineSubj = | eMedicineTopic = | MeshID = D012734 }} * {{cite web | url = http://www.dsdgenetics.org | title = Disorders of Sex Development Research }} – Provides information regarding the causes, frequency and implications of DSD. * {{cite web | url = https://www.accordalliance.org | title = Accord Alliance }} – Approaches to care for people that are affected by differences of sex development (DSD). * {{cite web | work = YourChild | url = https://www.mottchildren.org/conditions-treatments/disorders-sex-development | title = Disorders of Sex Development (DSD) Resources | publisher = University of Michigan Health System }} * {{cite web | url = http://www.aboutkidshealth.ca/HowTheBodyWorks/Sex-Development-Introduction.aspx?articleID=7671&categoryID=XS | title = Sex Development | date = December 2003 | publisher = The Hospital for Sick Children | location = Toronto | archive-url = https://web.archive.org/web/20100704031951/http://www.aboutkidshealth.ca/HowTheBodyWorks/Sex-Development-Introduction.aspx?articleID=7671&categoryID=XS | archive-date = 2010-07-04 }} An Overview Animation of prenatal genital development * {{cite web | url = https://dsdguidelines.org/htdocs/parents/ | title = Handbook for Parents | work = Consortium on the Management of Disorders of Sex Development }} * {{cite web | url = https://dsdguidelines.org/htdocs/clinical/ | title = Clinical Guidelines for the Management of Disorders of Sex Development in Childhood | work = Consortium on the Management of Disorders of Sex Development }}
{{Reproductive health |state=collapsed}} {{Congenital malformations of genital organs}} {{Intersex}} {{Human reproductive health}}
{{Authority control}}
{{DEFAULTSORT:Disorders Of Sex Development}} Category:Intersex topics Category:Congenital disorders of genital organs Category:Intersex healthcare Category:Sex differences in humans