Disorders of sex development

Overview

Genital anatomy

Conditions

• 47,XXY females - There are case reports of 47,XXY females; in some cases SRY or androgen receptor abnormalities are detected.
• 47,XXY males – see Klinefelter syndrome below
• 48, XXXX – A condition that describes a female with two extra X chromosomes. It is considered a variation of Triple X syndrome. Women with 48, XXXX may or may not have issues associated with the condition though most are developmentally delayed and only about 50% undergo puberty normally.
• 48, XXYY – A condition that describes a male with one extra X chromosome and one extra Y chromosome. It occurs in 1 in 18,000 to 40,000 male births. 48, XXYY may result in infertility, low testosterone, and neurodevelopmental disorders like ADHD or autism but some men have no issues.
• 49, XXXXX – A condition that describes a female with three extra X chromosomes. It is considered a variant of Triple X syndrome. Women with 49, XXXXX usually suffer from numerous health issues such as patent ductus arteriosus, scoliosis, kidney hypoplasia, and abnormal lobulation of the lungs. Physical deformities include microcephaly, micrognathia, and webbing of the neck.
• 49, XXXXY – A condition that describes a male with three extra X chromosomes. It is rare, occurring in 1 in 85,000 to 100,000 males. It is considered a variation of Klinefelter syndrome. Men with 49, XXXXY syndrome often suffer from mental retardation.
• 5α-reductase deficiency - 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.
• 17β-Hydroxysteroid dehydrogenase deficiency – A condition characterized by impaired androgen and estrogen synthesis in males and females, respectively. Results in pseudohermaphroditism/undervirilization in males and in excessive virilization of adult females.
• Androgen insensitivity syndrome – 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. 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, breasts, and a clitoris and people with this form are raised as females.
• Aphallia – A rare occurrence where a male is born without a penis or where a female is born without a clitoris. As of 2005, only 75 cases of aphallia have been documented. It should not be confused with intentional or accidental amputation of the genitalia.
• Aposthia - A congenital defect where a male is born without a foreskin.
• Aromatase deficiency – A disorder in which, in females, is characterized by androgen excess and estrogen deficiency, and can result in inappropriate virilization, though without pseudohermaphroditism . Aromatase deficiency can also be caused by mutations in P450 oxidoreductase gene.
• Aromatase excess syndrome - A condition that causes excessive estrogen production, resulting in feminization without pseudohermaphroditism in males and hyperfeminization in females.
• 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, 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.
• 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 in 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.
• Complete androgen insensitivity syndrome – 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. 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.
• Congenital adrenal hyperplasia – A condition that causes excessive androgen production, which causes excessive virilization. It is most problematic in genetic females, where severe virilization can result in her having vaginal agenesis and a functional penis which is capable of penetrative intercourse. 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.
• De la Chapelle syndrome – a condition where a genetically female 46,XX individual is phenotypically male, usually caused by atypical chromosomal crossover of the Y chromosome's SRY gene. XX males are shorter and weigh less than XY males, may have genital ambiguities, usually have small testes, and are universally sterile.
• 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 persistant Müllerian ducts in affected 46,XY males. The disorders are invariably fatal before the age of 15, causing kidney failure due to nephrotic syndrome.
• Diphallia – A condition where a male is born with two penises. It's extremely rare, with only 100 cases being recorded since 1609 and an occurrence rate of 1 in 5,500,000 in the United States. The penises may be side by side or one on top of the other, being of equal size or with one penis being distinctively larger than the other, and both penises may be suitable for urination and intercourse. Men with diphallia may be sterile.
• Estrogen insensitivity syndrome – 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.
• Gonadal Dysgenesis – is any congenital developmental disorder of the reproductive system characterized by a progressive loss of primordial germ cells on the developing gonads of an embryo.
• Isolated 17,20-lyase deficiency – A condition that is characterized by either partial or complete inability to produce androgens and estrogens. 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.
• Klinefelter 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. 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.
• 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.
• Micropenis – A penis that measures 3 inches or less in length when erect. It is a common condition, occurring in 1 in 200 men. Micropenis may be the result of undervirilization during fetal development or may be caused by an underlying intersex condition, such as mild androgen insensitivity syndrome, partial androgen insensitivity syndrome, or Klinefelter syndrome. It may also be considered a natural variation of penis size. While the majority of men have no issues with having a micropenis, some may opt to use a penile implant or undergo penile enlargement to increase the size of their penis.
• 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.
• Mild androgen insensitivity syndrome – 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 – is 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.
• Ovotesticular disorder – A condition where an individual has both testicular and ovary tissue.
• Partial androgen insensitivity syndrome – 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. 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.
• Penoscrotal transposition
• Persistent Müllerian duct syndrome A condition where Fallopian tubes, uterus, or the upper part of the vagina are present in an otherwise normal male.
• Pseudovaginal perineoscrotal hypospadias – 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.
• Swyer Syndrome is 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 and a typical medical treatment would include hormone replacement therapy with female hormones.
• Triple X syndrome – A condition that describes a female born with an extra X chromosome, making her karotype 47, XXX. It is a common occurrence, affecting 1 in 1,000 females. It generally causes no health issues or abnormal development.
• Turner syndrome – A condition that describes a female born with only one X chromosome or with an abnormal X chromosome, making her karotype 45, XO. It occurs in 1 in 2,000 to 5,000 females. Turner syndrome causes numerous health and development problems, including but not limited to short stature, lymphedema, infertility, webbed neck, coarctation of the aorta, ADHD, amenorrhoea, and obesity.
• Uterus didelphys – A condition where a female is born with two uteri. It is often accompanied by two vaginas. It is generally not considered a health issue and women with uterus didelphys usually have normal sex lives and pregnancies.
• Müllerian 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.

  Controversy

• Use of the term disorder of sex development is controversial among many activists and community organizations due to the label "disorders". Many governments and international institutions use the term 'intersex' in preference to 'DSD', or have called for the review of medical classifications. 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".
• 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. 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. 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.
• 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.
• Alternative terms have been offered: Milton Diamond has suggested the use of "variation" or of "difference", Elizabeth Reis has suggested "divergence"; Liao and Simmonds suggest "diverse sex development". 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. 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".
• 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".
• 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.
• During 2015, the Council of Europe, and Inter-American Commission on Human Rights called for a review of medical classifications that unnecessarily medicalize intersex traits an end to medical interventions without consent, and improved disclosure. The Council of Europe's Human Rights Commissioner recommended:
• The European Union Agency for Fundamental Rights and UN Treaty Bodies have called for informed consent by individuals subjected to medical treatment, improved disclosure, and access to redress.