Nietypowe genitalia – Etiologia i przyczyny

Nietypowe genitalia
Etiologia i przyczyny

Nietypowe genitalia, definiowane jako zewnętrzne narządy płciowe o niejednoznacznym fenotypie, wynikają z zaburzeń rozwoju chromosomalnego, gonadalnego lub anatomicznego płci, prowadząc do rozbieżności między fenotypem a genotypem (zwykle 46,XX lub 46,XY). Częstość występowania szacuje się na 1:1000 do 1:4500 żywych urodzeń. Etiologia obejmuje zaburzenia hormonalne, takie jak nadprodukcja androgenów w wrodzonym przerostu nadnerczy (CAH, najczęstsza przyczyna u 46,XX, z mutacjami w genie CYP21A2 i niedoborem 21-hydroksylazy u 90% pacjentów), mutacje genetyczne wpływające na determinację i różnicowanie płci (np. mutacje genu SRY, AR w zespole niewrażliwości na androgeny), a także aberracje chromosomalne (np. zespół Klinefeltera 47,XXY, zespół Turnera 45,X). Zaburzenia te mogą manifestować się różnorodnie, od wirylizacji u płodów 46,XX po niedostateczną wirylizację u 46,XY, a także dysgenezję gonad, ovotesticular DSD czy częściową/całkowitą niewrażliwość na androgeny.

Etiologia nietypowych genitaliów

Nietypowe genitalia (dawniej określane jako genitalia niejednoznaczne lub obojnacze) to rzadki stan, w którym zewnętrzne narządy płciowe dziecka nie są jednoznacznie męskie ani żeńskie. Stan ten występuje, gdy rozwój chromosomalny, gonadowy lub anatomiczny płci jest atypowy, powodując niedopasowanie między wyglądem zewnętrznych narządów płciowych a wewnętrznymi narządami płciowymi lub genetyczną płcią dziecka (typowo XX lub XY)¹². Częstość występowania nietypowych genitaliów szacuje się na około 1 na 1000 do 4500 żywych urodzeń³⁴.

Zaburzenia hormonalne w okresie płodowym

Nietypowe genitalia zazwyczaj powstają, gdy zmiany hormonalne podczas ciąży zaburzają lub zatrzymują rozwój narządów płciowych płodu¹⁵. Prawidłowy rozwój płciowy zależy od delikatnej równowagi hormonalnej – testosteron jest niezbędny do stabilizacji przewodów Wolffa, podczas gdy wydzielanie czynnika anty-Müllerowskiego jest kluczowe dla regresji przewodów Müllera³. Męskie zewnętrzne narządy płciowe wymagają obecności dihydrotestosteronu dla prawidłowego rozwoju fenotypowego³.

W przypadku płodów genetycznie męskich (46,XY), niewystarczająca produkcja hormonów zwanych androgenami lub ich brak może powodować atypowy rozwój genitaliów¹. Z kolei narażenie płodu genetycznie żeńskiego (46,XX) na androgeny podczas rozwoju prowadzi do wirylizacji i atypowych zewnętrznych narządów płciowych¹⁶.

Czynniki genetyczne

Zmiany w określonych genach mogą wpływać na rozwój płciowy płodu i powodować nietypowe genitalia¹⁵. Rozwój płciowy ssaków zachodzi w dwóch sekwencyjnych etapach: początkowa faza determinacji płci, a następnie różnicowanie płciowe³. Determinacja płci jest kierowana przez zestaw chromosomów płciowych odziedziczonych podczas poczęcia. Dziedziczenie chromosomu Y i późniejsza ekspresja genu SRY kieruje bipotencjalną gonadę w kierunku różnicowania w jądra specyficzne dla mężczyzn. Natomiast brak chromosomu Y prowadzi do rozwoju jajnika specyficznego dla kobiet³.

Mutacja w którymkolwiek z genów zaangażowanych w rozwój płciowy może prowadzić do zaburzeń rozwoju płci (DSD). Utrata genów związanych z męskim rozwojem płciowym może prowadzić do niedostatecznej wirylizacji męskiego płodu lub 46 XY z fenotypem żeńskim³. Zwiększona dostępność sekwencjonowania nowej generacji pozwoliła na identyfikację wielu nowych genów zaangażowanych w DSD, co wpłynęło na zmianę podejścia diagnostycznego i udoskonalenie molekularnej diagnozy genetycznej w wielu przypadkach⁷.

Nietypowe genitalia mogą być również cechą pewnych rzadkich lub złożonych zespołów, które wpływają na wiele narządów. Zespoły te mogą obejmować zmiany chromosomowe, takie jak brakujący chromosom płciowy lub dodatkowy¹⁸.

Przyczyny nietypowych genitaliów u dzieci 46,XX

Wrodzony przerost nadnerczy

Wrodzony przerost nadnerczy (CAH) jest najczęstszą przyczyną nietypowych genitaliów u noworodków z genotypem 46,XX, stanowiąc ponad 95% przypadków⁹¹⁰. Jest to stan genetyczny, w którym nadnercza wytwarzają zbyt dużo hormonów zwanych androgenami¹. Dziewczynki z tym schorzeniem mają męskie narządy płciowe z powodu braku określonego enzymu w nadnerczach¹¹¹².

CAH obejmuje kilka zaburzeń nadnerczy, z których każde jest związane z mutacją w jednym z enzymów niezbędnych do biosyntezy kortyzolu z cholesterolu¹³. Najczęstszą formą CAH jest niedobór 21-hydroksylazy, spowodowany wariantami w genie CYP21A2, co stanowi najczęstszą przyczynę genetyczną DSD z nietypowymi genitaliami przy urodzeniu u noworodków 46,XX¹³¹⁴.

Podstawowy defekt biochemiczny polega na bloku enzymatycznym, który uniemożliwia wystarczającą produkcję kortyzolu. U 90% pacjentów z CAH blok występuje na poziomie enzymu 21-hydroksylacji (niedobór 21-hydroksylazy). Inne przyczyny CAH obejmują niedobór 11-hydroksylazy oraz rzadziej spotykany niedobór 3-beta-dehydrogenazy hydroksysteroidowej¹⁴¹⁴.

Dzieci płci żeńskiej z CAH mają atypiczne narządy płciowe, podczas gdy chłopcy takich objawów nie mają¹⁵. Inna forma CAH, zwana „utraty soli”, jest bardzo poważna i często śmiertelna. Powoduje załamanie elektrolitowe u noworodka. Leczenie jest dostępne, jeśli zostanie zdiagnozowane wcześnie. Chłopcy i dziewczynki są dotknięci w równym stopniu¹⁵¹⁶.

Ekspozycja na androgeny w czasie ciąży

Niektóre leki zawierające androgeny lub powodujące, że organizm ciężarnej wytwarza te hormony, mogą powodować maskulinizację rozwijających się żeńskich narządów płciowych¹. Wysokie poziomy męskich hormonów mogą również przedostać się do łożyska poprzez matkę. Może to nastąpić, gdy matce podawany jest progesteron w celu zapobieżenia poronieniu lub jeśli ma ona guz wytwarzający hormony¹¹¹⁷.

Niedobór aromatazy

Niedobór aromatazy charakteryzuje się obniżonym poziomem estrogenu i podwyższonym poziomem testosteronu. Występuje u kobiet 46,XX z nietypowymi narządami płciowymi. Często mają one prawidłowe wewnętrzne narządy rozrodcze³.

Przyczyny nietypowych genitaliów u dzieci 46,XY

Problemy z rozwojem jąder

Problemy z rozwojem jąder mogą być spowodowane zmianami w genach lub przyczynami nieznanymi¹. Zaburzenia rozwoju jąder (dysgenezja gonadalna) obejmują dzieci z niedorozwiniętym narządem płciowym, wewnętrznymi narządami płciowymi często żeńskimi, zewnętrznymi genitaliami, które mogą się różnić między normalną żeńską a normalną męską (większość jest żeńska), oraz chromosomami, które są normalne, mają tylko chromosom X lub są mieszanką (mozaika)¹⁸.

Czysta dysgenezja gonadalna dotyczy dziewcząt. Osoby z tym schorzeniem mają męskie chromosomy, niedorozwinięte narządy płciowe, wewnętrzne żeńskie narządy rozrodcze i żeńskie zewnętrzne genitalia¹⁸. Mieszana dysgenezja gonadalna występuje u dzieci, które mają nieprawidłowości chromosomowe, które powodują, że rodzą się z dwoma różnymi gonadami – niezstąpionym jądrem i dysgenezyjną (zniekształconą) gonadą o pasmowym charakterze¹⁹.

Zespół niewrażliwości na androgeny

W tym zaburzeniu rozwijające się tkanki genitalne nie reagują prawidłowo na hormony wytwarzane przez jądra¹. Zespół niewrażliwości na androgeny (AIS) jest spowodowany mutacjami w genie receptora androgenowego (AR) na chromosomie X i determinuje odpowiedź na androgeny, takie jak testosteron lub DHT²⁰.

Dzieci z zespołem całkowitej niewrażliwości na androgeny mają normalne męskie chromosomy i normalne żeńskie zewnętrzne genitalia¹⁸. Zespół ten jest dziedziczny i spowodowany jest problemem z genem na chromosomie X¹¹.

W przypadku zespołu częściowej niewrażliwości na androgeny (PAIS), osoby doświadczają zmiennego stopnia braku odpowiedzi narządów końcowych na androgeny, co prowadzi do różnego stopnia rozwoju przewodu Wolffa i niejednoznaczności zewnętrznych genitaliów¹³.

Problemy z jądrami lub testosteronem

Różnorodne problemy mogą zakłócać aktywność jąder. Mogą to być problemy z formowaniem jąder oraz problemy z wytwarzaniem hormonu testosteronu¹. Produkcja testosteronu z cholesterolu wymaga pięciu etapów enzymatycznych, a defekty zostały zidentyfikowane na każdym etapie¹⁴.

Niedobór 5-alfa-reduktazy

Niedobór tego enzymu powoduje problemy z wytwarzaniem hormonów odpowiedzialnych za rozwój męskich genitaliów¹. Dzieci z tym schorzeniem mają normalny męski kariotyp i niejednoznaczne genitalia¹⁸.

Niedobór 5-alfa-reduktazy występuje, gdy płód 46,XY z normalnymi jądrami, ale bez enzymu 5-alfa reduktazy nie może wytwarzać DHT¹⁴. Enzym ten jest potrzebny, aby pomóc męskim narządom płciowym w zakończeniu ich rozwoju¹¹.

Stan ten jest dziedziczny i przekazywany przez autosomalny recesywny gen. Autosomalny recesywny oznacza, że każdy rodzic nosi jedną kopię genu i przekazuje gen dziecku. Rodzice będący nosicielami mają 1 na 4 szanse na urodzenie dziecka z tym schorzeniem przy każdej ciąży¹¹¹².

Inne przyczyny nietypowych genitaliów

Zaburzenia dysgenezji gonadów

W przypadku zaburzeń różnicowania gonadów narządy płciowe dziecka nie rozwijają się całkowicie w jądra lub jajniki². Mieszana dysgenezja gonadalna oznacza, że narządy płciowe (jądra lub jajniki) mogą nie rozwinąć się w pełni. Częściowa dysgenezja gonadalna oznacza, że narządy płciowe dziecka tworzą tylko niektóre tkanki jądrowe, a jądra nie będą działać prawidłowo. Dysgenezja gonadalna oznacza, że obie gonady pozostają niedojrzałe i nie rozwiną się w jądra ani jajniki².

Ovotesticular DSD

W przypadku ovotesticular DSD narządy płciowe dziecka mają tkankę jajnikową i jądrową, lub dziecko ma jeden jajnik i jedno jądro. Jest to bardzo rzadkie². Stan ten był wcześniej nazywany „prawdziwym hermafrotyzmem”⁶. W większości przypadków przyczyna tego stanu jest nieznana⁶.

Nieprawidłowości chromosomalne

Nieprawidłowości chromosomalne, w tym zespół Klinefeltera (47,XXY) i zespół Turnera (45,X), mogą prowadzić do nietypowych genitaliów²¹²². Stan określany jako „złożony lub nieokreślony interseks” dotyczy konfiguracji chromosomów innych niż 46,XX lub 46,XY. Stan ten nie powoduje nierównowagi między wewnętrznymi a zewnętrznymi genitaliami. Może jednak powodować problemy z poziomami hormonów płciowych, ogólnym rozwojem seksualnym i zmienioną liczbą chromosomów płciowych⁶.

Przyczyny idiopatyczne

Nietypowe genitalia mogą mieć wiele różnych przyczyn. W wielu przypadkach lekarze nie znają przyczyny i wydaje się, że występuje ona przypadkowo¹¹⁵. W szczególności znaczna liczba przypadków nie ma możliwej do zidentyfikowania przyczyny, zwłaszcza wśród 46,XY DSD, co podkreśla znaczenie doświadczonego zespołu o multidyscyplinarnym podejściu²⁰.

W przypadku dzieci z nietypowymi genitaliami narządy płciowe mogą działać prawidłowo pomimo ich wyglądu zewnętrznego²³. Niektóre dzieci urodzone z nietypowymi genitaliami mogą mieć normalne wewnętrzne narządy płciowe, które pozwalają im żyć normalnym, płodnym życiem, ale inne mogą mieć problemy z płodnością w wieku dorosłym²⁴²⁵.

Czynniki ryzyka i uwarunkowania rodzinne

Historia rodzinna może odgrywać rolę w rozwoju nietypowych genitaliów. Wynika to z faktu, że wiele różnic w rozwoju płciowym wynika ze zmian genowych, które mogą być przekazywane w rodzinach⁵²⁶.

Niektóre stany związane z nietypowymi genitaliami są dziedziczone autosomalnie recesywnie, co oznacza, że każdy rodzic nosi jedną kopię zmutowanego genu i przekazuje ten gen dziecku. Rodzice-nosiciele mają 1 na 4 szanse na posiadanie dziecka z takim schorzeniem przy każdej ciąży¹¹²⁷.

Inne stany, takie jak zespół niewrażliwości na androgeny, są dziedziczone i spowodowane problemem z genem na chromosomie X¹¹. Poradnictwo genetyczne dla rodziców i przekazywanie wyników testów jest bardzo trudne ze względu na złożoność i wrażliwość informacji, które należy przekazać²⁸.

Wnioski

Nietypowe genitalia to złożony stan, który może wynikać z różnych przyczyn, w tym zaburzeń hormonalnych, genetycznych i chromosomalnych. Najczęstszą przyczyną jest wrodzony przerost nadnerczy, szczególnie u dzieci z genotypem 46,XX. Inne przyczyny obejmują zespół niewrażliwości na androgeny, niedobór 5-alfa-reduktazy oraz zaburzenia rozwoju gonad.

Zrozumienie etiologii nietypowych genitaliów jest kluczowe dla właściwego leczenia i podejmowania decyzji dotyczących płci dziecka. Z odpowiednią opieką medyczną, chirurgiczną i psychospołeczną większość dzieci z zaburzeniami rozwoju płciowego prowadzi zdrowe, normalne życie¹⁹.

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Materiały źródłowe

#1 Atypical genitalia
https://johnsonmemorial.org/jmh-health/disease-conditions/con-20369257
Atypical genitalia usually happen when hormone changes during pregnancy stop or disturb an unborn baby’s developing sex organs. […] A change in the steps that influence fetal sex development can result in a mismatch between the appearance of a baby’s external genitals and the baby’s internal sex organs or genetic sex, typically XX or XY. […] If a genetic male fetus doesn’t make hormones called androgens or doesn’t have enough of these hormones, it can cause atypical genitalia. Exposure to androgens during development in a genetic female fetus results in atypical external genitalia. […] Changes in certain genes can affect fetal sex development and cause atypical genitalia. […] Atypical genitalia also can be a feature of certain rare or complex syndromes that affect many organs. These syndromes can include chromosome changes such as a missing sex chromosome or an extra one.
#1 Atypical genitalia
https://johnsonmemorial.org/jmh-health/disease-conditions/con-20369257
Causes of atypical genitalia in genetic females may include: Congenital adrenal hyperplasia. Certain forms of this genetic condition cause the adrenal glands to make too much of hormones called androgens. […] Exposure to certain hormones before birth. Some drugs that contain androgens or that cause a pregnant person’s body to make these hormones can cause developing female genitals to become more masculine. […] Causes of atypical genitalia in genetic males may include: Problems with testicle development. This may be due to changes in genes or due to unknown causes. […] Androgen insensitivity syndrome. In this condition, developing genital tissues don’t respond as they should to hormones made by the testicles. […] Problems with the testicles or testosterone. A variety of problems can interfere with the testicles’ activity. These can include problems with how the testicles are formed and problems with making the hormone testosterone. […] 5-alpha-reductase deficiency. Not having enough of this enzyme causes problems with making hormones that cause the development of male genitals.
#2 Ambiguous Genitalia: Definition & Causes
https://my.clevelandclinic.org/health/diseases/22470-atypical-genitalia-formerly-known-as-ambiguous-genitalia
Atypical genitalia, formerly known as ambiguous genitalia, is a rare condition where your newborn’s external genitals don’t look typically male or typically female. Ambiguous genitalia (intersex genitals) is a difference of sexual development caused by hormonal irregularities during pregnancy. […] Infants with atypical (intersex) genitals may have external genitals that don’t match their internal sex organs or genetic sex. Atypical genitalia is a difference of sexual development (DSD). […] Hormonal irregularities during pregnancy generally cause atypical genitalia. These irregularities interfere with your fetus’s developing sex organs. Causes vary depending on the number or combination of sex chromosomes that are present. […] With 46 XX DSD, your baby’s internal sex organs include ovaries and a uterus, but their external sex organs may resemble a penis and testicles. 46 XX occurs when your baby is exposed to too many male hormones (androgens) when their external genitals are forming. The most common cause of 46 XX DSD is a disorder called congenital adrenal hyperplasia (CAH). In this condition, your baby’s adrenal glands produce excessive amounts of androgens.
#2 Ambiguous Genitalia: Definition & Causes
https://my.clevelandclinic.org/health/diseases/22470-atypical-genitalia-formerly-known-as-ambiguous-genitalia
With 46 XY DSD, your baby’s internal sex organs are male but external sex organs are unclear. 46 XY occurs when your baby’s testes don’t develop properly, they don’t make enough testosterone or your baby’s body can’t use the testosterone correctly. […] With disorders of gonadal differentiation, your baby’s sex organs don’t develop completely into testes or ovaries. Mixed gonadal dysgenesis means the sex organs (testes or ovaries) may not fully develop. Partial gonadal dysgenesis means your baby’s sex organs form only some testicular tissue and the testes won’t work properly. Gonadal dysgenesis means both gonads stay premature and they won’t develop into testes or ovaries. […] With ovotesticular DSD, your baby’s sex organs have ovarian and testicular tissue, or your baby has one ovary and one teste. This is very rare.
#3 Ambiguous Genitalia and Disorders of Sexual Differentiation – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK557435/
The incidence of a child with a disorder of sexual development (DSD) is approximately 1 in 1000 to 4500 live births. The most frequently occurring etiology was congenital adrenal hyperplasia (CAH), followed by androgen insensitivity and mixed gonadal dysgenesis. […] In summary, any deviation from the intricate sequence of sexual development may give rise to disorders of sexual development.
#3 Ambiguous Genitalia and Disorders of Sexual Differentiation – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK557435/
A mutation in any of these above genes may lead to the development of DSD. A loss of genes involved in male sexual development can lead to an undervirilized male or 46 XY with a female phenotype. […] A finely balanced hormonal milieu is required for normal sexual development; testosterone is necessary to stabilize the Wolffian ducts, while secretion of anti-Mullerian factors is essential for the regression of Mullerian ducts. […] The male external genitalia requires the presence of dihydrotestosterone for normal phenotypic development. The deficiency of this hormone or resistance may lead to undervirilized genitalia. Exposure of female genitalia to excess androgens leads to virilization, which may be due to excess production or exogenous exposure. […] Aromatase deficiency is characterized by reduced levels of estrogen and increased levels of testosterone. This is seen in 46,XX females with ambiguous genitalia. They often have normal internal reproductive organs.
#3 Ambiguous Genitalia and Disorders of Sexual Differentiation – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK557435/
Sexual development in mammals occurs in two sequential stages: the initial phase of sex determination followed by sex differentiation. Sex determination is guided by the complement of sex chromosomes inherited at conception. The inheritance of the Y chromosome and the subsequent expression of the SRY gene drives the bipotential gonad toward differentiation into male-specific testes. In contrast, the absence of the Y chromosome results in the development of the female-specific ovary. The second stage of sex differentiation is characterized by the secretion of certain hormones and other factors by the differentiated gonad, which guides the internal and external genital development and maturation. The secretion of testosterone and anti-mullerian factor by the Leydig and Sertoli cells, respectively, cause the development of male internal organs and reciprocal regression of female sex organs. The absence of these hormones leads to the formation of the female sexual organs.
#4 Evaluation of the infant with atypical genital appearance (difference of sex development) – UpToDate
https://www.uptodate.com/contents/evaluation-of-the-infant-with-atypical-genital-appearance-difference-of-sex-development
Infants born with genitals that do not appear typically male or female, or that have an appearance discordant with the chromosomal sex, are classified as having a difference (or disorder) of sex development (DSD; terminology discussed further below). DSDs with a genital appearance that is sufficiently atypical to prompt evaluation occur in approximately 1 in 1000 to 4500 live births. […] Specific causes of DSDs and the management of affected infants are discussed separately. […] Concerns have been raised that DSD is an overly broad term that could be interpreted to encompass conditions in which no issues with genital appearance or gender identity are expected; and also that a broad umbrella term like DSD is unnecessary because it lacks sufficient specificity to be helpful diagnostically. […] Many of these individuals present as newborns with an atypical genital appearance sometimes termed „ambiguous genitalia.”
#5 Atypical genitalia | Beacon Health System
https://www.beaconhealthsystem.org/library/diseases-and-conditions/atypical-genitalia?content_id=CON-20369257
In this rare condition, a baby’s genitals are not clearly male or female. Genitals may not be fully developed or the baby may have features of more than one sex. […] Atypical genitalia, formerly called ambiguous genitalia, is a rare condition in which an infant’s genitals don’t appear to be clearly male or female on the outside. […] Atypical genitalia usually happen when hormone changes during pregnancy stop or disturb an unborn baby’s developing sex organs. […] A change in the steps that influence fetal sex development can result in a mismatch between the appearance of a baby’s external genitals and the baby’s internal sex organs or genetic sex, typically XX or XY. […] Causes of atypical genitalia in genetic females may include: Congenital adrenal hyperplasia. Certain forms of this genetic condition cause the adrenal glands to make too much of hormones called androgens.
#5 Atypical genitalia | Beacon Health System
https://www.beaconhealthsystem.org/library/diseases-and-conditions/atypical-genitalia?content_id=CON-20369257
Causes of atypical genitalia in genetic males may include: Problems with testicle development. This may be due to changes in genes or due to unknown causes. […] Family history may play a role in the development of atypical genitalia. This is because many differences of sex development result from gene changes that can be passed down in families. […] Sometimes it’s not possible to find the cause of atypical genitalia.
#6 Intersex – Wikipedia
https://en.wikipedia.org/wiki/Intersex
Intersex can be divided into four categories which are: 46, XX intersex; 46, XY intersex; true gonadal intersex; and complex or undetermined intersex. […] This condition used to be called „female pseudohermaphroditism”. Persons with this condition have female internal genitalia and karyotype (XX) and various degrees of external genitalia virilization. […] External genitalia is masculinized congenitally when a female fetus is exposed to an excess androgenic environment. […] The causes of this can be male hormones taken during pregnancy, congenital adrenal hyperplasia, male-hormone-producing tumors in the mother and aromatase deficiency. […] This condition used to be called „male pseudohermaphroditism”. This is defined as incomplete masculinization of the external genitalia. […] Thus, the person has male chromosomes, but the external genitals are incompletely formed, ambiguous, or clearly female.
#6 Intersex – Wikipedia
https://en.wikipedia.org/wiki/Intersex
46, XY intersex has many possible causes, which can be problems with the testes and testosterone formation. […] Androgen insensitivity syndrome is the most common cause of 46, XY intersex. […] This condition used to be called „true hermaphroditism”. This is defined as having asymmetrical gonads with ovarian and testicular differentiation on either side separately or combined as ovotestis. […] In most cases, the cause of this condition is unknown. […] This is the condition of having any chromosome configurations rather than 46, XX or 46, XY intersex. This condition does not result in an imbalance between internal and external genitalia. However, there may be problems with sex hormone levels, overall sexual development, and altered numbers of sex chromosomes.
#7 Disorders or Differences of Sex Development | SpringerLink
https://link.springer.com/10.1007/978-3-030-23709-7_1
Disorders or Differences of sex development (DSD) refer to a diverse group of conditions in which chromosomal, gonadal, or anatomic sex development is atypical. […] DSDs can be classified based on karyotype with further subdivision in disorders of gonadal development and problems of hormone synthesis or action. […] The increased availability of next generation sequencing has allowed for the identification of many new genes involved in DSD and the advent and increased accessibility of this technology has changed the diagnostic approach and refined the molecular genetic diagnosis in many cases.
#8 Atypical genitalia | Health Library | Memorial Health System
https://www.mhsystem.org/health-library/con-20369257/
Atypical genitalia also can be a feature of certain rare or complex syndromes that affect many organs. These syndromes can include chromosome changes such as a missing sex chromosome or an extra one. […] Causes of atypical genitalia in genetic females may include: Congenital adrenal hyperplasia. Certain forms of this genetic condition cause the adrenal glands to make too much of hormones called androgens. […] Causes of atypical genitalia in genetic males may include: Problems with testicle development. This may be due to changes in genes or due to unknown causes. […] Androgen insensitivity syndrome. In this condition, developing genital tissues dont respond as they should to hormones made by the testicles. […] A variety of problems can interfere with the testicles activity. These can include problems with how the testicles are formed and problems with making the hormone testosterone. […] Not having enough of this enzyme causes problems with making hormones that cause the development of male genitals.
#9 Atypical genitalia in neonates – Symptoms, diagnosis and treatment | BMJ Best Practice US
https://bestpractice.bmj.com/topics/en-us/868?locale=th
Atypical genitalia (i.e., a genital phenotype that is neither clearly male nor female) are caused by the atypical development of chromosomal, gonadal, or anatomical sex. The complex group of disorders that cause atypical genitalia are called differences of sex development (DSD). […] 46,XX DSD are conditions characterized by excess exposure to androgens. Over 95% of causes of atypical genitalia with a 46,XX genotype are due to congenital adrenal hyperplasia secondary to 21 hydroxylase deficiency. […] 46,XY DSD can be due to several etiologies and usually requires a more extensive diagnostic evaluation.
#10 Ambiguous Genitalia | Doctor
https://patient.info/doctor/ambiguous-genitalia
Ambiguous genitalia may be a result of a disorder of sexual development (DSD), previously called intersex conditions. […] The term DSD is now used for congenital conditions in which chromosomal, gonadal or anatomical sex is atypical. […] DSDs are caused by a variety of different conditions which vary greatly in incidence: […] The most common cause of ambiguous genitalia in the newborn is congenital adrenal hyperplasia (CAH). […] Mixed gonadal dysgenesis (MGD) is the next most common cause of ambiguous genitalia. […] Hypospadias is quite common (1 in 300 live births) but this is combined with undescended testes in less than 1% of such cases. […] To make a diagnosis, it is essential not only to understand normal development but also to understand the different pathophysiological mechanisms responsible for DSDs.
#11 Disorders of Sex Development
https://library.sarahbush.org/Wellness/Weight/90,P03079
Girl babies with this condition have male sex organs. The condition is caused by a lack of a certain enzyme in the adrenal gland. It’s the most common cause of atypical genitalia in newborns. […] High levels of male hormones may also enter the placenta via the mother. This could be when the mother is given progesterone to prevent a miscarriage. Or if she has a hormone-producing tumor.
#11 Disorders of Sex Development
https://library.sarahbush.org/Wellness/Weight/90,P03079
When a child’s gender is not clear at birth, the child has atypical genitalia (ambiguous genitalia). This means that the genitals don’t seem to be clearly male or female. […] Many genetic and environmental factors can affect the developing baby and lead to atypical genitalia. […] Atypical genitalia can have a number of different causes. In many cases, healthcare providers dont know the cause. It seems to occur by chance. […] The two primary causes of male pseudohermaphroditism are androgen insensitivity syndrome and 5-alpha reductase deficiency. […] This is called androgen insensitivity syndrome because male babies dont respond to testosterone (androgens). This syndrome is inherited. It’s caused by a problem with a gene on the X chromosome. […] Children with this condition lack an enzyme (5-alpha reductase). This enzyme is needed to help the male sex organs complete their development. This condition is inherited. It’s caused by an autosomal recessive gene.
#12 Disorders of Sex Development
https://healthlibrary.wvumedicine.org/SummerHeat/90,P03079
When a child’s gender is not clear at birth, the child has atypical genitalia (ambiguous genitalia). This means that the genitals don’t seem to be clearly male or female. […] Many genetic and environmental factors can affect the developing baby and lead to atypical genitalia. […] Atypical genitalia can have a number of different causes. In many cases, healthcare providers dont know the cause. It seems to occur by chance. […] The two primary causes of male pseudohermaphroditism are androgen insensitivity syndrome and 5-alpha reductase deficiency. […] This condition is inherited and passed on by an autosomal recessive gene. Autosomal recessive means that each parent carries one copy of the gene and passes on the gene to the child. Carrier parents have a 1 in 4 chance of having a child with this condition with each pregnancy. […] Girl babies with this condition have male sex organs. The condition is caused by a lack of a certain enzyme in the adrenal gland. It’s the most common cause of atypical genitalia in newborns. […] Other, rarer enzyme problems can also cause CAH in either boy babies or girl babies.
#13 Ambiguous Genitalia in the Newborn – Endotext – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK279168/
Ambiguous genitalia in a chromosomal 46,XX fetus invariably results from androgen excess during fetal development, and the degree of virilization often provides clues about the timing and severity of the underlying disorder. […] The term congenital adrenal hyperplasia (CAH) encompasses several adrenal disorders, each linked to a mutation in one of the enzymes necessary for the biosynthesis of cortisol from cholesterol. […] 21-hydroxylase deficiency CAH, caused by variants in CYP21A2, represents the most common form of CAH and is the most frequent genetic cause of DSD with ambiguous genitalia at birth in 46,XX newborns. […] Overall, individuals with PAIS experience variable degrees of end-organ unresponsiveness to androgens, resulting in varying degrees of Wolffian duct development and external genital ambiguity.
#14 Differences (Disorders) of Sex Development (DSDs): Practice Essentials, Background, Pathophysiology
https://emedicine.medscape.com/article/1015520-overview
Infants born with ambiguous or abnormal genitalia may have indeterminate phenotypic sex. […] DSDs may be caused by virilization of a child with 46,XX or undervirilization of a child with 46,XY. […] Congenital adrenal hyperplasia (CAH) is the most common cause of DSDs. […] The most common cause of CAH is 21-hydroxylase deficiency resulting in virilization of a child with 46,XX. […] 46,XX DSDs can be caused by CAH or maternal androgens. […] Overall, CAH is the most frequent cause of ambiguous genitalia in the newborn, constituting approximately 60% of all DSDs. […] The basic biochemical defect is an enzymatic block that prevents sufficient cortisol production. […] In 90% of patients with CAH, the block is at the 21-hydroxylation enzyme (21-hydroxylase deficiency). […] Another cause of CAH is 11-hydroxylase deficiency.
#14 Differences (Disorders) of Sex Development (DSDs): Practice Essentials, Background, Pathophysiology
https://emedicine.medscape.com/article/1015520-overview
A less frequently seen version of CAH is caused by 3-beta-hydroxysteroid dehydrogenase deficiency. […] Common causes of 46,XY DSDs include deficient biosynthesis of testosterone, complete androgen insensitivity syndrome, partial androgen insensitivity syndrome, 5-alpha-reductase deficiency, and isolated MIS deficiency. […] Production of testosterone from cholesterol involves five enzymatic steps, and defects have been identified at each step. […] Complete androgen insensitivity syndrome involves a failure of the end organs in a 46,XY gonadal male fetus to respond to appropriately produced levels of dihydrotestosterone (DHT). […] Partial androgen insensitivity syndrome occurs, demonstrating a spectrum of external genitalia ranging from very feminine to most masculine. […] A 46,XY fetus with normal testes but without the enzyme 5-alpha reductase cannot produce DHT.
#15 Content – Health Encyclopedia – University of Rochester Medical Center
https://www.urmc.rochester.edu/encyclopedia/content?ContentTypeID=90&ContentID=P03079
When a child’s gender is not clear at birth, the child has atypical genitalia (ambiguous genitalia). This means that the genitals don’t seem to be clearly male or female. […] Many genetic and environmental factors can affect the developing baby and lead to atypical genitalia. […] Atypical genitalia can have a number of different causes. In many cases, healthcare providers dont know the cause. It seems to occur by chance. […] The two primary causes of male pseudohermaphroditism are androgen insensitivity syndrome and 5-alpha reductase deficiency. […] This condition is inherited and passed on by an autosomal recessive gene. Autosomal recessive means that each parent carries one copy of the gene and passes on the gene to the child. Carrier parents have a 1 in 4 chance of having a child with this condition with each pregnancy. […] Girl babies with this condition have atypical genitalia. Boy babies don’t. […] Another type of CAH is called salt-losing. This is very serious and often fatal. It causes an electrolyte collapse in the newborn. Treatment is available if diagnosed early. Boys and girls are equally affected.
#16 Disorders of Sex Development
https://healthlibrary.somc.org/Library/DiseasesConditions/Adult/Surgical/90,P03079
Girl babies with this condition have male sex organs. The condition is caused by a lack of a certain enzyme in the adrenal gland. It’s the most common cause of atypical genitalia in newborns. […] Another type of CAH is called salt-losing. This is very serious and often fatal. It causes an electrolyte collapse in the newborn. Treatment is available if diagnosed early. Boys and girls are equally affected. […] High levels of male hormones may also enter the placenta via the mother. This could be when the mother is given progesterone to prevent a miscarriage. Or if she has a hormone-producing tumor.
#17 Ambiguous genitalia: MedlinePlus Medical EncyclopediaLock
https://medlineplus.gov/ency/article/003269.htm
Ambiguous genitalia is a rare condition where a child is born with outer genitals that do not clearly look either male or female. This condition is also called uncertain genitalia or atypical genitalia. Ambiguous genitalia is common in children with differences of sex development (DSD). […] The male and female reproductive organs and genitals both come from the same tissue in the fetus. Ambiguous genitalia can develop if the process that causes this fetal tissue to become „male” or „female” is disrupted. […] Causes for ambiguous genitalia include: 46,XX disorder of sex development (DSD) and 46,XY DSD. The genitalia are of one sex, but some physical characteristics of the other sex are present. Ovotesticular DSD. This is a very rare condition, in which tissue from both the ovaries and testicles is present. The child may have parts of both male and female genitals. Congenital adrenal hyperplasia. This condition has several forms, but the most common form causes a genetic female to appear male.
#18 Disorders of Sex Development
https://healthlibrary.somc.org/library/diseasesconditions/adult/Environmental/90,P03079
Gonadal dysgenesis: These children have an undeveloped sex organ, internal sex organs that are often female, external genitals that may vary between normal female and normal male (most are female), and chromosomes that are normal, have only an X chromosome, or are a mixture (mosaic). […] Pure gonadal dysgenesis: This affects girls. Those with this condition have male chromosomes, underdeveloped sex organs, internal female reproductive organs, and female external genitalia. […] Pseudohermaphroditism in males: Children with this condition have questionable external genitalia. But they have only one gender’s internal sex organs. Male pseudohermaphrodite means the child has male internal sex organs. Female pseudohermaphrodite means the child has female internal sex organs. […] The two primary causes of male pseudohermaphroditism are androgen insensitivity syndrome and 5-alpha reductase deficiency.
#18 Disorders of Sex Development
https://healthlibrary.somc.org/library/diseasesconditions/adult/Environmental/90,P03079
Androgen insensitivity syndrome: These children have normal male chromosomes and normal female external genitalia. […] 5-alpha-reductase deficiency: Children with this condition have normal male chromosomes and genitals that are ambiguous. […] Female pseudohermaphroditism has a number of causes. […] Congenital adrenal hyperplasia (CAH): Girl babies with this condition have male sex organs. The condition is caused by a lack of a certain enzyme in the adrenal gland. It’s the most common cause of atypical genitalia in newborns. […] Overproduction of male hormones before birth: This condition is often caused by a problem with the adrenal glands. High levels of male hormones may also enter the placenta via the mother.
#19 Disorders of Sexual Differentiation Program – Children’s Hospital of Orange County
https://choc.org/programs-services/urology/disorders-sexual-differentiation-program/
Congenital adrenal hyperplasia (CAH) is a genetic disorder in which the adrenal gland over produces androgens, a male hormone. Due to this, a child born with CAH will likely have genitalia that does not appear typical. […] Mixed gonadal dysgenesis occurs in children who have a chromosomal abnormality that causes them to be born with two different gonadsâan undescended testis and a dygenetic (malformed) âstreakâ gonad. […] Children with androgen insensitivity syndrome have a 46, XY karyotype for a normal male. The cells within the body in these children do not respond to the male sex hormone, androgen (testosterone). […] Children with pure gonadal dysgenesis syndrome have a 46, XY karyotype of a normal male but have underdeveloped gonads and both internal and external female genitalia.
#19 Disorders of Sexual Differentiation Program – Children’s Hospital of Orange County
https://choc.org/programs-services/urology/disorders-sexual-differentiation-program/
Children with 5-alpha-reductase deficiency have a 46, XY karyotype of a normal male but have a deficient enzyme (5-alpha reductase) that prevents the body from being able to change testosterone into dihydrotestosterone. […] Treatments for disorders of sexual differentiation (DSD) vary depending on the degree and type of disorder. Each treatment plan is individualized to each child and their family. […] With proper medical, surgical and psychosocial care, most children with disorders of sexual differentiation (DSD) lead healthy, normal lives.
#20 Disorders/differences of sex development (DSDs) for primary care: the approach to the infant with ambiguous genitalia – Indyk – Translational Pediatrics
https://tp.amegroups.org/article/view/16975/html
In addition to CAH being often recognized as the most common cause of genital ambiguity in infants and neonates, other notable causes include partial androgen insensitivity syndrome (Partial AIS or PAIS). AIS is caused by mutations in the androgen receptor (AR) gene on the X chromosome, and dictates response to androgen such as testosterone or DHT. […] Unfortunately, a great number of cases do not have an identifiable cause, particularly among 46XY DSD, which highlights the importance of an experienced team with multidisciplinary focus. […] Please note that congenital malformations can also cause genital ambiguity, many of which have a primary genetic cause, and others which have a more structural or developmental cause and do not have any hormonal basis.
#21 Ambiguous genitalia Information | Mount Sinai – New York
https://www.mountsinai.org/health-library/symptoms/ambiguous-genitalia
Ovotesticular DSD. This is a very rare condition, in which tissue from both the ovaries and testicles is present. The child may have parts of both male and female genitals. […] Congenital adrenal hyperplasia. This condition has several forms, but the most common form causes a genetic female to appear male. […] Chromosomal abnormalities, including Klinefelter syndrome (47,XXY) and Turner syndrome (45,X). […] If the mother takes certain medicines (such as androgenic steroids), a genetic female may look more male. […] Lack of production of certain hormones can cause the embryo to develop with a female body type, regardless of genetic sex. […] Androgen insensitivity syndrome. Even if the body makes the hormones needed to develop into a physical male, the body does not respond normally to those hormones. This may produce female characteristics, even though the genetic sex is male.
#22 HIE Multimedia – Ambiguous genitalia
https://adamcertificationdemo.adam.com/content.aspx?productid=117&pid=1&gid=003269
Congenital adrenal hyperplasia. This condition has several forms, but the most common form causes a genetic female to appear male. […] Chromosomal abnormalities, including Klinefelter syndrome (47,XXY) and Turner syndrome (45,X). […] If the mother takes certain medicines (such as androgenic steroids), a genetic female may look more male. […] Lack of production of certain hormones can cause the embryo to develop with a female body type, regardless of genetic sex. […] Androgen insensitivity syndrome. Even if the body makes the hormones needed to develop into a physical male, the body does not respond normally to those hormones. This may produce female characteristics, even though the genetic sex is male.
#23 Atypical genitalia – Diagnosis and treatment – Mayo Clinic
https://www.mayoclinic.org/diseases-conditions/atypical-genitalia/diagnosis-treatment/drc-20369278
The timing of surgery depends on your child’s specific situation. […] For children with atypical genitalia, the sex organs may work properly in spite of how the genitals look on the outside. […] What caused my baby’s atypical genitalia? […] What genetic testing has been done? […] What other tests might my baby need?
#24 Disorders of Sex Development
https://healthlibrary.ecuhealth.org/Library/DiseasesConditions/Adult/Kidney/90,P03079
The condition is inherited and passed on by an autosomal recessive gene. Autosomal recessive means that each parent carries one copy of the gene and passes on the gene to the child. Carrier parents have a 1 in 4 chance of having a child with this condition with each pregnancy. […] Making a correct determination of gender is important for treatment. But it’s also important for the child’s emotional well-being. Some children born with atypical genitalia may have normal internal sex organs that allow them to live normal, fertile lives. But others may have problems with fertility as adults.
#25 Disorders of Sex Development
https://healthlibrary.orovillehospital.com/Library/DiseasesConditions/Adult/NervousSystem/90,P03079
Androgen insensitivity syndrome […] 5-alpha-reductase deficiency […] Pseudohermaphroditism in females […] Congenital adrenal hyperplasia (CAH) […] Overproduction of male hormones before birth […] Treatment for atypical genitalia depends on the type of the disorder. But it often includes surgery to remove or create sex organs appropriate for the child’s gender. Treatment may also include hormone therapy. […] Long-term outlook for children born with atypical genitalia. Making a correct determination of gender is important for treatment. But it’s also important for the child’s emotional well-being. Some children born with atypical genitalia may have normal internal sex organs that allow them to live normal, fertile lives. But others may have problems with fertility as adults.
#26 Ambiguous Genitalia (Atypical Genitalia) | Children’s Hospital Colorado
https://www.childrenscolorado.org/conditions-and-advice/conditions-and-symptoms/conditions/ambiguous-genetalia/
Ambiguous genitalia is a rare condition where a baby is born with external genitalia that aren’t clearly defined as male or female. […] Ambiguous genitalia is also called atypical genitalia. It’s considered a disorder or difference of sex development (DSD), a group of conditions (previously called intersex) that occur when biological sex and external genitalia don’t match. […] Ambiguous genitalia form when any of these steps are disrupted. Disruptions can occur because of: Chromosomal problems, such as an extra or missing chromosome, Gene changes (mutations), Lack of or overexposure to male hormones in utero. […] Your family history can increase the chances of having a baby with ambiguous genitalia. Risk factors include a family history of atypical genitalia.
#27 Sex Development Disorders | Valley Children’s Healthcare
https://www.valleychildrens.org/services/diabetes-and-endocrinology/conditions-we-treat/sex-development-disorders
This condition is inherited and passed on by an autosomal recessive gene. Autosomal recessive means that each parent carries one copy of the gene and passes on the gene to the child. Carrier parents have a 1 in 4 chance of having a child with this condition with each pregnancy. […] Girl babies with this condition have male sex organs. The condition is caused by a lack of a certain enzyme in the adrenal gland. It’s the most common cause of atypical genitalia in newborns. […] Overproduction of male hormones before birth. This condition is often caused by a problem with the adrenal glands. High levels of male hormones may also enter the placenta via the mother.
#28 Genetic counseling in atypical genitalia: Challenges and proposed communication approach – Wadia Journal of Women and Child Health
https://wjwch.com/genetic-counseling-in-atypical-genitalia-challenges-and-proposed-communication-approach/
Genetic counseling for the parents and conveying the test results is very challenging considering the complexity and sensitivity of the information to be shared. […] Time taken for chromosomal karyotype report is also one of the concerns as it takes around weeks time. […] Educating them about genetic evaluation and confirmation of the cause will help them in the management of the child, and to make them understand the importance of preventing the same in the next pregnancy is also at times challenging. […] DSD is a complex congenital condition. Laboratory genetic diagnosis is very important for counseling parents or patient. […] Since genetic reports are complex and not applicable to the patient, only genetic counseling should be carried out by a trained genetic counselor or a medical geneticist.