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{{Split-apart|date=September 2010}}
#REDIRECT [[Androgen insensitivity syndrome#Complete AIS]]{{R from alternative name}}{{R to section}}
{{Infobox disease
| Name = Complete androgen insensitivity syndrome
| Image = Orchids01.JPG
| Caption = Women with AIS and [[Disorders of sex development|DSD]] related conditions.
| DiseasesDB = 29662
| DiseasesDB_mult = {{DiseasesDB2|12975}}
| ICD10 = {{ICD10|E|34|5|e|20}}
| ICD9 = {{ICD9|259.5}}
| ICDO =
| OMIM = 312300
| OMIM_mult = {{OMIM2|300068}}
| MedlinePlus =
| eMedicineSubj = ped
| eMedicineTopic = 2222
| MeshID = D013734
| GeneReviewsID = androgen
| GeneReviewsName = Androgen Insensitivity Syndrome
}}

'''Complete androgen insensitivity syndrome''' (CAIS) is a condition that results in the complete inability of the [[Eukaryote#Animal_cell|cell]] to respond to [[androgen]]s<ref name="2006 hughes 20" /><ref name="2008 galani 7" /><ref name="1995 quigley 16" />. The unresponsiveness of the cell to the presence of androgenic hormones prevents the [[Development_of_the_reproductive_system#External_genitalia|masculinization of male genitalia]] in the developing fetus, as well as the development of male [[Secondary sex characteristics|secondary sexual characteristics]] at [[puberty]], but does not significantly impair female genital or sexual development<ref name="1995 quigley 16" /><ref name="2002 giwercman 87" />. As such, the insensitivity to androgens is only clinically significant when it occurs in genetic males (i.e. individuals with a [[Y chromosome]], or more specifically, an [[SRY|SRY gene]])<ref name="2006 hughes 20" />. Clinical [[phenotypes]] in these individuals ranges from a full [[Female body shape|female habitus]], despite the presence of a Y chromosome<ref name="2006 hughes 20" /><ref name="2008 zuccarello 68" /><ref name="2006 ferlin 65" /><ref name="2009 stouffs 15" /><ref name="2001 giwercman 54" /><ref name="2003 lund 79" />.

CAIS is one of three types of [[androgen insensitivity syndrome]], which is divided into three categories that are differentiated by the degree of [[Development_of_the_reproductive_system#External_genitalia|genital masculinization]]: complete androgen insensitivity syndrome (CAIS) is indicated when the external genitalia is that of a normal female, [[mild androgen insensitivity syndrome]] (MAIS) is indicated when the external genitalia is that of a normal male, and [[partial androgen insensitivity syndrome]] (PAIS) is indicated when the external genitalia is partially, but not fully masculinized <ref name="2006 hughes 20" /><ref name="2008 galani 7" /><ref name="2008 zuccarello 68" /><ref name="2006 ferlin 65" /><ref name="2009 stouffs 15" /><ref name="2010 ozulker 24" /><ref name="2007 davis-dao 92" /><ref name="2005 kawate 90" /><ref name="2005 gottlieb 10" />.

Androgen insensitivity syndrome is the largest single entity that leads to 46,XY [[Intersexuality#Conditions|undermasculinization]] <ref name="1999 ahmed 80" />.

==Signs and symptoms==
[[File:Complete androgen insensitivity syndrome.jpg|thumb|Women with complete androgen insensitivity are born phenotypically female, despite having a 46,XY karyotype<ref name="1976 simpson" /><ref name="2000 gilbert" />.]]
Individuals with complete androgen insensitivity syndrome (grades 6 and 7 on the Quigley scale) are born [[Female body shape|phenotypically female]], without any signs of genital masculinization, despite having a [[karyotype|46,XY karyotype]] <ref name="2008 oakes 21" />. Symptoms of CAIS do not appear until [[puberty]] <ref name="2008 galani 7" />, which may be slightly delayed <ref name="2009 nichols 91" />, but is otherwise normal except for absent [[menses]] and diminished or absent [[Secondary sex characteristic|secondary]] [[terminal hair]] <ref name="2006 hughes 20" />. [[Axillary hair]] (i.e. armpit hair) fails to develop in one third of all cases <ref name="2003 melo 88" />. External genitalia is normal, although the [[Labia minora|labia]] and [[clitoris]] are sometimes underdeveloped <ref name="2003 minto 80" /><ref name="1997 sinnecker 156" />. The [[vagina|vaginal depth]] is widely variable, but is typically shorter than unaffected women <ref name="2006 hughes 20" />; one study of eight women with CAIS measured the average vaginal depth to be 5.9&nbsp;cm <ref name="2007 ismail-pratt 22" /> (vs. 11.1 ± 1.0&nbsp;cm for unaffected women <ref name="1995 weber 86" />). In some extreme cases, the vagina has been reported to be [[aplasia|aplastic]] (resembling a "dimple"), though the exact incidence of this is unknown <ref name="2010 quint 53" />.

The [[gonads]] in these women are not [[ovaries]], but instead, are [[testes]]; during the [[Human embryogenesis|embryonic stage of development]], testes form in an androgen-independent process that occurs due to the influence of the [[SRY|SRY gene]] on the [[Y chromosome]] <ref name="2006 achermann" /><ref name="1995 simpson" />. They may be located intra-abdominally, at the internal [[inguinal ring]], or may [[Inguinal hernia|herniate]] into the [[labia majora]] <ref name="2006 hughes 20" /><ref name="2008 decaestecker 89" /><ref name="1953 morris 65" /><ref name="1984 muller 59" />. [[Germ cells]] in the testes are arrested at an early stage and do not mature into [[sperm]], since sensitivity to androgens is required in order for [[spermatogenesis]] to complete <ref name="2001 johnston 142" /><ref name="2003 yong 9" />. [[Germ cell tumor|Germ cell malignancy]] risk, once thought to be relatively high, is now thought to be approximately 2% <ref name="2006 hughes 91" />. [[Wolffian structures]] (the [[epididymis|epididymides]], [[vas deferens|vasa deferentia]], and [[seminal vesicles]]) are typically absent, but will develop at least partially in approximately 30% of cases, depending on which mutation is causing the CAIS <ref name="2004 hannema 89" />. The [[prostate]], like the [[Male external genitalia|external male genitalia]], cannot [[Development_of_the_reproductive_system#External_genitalia|masculinize]] in the absence of [[androgen receptor]] function, and thus remains in the [[Prostate#Female_prostate_gland|female form]] <ref name="2008 oakes 21" /><ref name="1999 roy 55" /><ref name="1999 kokontis 55" /><ref name="2009 rajender 91" />.

The [[Müllerian system]] (the [[fallopian tubes]], [[uterus]], and upper portion of the [[vagina]]) typically regresses due to the presence of [[anti-Müllerian hormone]] originating from the [[Sertoli cells]] of the [[testes]] <ref name="2009 nichols 91" />. These women are thus born without fallopian tubes, a [[cervix]], or a uterus <ref name="2009 nichols 91" />, and the vagina ends "blindly" in a pouch <ref name="2006 hughes 20" />. [[Anti-Müllerian_hormone#Function|Müllerian regression]] does not fully complete in approximately one third of all cases, resulting in Müllerian "remnants" <ref name="2009 nichols 91" />. Although rare, a few cases of women with CAIS and fully developed Müllerian structures have been reported. In one exceptional case, a 22 year old with CAIS was found to have a normal cervix, uterus, and fallopian tubes <ref name="1999 chen 72" />. In an unrelated case, a fully developed uterus was found in a 22 year old adult with CAIS <ref name="2009 rajender 91" />.

Other subtle differences that have been reported include slightly longer limbs and larger hands and feet due to a proportionally greater stature than unaffected women <ref name="2006 papadimitriou 65" /><ref name="2000 wisniewski 85" /><ref name="1984 varella 11" />, larger teeth <ref name="1980 alvesalo 32" /><ref name="1997 pietila 19" />, minimal or no acne <ref name="2002 sultan 20" />, well developed breasts <ref name="1986 zachmann 108" />, and a greater incidence of [[Meibomian_gland#Dysfunction|meibomian gland dysfunction]] (i.e. [[Keratoconjunctivitis sicca|dry eye syndromes]] and [[Photophobia|light sensitivity]]) <ref name="2003 cermak 22" />.

===Comorbidity===
[[File:Histopathology of androgen insensitivity.jpg|thumb|Histopathology of testicular tissue showing immature germ cells and spermatagonia with decreased tubular diameter. Scattered groups of Leydig cells appearing immature<ref name="2009 nichols 91" />.]]
All forms of androgen insensitivity are associated with [[infertility]], though exceptions have been reported for both the mild and partial forms <ref name="2008 zuccarello 68" /><ref name="2009 stouffs 15" /><ref name="2002 chu 87" /><ref name="2005 menakaya 25" /><ref name="2000 giwercman 85" /><ref name="2002 giwercman 87" />.

CAIS is associated with a decreased [[bone mineral density]] <ref name="2007 danilovic 18" /><ref name="2006 sobel 91" /><ref name="2000 marcus 85" /><ref name="1998 bertelloni 50" /><ref name="1995 soule 43" /><ref name="1995 munoz-torres 57" />. Some have hypothesized that the decreased bone mineral density observed in women with CAIS is related to the timing of [[gonadectomy]] and inadequate [[estrogen]] [[Hormone replacement therapy (menopause)|supplementation]] <ref name="1995 soule 43" />. However, recent studies show that bone mineral density is similar whether gonadectomy occurs before or after [[puberty]], and is decreased despite estrogen supplementation, leading some to hypothesize that the deficiency is directly attributable to the role of androgens in bone [[Mineralization (biology)|mineralization]] <ref name="2007 danilovic 18" /><ref name="2006 sobel 91" /><ref name="2000 marcus 85" /><ref name="1998 bertelloni 50" />.

CAIS is also associated with an increased risk for [[germ cell tumor|gonadal tumors]] (e.g. germ cell malignancy) in adulthood if gonadectomy is not performed <ref name="2006 hughes 91" /><ref name="2006 hannema 208" /><ref name="1991 rutgers 10" /><ref name="1976 manuel 124" />. The risk of [[malignancy|malignant]] germ cell tumors in women with CAIS increases with age and has been estimated to be 3.6% at 25 years and 33% at 50 years <ref name="1976 manuel 124" />. The incidence of gonadal tumors in childhood is thought to be relatively low; a recent review of the medical literature <ref name="2006 hannema 208" /> found that only three cases of malignant germ cell tumors in prepubescent girls have been reported in association with CAIS in the last 100 years. Some have estimated the incidence of germ cell malignancy to be as low as 0.8% before puberty <ref name="2006 hughes 20" />.

Vaginal [[hypoplasia]], a relatively frequent finding in CAIS and some forms of PAIS <ref name="2007 ismail-pratt 22" /><ref name="2010 quint 53" />, is associated with sexual difficulties including vaginal penetration difficulties and [[dyspareunia]] <ref name="2003 minto 80" /><ref name="2010 quint 53" />.

At least one study indicates that individuals with an [[intersex]] condition may be more prone to psychological difficulties, due at least in part to parental attitudes and behaviors <ref name="1998 froukje 27" />, and concludes that preventative long-term [[psychotherapy|psychological counseling]] for parents as well as for affected individuals should be initiated at the time of diagnosis.

Lifespan is not thought to be affected by AIS <ref name="2006 hughes 20" />.

==Diagnosis==
[[File:Complete androgen insensitivity presenting with inguinal hernia.jpg|thumb|Bilateral inguinal hernia. CAIS is not usually suspected until after puberty unless an inguinal hernia presents<ref name="2006 borisa 48" />.]]
CAIS can only be diagnosed in normal phenotypic females <ref name="2008 galani 7" />. It is not usually suspected unless the [[menses]] fail to develop at puberty, or an [[inguinal hernia]] presents during [[Menarche|premenarche]] <ref name="2006 hughes 20" /><ref name="2008 galani 7" />. As many as 1-2% of prepubertal girls that present with an inguinal hernia will also have CAIS <ref name="2006 hughes 20" /><ref name="2009 nichols 91" />.

A diagnosis of CAIS or [[Swyer syndrome]] can be made [[in utero]] by comparing a [[karyotype]] obtained by [[amniocentesis]] with the external genitalia of the fetus during a prenatal [[ultrasound]] <ref name="2008 galani 7" /><ref name="2003 michailidis 76" />. Many infants with CAIS do not experience the normal, spontaneous neonatal [[testosterone]] surge, a fact which can be diagnostically exploited by obtaining baseline [[luteinizing hormone]] and testosterone measurements, followed by a [[human chorionic gonadotropin]] (hGC) stimulation test <ref name="2006 hughes 20" />.

The main [[differential diagnosis|differentials]] for CAIS are complete gonadal dysgenesis ([[Swyer syndrome]]) and Müllerian agenesis ([[Mayer-Rokitansky-Kuster-Hauser syndrome]] or MRKH) <ref name="2006 hughes 20" /><ref name="2010 quint 53" />. Both CAIS and Swyer syndrome are associated with a [[karyotype|46,XY karyotype]], whereas MRKH is not; MRKH can thus be ruled out by checking for the presence of a [[Y chromosome]], which can be done either by [[fluorescence in situ hybridization]] (FISH) analysis or on full karyotype <ref name="2006 hughes 20" />. Swyer syndrome is distinguished by poor breast development and shorter stature <ref name="2006 hughes 20" />. The diagnosis of CAIS is confirmed when [[androgen receptor|AR]] [[gene sequencing]] reveals a [[mutation]], although up to 5% of individuals with CAIS do not have an AR mutation <ref name="2008 galani 7" />.

Up until the 1990s, a CAIS diagnosis was often hidden from the affected individual and / or family <ref name="2008 oakes 21" />. It is current practice to disclose the [[genotype]] at the time of diagnosis, particularly when the affected girl is at least of adolescent age <ref name="2008 oakes 21" />. If the affected individual is a child or infant, it is generally up to the parents, often in conjunction with a psychologist, to decide when to disclose the diagnosis <ref name="2008 oakes 21" />.

==Management==
Management of AIS is currently limited to [[symptomatic treatment|symptomatic management]]; methods to correct a malfunctioning [[androgen receptor]] protein that result from an AR gene [[mutation]] are not currently available. Areas of management include [[sex assignment]], [[genitoplasty]], [[gonadectomy]] in relation to [[germ cell tumor|tumor]] risk, [[Hormone replacement therapy (menopause)|hormone replacement therapy]], and [[genetic counseling|genetic]] and [[psychotherapy|psychological counseling]].

Individuals with CAIS are raised as females <ref name="2006 hughes 20" />. They are born [[phenotype|phenotypically]] female and almost always have a heterosexual female [[gender identity]] <ref name="2000 wisniewski 85" /><ref name="2009 kulshreshtha 38" />; the incidence of homosexuality in women with CAIS is thought to be less than unaffected women <ref name="1984 money 9" />. At least one case study exists that describes an individual with CAIS and a male gender identity, although its author suggests that cultural and societal circumstances may have exerted undue influence <ref name="2009 kulshreshtha 38" />.

[[File:Results of vaginal lengthening by pressure dilation methods.jpg|thumb|Vaginal length in 8 women with CAIS before and after dilation therapy as first line treatment. The normal reference range (shaded) is derived from 20 control women. Duration and extent of therapy varied; the median time to completion of treatment was 5.2 months, and the median number of 30-minute dilations per week was 5<ref name="2007 ismail-pratt 22" />.]]
Most cases of vaginal [[hypoplasia]] associated with CAIS can be corrected using non-surgical pressure [[dilation]] methods <ref name="2007 ismail-pratt 22" /><ref name="2010 quint 53" />. The elastic nature of vaginal tissue, as demonstrated by its ability to accommodate the differences in size between a [[tampon]], a penis, and a baby's head <ref name="1996 grover 1" />, make dilation possible even in cases when the vaginal depth is significantly compromised <ref name="2007 ismail-pratt 22" /><ref name="2010 quint 53" />. [[Compliance (medicine)|Treatment compliance]] is thought to be critical to achieve satisfactory results <ref name="2003 minto 80" /><ref name="2007 ismail-pratt 22" /><ref name="2010 quint 53" />. Dilation can also be achieved via the [[Vaginoplasty#Vecchietti_procedure|Vecchietti procedure]], which stretches vaginal tissues into a functional vagina using a [[traction]] device that is anchored to the [[abdominal wall]], [[Peritoneum|subperitoneal]] [[sutures]], and a mold that is placed against the vaginal dimple <ref name="2010 quint 53" />. Vaginal stretching occurs by increasing the tension on the sutures, which is performed daily <ref name="2010 quint 53" />. The non-operative pressure dilation method is currently recommended as the first choice, since it is [[Invasiveness_of_surgical_procedures#Non-invasive_procedure|non-invasive]], and highly successful <ref name="2010 quint 53" />. Vaginal dilation should not be performed before [[puberty]] <ref name="2006 hughes 91" />.

While it is recommended that women with CAIS eventually undergo [[gonadectomy]] to mitigate cancer risk, there are differing opinions regarding early versus late gonadectomy <ref name="2006 hughes 20" />. The risk of [[malignant]] [[germ cell tumors]] in women with CAIS increases with age and has been estimated to be 3.6% at 25 years and 33% at 50 years <ref name="1976 manuel 124" />. However, only three cases of malignant germ cell tumors in prepubescent girls with CAIS have been reported in the last 100 years <ref name="2006 hannema 208" />. The youngest of these girls was 14 years old <ref name="1989 hurt 161" />. If gonadectomy is performed early, then puberty must be artificially induced using gradually increasing doses of [[estrogen]] <ref name="2006 hughes 20" />. If gonadectomy is performed late, then puberty will occur on its own, due to the [[aromatase|aromatization of testosterone into estrogen]] <ref name="2006 hughes 20" />. Some choose to perform gonadectomy if and when [[inguinal hernia]] presents <ref name="2006 hughes 20" />. Postoperative [[Hormone replacement therapy (menopause)|estrogen replacement therapy]] is critical to minimize [[bone mineral density]] deficiencies later in life <ref name="2000 marcus 85" /><ref name="1995 soule 43" />.

Some have hypothesized that supraphysiological levels of [[estrogen]] may reduce the diminished bone mineral density associated with CAIS <ref name="2000 marcus 85" />. Data has been published that suggests affected women who were not compliant with estrogen replacement therapy, or who had a lapse in estrogen replacement, experienced a more significant loss of bone mineral density <ref name="2006 sobel 91" /><ref name="2000 marcus 85" />. [[Progestin]] replacement therapy is seldom initiated, due to the absence of a [[uterus]] <ref name="2006 hughes 20" />. [[Androgen replacement therapy|Androgen replacement]] has been reported to increase a sense of well-being in gonadectomized women with CAIS, although the mechanism by which this benefit is achieved is not well understood <ref name="2006 hughes 20" />.

It is no longer common practice to [[Medical_ethics#Truth-telling|hide a diagnosis]] of CAIS from the affected individual or her family <ref name="2008 oakes 21" />. Parents of children with CAIS need considerable support in planning and implementing disclosure for their child once the diagnosis has been established <ref name="2006 hughes 20" /><ref name="2008 oakes 21" />. For parents with young children, information disclosure is an ongoing, collaborative process requiring an individualized approach that evolves in concordance with the child's cognitive and [[psychological development]] <ref name="2006 hughes 20" />. In all cases, the assistance of a psychologist experienced in the subject is recommended <ref name="2006 hughes 20" /><ref name="2008 oakes 21" />.

===Neovaginal Construction===
Many surgical procedures have been developed to create a neovagina, as none of them is ideal <ref name="2010 quint 53" />. [[Invasiveness_of_surgical_procedures#Open_surgery|Surgical intervention]] should only be considered after non-surgical pressure dilation methods have failed to produce a satisfactory result <ref name="2010 quint 53" />. [[Neovaginoplasty]] can be performed using [[Skin grafting|skin grafts]], a segment of [[bowel]], [[ileum]], [[peritoneum]], Interceed, [[buccal mucosa]], [[amnion]], or [[dura mater]] <ref name="2010 quint 53" /><ref name="2002 steiner 84" /><ref name="2008 breech" />. Success of such methods should be determined by [[sexual function]], and not just by vaginal length, as has been done in the past <ref name="2008 breech" />. [[ileum|Ileal]] or [[cecum|cecal]] segments may be problematic because of a shorter [[mesentery]], which may produce tension on the neovagina, leading to [[stenosis]] <ref name="2008 breech" />. The [[Sigmoid colon|sigmoid]] neovagina is thought to be self-lubricating, without the excess [[mucus]] production associated with segments of [[small bowel]] <ref name="2008 breech" />. Vaginoplasty may create scarring at the [[introitus]] (the vaginal opening), which requires additional surgery to correct. Vaginal dilators are required postoperatively to prevent vaginal stenosis from scarring <ref name="2007 ismail-pratt 22" /><ref name="2010 quint 53" />. Other complications include [[bladder]] and bowel injuries <ref name="2010 quint 53" />. Yearly exams are required as neovaginoplasty carries a risk of [[carcinoma]] <ref name="2010 quint 53" />, although carcinoma of the neovagina is uncommon <ref name="2002 steiner 84" /><ref name="2008 breech" />. Neither neovaginoplasty nor vaginal dilation should be performed before [[puberty]] <ref name="2010 quint 53" /><ref name="2006 hughes 91" />.

==References==
{{Reflist | colwidth = 30em | refs =

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}}

==External links==
;Information
* {{GeneTests|androgen}}
* [http://www.rch.org.au/publications/CAIS.html An Australian parent/patient booklet on CAIS]
* [http://www.independent.co.uk/life-style/health-and-wellbeing/health-news/the-secret-of-my-sex-411032.html ''The Secret of My Sex''] news article
* [http://abcnews.go.com/Health/MedicalMysteries/Story?id=5465752&page=1 Women With Male DNA All Female] news article at ABCnews.com

;Patient groups
* [http://www.aissg.org AIS Support Group AISSG (UK and International)]
* [http://www.indiana.edu/~ais/html/home.html AIS Support Group (US)]
* [http://www.vicnet.net.au/~aissg AIS Support Group (Australasia)]
* [http://www.bodieslikeours.com/forums/ Intersex Support Forums (US and International)]

{{Endocrine pathology}}
{{X-linked disorders}}
{{Receptor deficiencies}}

{{DEFAULTSORT:Androgen Insensitivity Syndrome}}
[[Category:Genetic disorders]]
[[Category:Intersexuality]]
[[Category:Syndromes]]

[[ar:متلازمة نقص الاندروجين (متلازمة هرمون التذكير)]]
[[de:Komplette Androgenresistenz]]
[[et:Androgeenresistentsuse sündroom]]
[[es:Insensibilidad a los andrógenos]]
[[fr:Syndrome de l'insensibilité aux androgènes]]
[[ko:안드로젠 불감 증후군]]
[[it:Sindrome di Morris]]
[[lt:Adrenogenitalinis sindromas]]
[[hu:Androgén-inszenzitivitási szindróma]]
[[nl:Androgeenongevoeligheidssyndroom]]
[[ja:アンドロゲン不応症]]
[[pl:Zespół niewrażliwości na androgeny]]
[[ru:Синдром нечувствительности андрогенов]]
[[sv:Androgenokänslighet]]
[[th:กลุ่มอาการต่อต้านแอนโดรเจน]]

Revision as of 06:03, 31 October 2010

Complete androgen insensitivity syndrome
SpecialtyGynaecology, endocrinology Edit this on Wikidata

Complete androgen insensitivity syndrome (CAIS) is a condition that results in the complete inability of the cell to respond to androgens[1][2][3]. The unresponsiveness of the cell to the presence of androgenic hormones prevents the masculinization of male genitalia in the developing fetus, as well as the development of male secondary sexual characteristics at puberty, but does not significantly impair female genital or sexual development[3][4]. As such, the insensitivity to androgens is only clinically significant when it occurs in genetic males (i.e. individuals with a Y chromosome, or more specifically, an SRY gene)[1]. Clinical phenotypes in these individuals ranges from a full female habitus, despite the presence of a Y chromosome[1][5][6][7][8][9].

CAIS is one of three types of androgen insensitivity syndrome, which is divided into three categories that are differentiated by the degree of genital masculinization: complete androgen insensitivity syndrome (CAIS) is indicated when the external genitalia is that of a normal female, mild androgen insensitivity syndrome (MAIS) is indicated when the external genitalia is that of a normal male, and partial androgen insensitivity syndrome (PAIS) is indicated when the external genitalia is partially, but not fully masculinized [1][2][5][6][7][10][11][12][13].

Androgen insensitivity syndrome is the largest single entity that leads to 46,XY undermasculinization [14].

Signs and symptoms

Women with complete androgen insensitivity are born phenotypically female, despite having a 46,XY karyotype[15][16].

Individuals with complete androgen insensitivity syndrome (grades 6 and 7 on the Quigley scale) are born phenotypically female, without any signs of genital masculinization, despite having a 46,XY karyotype [17]. Symptoms of CAIS do not appear until puberty [2], which may be slightly delayed [18], but is otherwise normal except for absent menses and diminished or absent secondary terminal hair [1]. Axillary hair (i.e. armpit hair) fails to develop in one third of all cases [19]. External genitalia is normal, although the labia and clitoris are sometimes underdeveloped [20][21]. The vaginal depth is widely variable, but is typically shorter than unaffected women [1]; one study of eight women with CAIS measured the average vaginal depth to be 5.9 cm [22] (vs. 11.1 ± 1.0 cm for unaffected women [23]). In some extreme cases, the vagina has been reported to be aplastic (resembling a "dimple"), though the exact incidence of this is unknown [24].

The gonads in these women are not ovaries, but instead, are testes; during the embryonic stage of development, testes form in an androgen-independent process that occurs due to the influence of the SRY gene on the Y chromosome [25][26]. They may be located intra-abdominally, at the internal inguinal ring, or may herniate into the labia majora [1][27][28][29]. Germ cells in the testes are arrested at an early stage and do not mature into sperm, since sensitivity to androgens is required in order for spermatogenesis to complete [30][31]. Germ cell malignancy risk, once thought to be relatively high, is now thought to be approximately 2% [32]. Wolffian structures (the epididymides, vasa deferentia, and seminal vesicles) are typically absent, but will develop at least partially in approximately 30% of cases, depending on which mutation is causing the CAIS [33]. The prostate, like the external male genitalia, cannot masculinize in the absence of androgen receptor function, and thus remains in the female form [17][34][35][36].

The Müllerian system (the fallopian tubes, uterus, and upper portion of the vagina) typically regresses due to the presence of anti-Müllerian hormone originating from the Sertoli cells of the testes [18]. These women are thus born without fallopian tubes, a cervix, or a uterus [18], and the vagina ends "blindly" in a pouch [1]. Müllerian regression does not fully complete in approximately one third of all cases, resulting in Müllerian "remnants" [18]. Although rare, a few cases of women with CAIS and fully developed Müllerian structures have been reported. In one exceptional case, a 22 year old with CAIS was found to have a normal cervix, uterus, and fallopian tubes [37]. In an unrelated case, a fully developed uterus was found in a 22 year old adult with CAIS [36].

Other subtle differences that have been reported include slightly longer limbs and larger hands and feet due to a proportionally greater stature than unaffected women [38][39][40], larger teeth [41][42], minimal or no acne [43], well developed breasts [44], and a greater incidence of meibomian gland dysfunction (i.e. dry eye syndromes and light sensitivity) [45].

Comorbidity

Histopathology of testicular tissue showing immature germ cells and spermatagonia with decreased tubular diameter. Scattered groups of Leydig cells appearing immature[18].

All forms of androgen insensitivity are associated with infertility, though exceptions have been reported for both the mild and partial forms [5][7][46][47][48][4].

CAIS is associated with a decreased bone mineral density [49][50][51][52][53][54]. Some have hypothesized that the decreased bone mineral density observed in women with CAIS is related to the timing of gonadectomy and inadequate estrogen supplementation [53]. However, recent studies show that bone mineral density is similar whether gonadectomy occurs before or after puberty, and is decreased despite estrogen supplementation, leading some to hypothesize that the deficiency is directly attributable to the role of androgens in bone mineralization [49][50][51][52].

CAIS is also associated with an increased risk for gonadal tumors (e.g. germ cell malignancy) in adulthood if gonadectomy is not performed [32][55][56][57]. The risk of malignant germ cell tumors in women with CAIS increases with age and has been estimated to be 3.6% at 25 years and 33% at 50 years [57]. The incidence of gonadal tumors in childhood is thought to be relatively low; a recent review of the medical literature [55] found that only three cases of malignant germ cell tumors in prepubescent girls have been reported in association with CAIS in the last 100 years. Some have estimated the incidence of germ cell malignancy to be as low as 0.8% before puberty [1].

Vaginal hypoplasia, a relatively frequent finding in CAIS and some forms of PAIS [22][24], is associated with sexual difficulties including vaginal penetration difficulties and dyspareunia [20][24].

At least one study indicates that individuals with an intersex condition may be more prone to psychological difficulties, due at least in part to parental attitudes and behaviors [58], and concludes that preventative long-term psychological counseling for parents as well as for affected individuals should be initiated at the time of diagnosis.

Lifespan is not thought to be affected by AIS [1].

Diagnosis

Bilateral inguinal hernia. CAIS is not usually suspected until after puberty unless an inguinal hernia presents[59].

CAIS can only be diagnosed in normal phenotypic females [2]. It is not usually suspected unless the menses fail to develop at puberty, or an inguinal hernia presents during premenarche [1][2]. As many as 1-2% of prepubertal girls that present with an inguinal hernia will also have CAIS [1][18].

A diagnosis of CAIS or Swyer syndrome can be made in utero by comparing a karyotype obtained by amniocentesis with the external genitalia of the fetus during a prenatal ultrasound [2][60]. Many infants with CAIS do not experience the normal, spontaneous neonatal testosterone surge, a fact which can be diagnostically exploited by obtaining baseline luteinizing hormone and testosterone measurements, followed by a human chorionic gonadotropin (hGC) stimulation test [1].

The main differentials for CAIS are complete gonadal dysgenesis (Swyer syndrome) and Müllerian agenesis (Mayer-Rokitansky-Kuster-Hauser syndrome or MRKH) [1][24]. Both CAIS and Swyer syndrome are associated with a 46,XY karyotype, whereas MRKH is not; MRKH can thus be ruled out by checking for the presence of a Y chromosome, which can be done either by fluorescence in situ hybridization (FISH) analysis or on full karyotype [1]. Swyer syndrome is distinguished by poor breast development and shorter stature [1]. The diagnosis of CAIS is confirmed when AR gene sequencing reveals a mutation, although up to 5% of individuals with CAIS do not have an AR mutation [2].

Up until the 1990s, a CAIS diagnosis was often hidden from the affected individual and / or family [17]. It is current practice to disclose the genotype at the time of diagnosis, particularly when the affected girl is at least of adolescent age [17]. If the affected individual is a child or infant, it is generally up to the parents, often in conjunction with a psychologist, to decide when to disclose the diagnosis [17].

Management

Management of AIS is currently limited to symptomatic management; methods to correct a malfunctioning androgen receptor protein that result from an AR gene mutation are not currently available. Areas of management include sex assignment, genitoplasty, gonadectomy in relation to tumor risk, hormone replacement therapy, and genetic and psychological counseling.

Individuals with CAIS are raised as females [1]. They are born phenotypically female and almost always have a heterosexual female gender identity [39][61]; the incidence of homosexuality in women with CAIS is thought to be less than unaffected women [62]. At least one case study exists that describes an individual with CAIS and a male gender identity, although its author suggests that cultural and societal circumstances may have exerted undue influence [61].

Vaginal length in 8 women with CAIS before and after dilation therapy as first line treatment. The normal reference range (shaded) is derived from 20 control women. Duration and extent of therapy varied; the median time to completion of treatment was 5.2 months, and the median number of 30-minute dilations per week was 5[22].

Most cases of vaginal hypoplasia associated with CAIS can be corrected using non-surgical pressure dilation methods [22][24]. The elastic nature of vaginal tissue, as demonstrated by its ability to accommodate the differences in size between a tampon, a penis, and a baby's head [63], make dilation possible even in cases when the vaginal depth is significantly compromised [22][24]. Treatment compliance is thought to be critical to achieve satisfactory results [20][22][24]. Dilation can also be achieved via the Vecchietti procedure, which stretches vaginal tissues into a functional vagina using a traction device that is anchored to the abdominal wall, subperitoneal sutures, and a mold that is placed against the vaginal dimple [24]. Vaginal stretching occurs by increasing the tension on the sutures, which is performed daily [24]. The non-operative pressure dilation method is currently recommended as the first choice, since it is non-invasive, and highly successful [24]. Vaginal dilation should not be performed before puberty [32].

While it is recommended that women with CAIS eventually undergo gonadectomy to mitigate cancer risk, there are differing opinions regarding early versus late gonadectomy [1]. The risk of malignant germ cell tumors in women with CAIS increases with age and has been estimated to be 3.6% at 25 years and 33% at 50 years [57]. However, only three cases of malignant germ cell tumors in prepubescent girls with CAIS have been reported in the last 100 years [55]. The youngest of these girls was 14 years old [64]. If gonadectomy is performed early, then puberty must be artificially induced using gradually increasing doses of estrogen [1]. If gonadectomy is performed late, then puberty will occur on its own, due to the aromatization of testosterone into estrogen [1]. Some choose to perform gonadectomy if and when inguinal hernia presents [1]. Postoperative estrogen replacement therapy is critical to minimize bone mineral density deficiencies later in life [51][53].

Some have hypothesized that supraphysiological levels of estrogen may reduce the diminished bone mineral density associated with CAIS [51]. Data has been published that suggests affected women who were not compliant with estrogen replacement therapy, or who had a lapse in estrogen replacement, experienced a more significant loss of bone mineral density [50][51]. Progestin replacement therapy is seldom initiated, due to the absence of a uterus [1]. Androgen replacement has been reported to increase a sense of well-being in gonadectomized women with CAIS, although the mechanism by which this benefit is achieved is not well understood [1].

It is no longer common practice to hide a diagnosis of CAIS from the affected individual or her family [17]. Parents of children with CAIS need considerable support in planning and implementing disclosure for their child once the diagnosis has been established [1][17]. For parents with young children, information disclosure is an ongoing, collaborative process requiring an individualized approach that evolves in concordance with the child's cognitive and psychological development [1]. In all cases, the assistance of a psychologist experienced in the subject is recommended [1][17].

Neovaginal Construction

Many surgical procedures have been developed to create a neovagina, as none of them is ideal [24]. Surgical intervention should only be considered after non-surgical pressure dilation methods have failed to produce a satisfactory result [24]. Neovaginoplasty can be performed using skin grafts, a segment of bowel, ileum, peritoneum, Interceed, buccal mucosa, amnion, or dura mater [24][65][66]. Success of such methods should be determined by sexual function, and not just by vaginal length, as has been done in the past [66]. Ileal or cecal segments may be problematic because of a shorter mesentery, which may produce tension on the neovagina, leading to stenosis [66]. The sigmoid neovagina is thought to be self-lubricating, without the excess mucus production associated with segments of small bowel [66]. Vaginoplasty may create scarring at the introitus (the vaginal opening), which requires additional surgery to correct. Vaginal dilators are required postoperatively to prevent vaginal stenosis from scarring [22][24]. Other complications include bladder and bowel injuries [24]. Yearly exams are required as neovaginoplasty carries a risk of carcinoma [24], although carcinoma of the neovagina is uncommon [65][66]. Neither neovaginoplasty nor vaginal dilation should be performed before puberty [24][32].

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  65. ^ a b Steiner E, Woernle F, Kuhn W, Beckmann K, Schmidt M, Pilch H, Knapstein PG (2002). "Carcinoma of the neovagina: case report and review of the literature". Gynecol. Oncol. 84 (1): 171–5. doi:10.1006/gyno.2001.6417. PMID 11748997. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  66. ^ a b c d e Breech LL (2008). "Complications of vaginoplasty and clitoroplasty". In Teich S, Caniano DA (ed.). Reoperative pediatric surgery. Totowa, N.J: Humana. pp. 499–514. ISBN 1-58829-761-6.

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