Complete androgen insensitivity syndrome
Encyclopedia
Complete androgen insensitivity syndrome (CAIS) is a condition that results in the complete inability of the cell to respond to androgen
s. 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. 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
). Clinical phenotypes in these individuals ranges from a full female habitus
, despite the presence of a Y chromosome.
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 .
Androgen insensitivity syndrome is the largest single entity that leads to 46,XY undermasculinization .
, without any signs of genital masculinization, despite having a 46,XY karyotype
. Symptoms of CAIS do not appear until puberty
, which may be slightly delayed , but is otherwise normal except for absent menses and diminished or absent secondary
terminal hair
. Axillary hair (i.e. armpit hair) fails to develop in one third of all cases . External genitalia is normal, although the labia
and clitoris
are sometimes underdeveloped . The vaginal depth
is widely variable, but is typically shorter than unaffected women ; one study of eight women with CAIS measured the average vaginal depth to be 5.9 cm (vs. 11.1 ± 1.0 cm for unaffected women ). In some extreme cases, the vagina has been reported to be aplastic
(resembling a "dimple"), though the exact incidence of this is unknown .
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
. They may be located intra-abdominally, at the internal inguinal ring, or may herniate
into the labia majora
. 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 . Germ cell malignancy
risk, once thought to be relatively high, is now thought to be approximately 2% . 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 . The prostate
, like the external male genitalia
, cannot masculinize in the absence of androgen receptor
function, and thus remains in the female form .
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 . These women are thus born without fallopian tubes, a cervix
, or a uterus , and the vagina ends "blindly" in a pouch . Müllerian regression does not fully complete in approximately one third of all cases, resulting in Müllerian "remnants" . 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 . In an unrelated case, a fully developed uterus was found in a 22 year old adult with CAIS .
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 , larger teeth , minimal or no acne , well developed breasts , and a greater incidence of meibomian gland dysfunction (i.e. dry eye syndromes
and light sensitivity
) .
, though exceptions have been reported for both the mild and partial forms .
CAIS is associated with a decreased bone mineral density . 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
. 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
.
CAIS is also associated with an increased risk for gonadal tumors
(e.g. germ cell malignancy) in adulthood if gonadectomy is not performed . 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 . The incidence of gonadal tumors in childhood is thought to be relatively low; a recent review of the medical literature 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 .
Vaginal hypoplasia
, a relatively frequent finding in CAIS and some forms of PAIS , is associated with sexual difficulties including vaginal penetration difficulties and dyspareunia
.
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 , 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 .
presents during premenarche
. As many as 1-2% of prepubertal girls that present with an inguinal hernia will also have CAIS .
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
. 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 .
The main differentials
for CAIS are complete gonadal dysgenesis (Swyer syndrome
) and Müllerian agenesis (Mayer-Rokitansky-Kuster-Hauser syndrome or MRKH) . 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 . Swyer syndrome is distinguished by poor breast development and shorter stature . 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 .
Up until the 1990s, a CAIS diagnosis was often hidden from the affected individual and / or family . It is current practice to disclose the genotype
at the time of diagnosis, particularly when the affected girl is at least of adolescent age . 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 .
; 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 . They are born phenotypically
female and almost always have a heterosexual female gender identity
; the incidence of homosexuality in women with CAIS is thought to be less than unaffected women . However, at least two case studies have reported male gender identity in individuals with CAIS .
Most cases of vaginal hypoplasia
associated with CAIS can be corrected using non-surgical pressure dilation
methods . 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 , make dilation possible even in cases when the vaginal depth is significantly compromised . Treatment compliance
is thought to be critical to achieve satisfactory results . 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 . Vaginal stretching occurs by increasing the tension on the sutures, which is performed daily . The non-operative pressure dilation method is currently recommended as the first choice, since it is non-invasive, and highly successful . Vaginal dilation should not be performed before puberty
.
While it is recommended that women with CAIS eventually undergo gonadectomy to mitigate cancer risk, there are differing opinions regarding early versus late gonadectomy . 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 . However, only three cases of malignant germ cell tumors in prepubescent girls with CAIS have been reported in the last 100 years . The youngest of these girls was 14 years old . If gonadectomy is performed early, then puberty must be artificially induced using gradually increasing doses of estrogen
. If gonadectomy is performed late, then puberty will occur on its own, due to the aromatization of testosterone into estrogen
. Some choose to perform gonadectomy if and when inguinal hernia
presents . Postoperative estrogen replacement therapy
is critical to minimize bone mineral density deficiencies later in life .
Some have hypothesized that supraphysiological levels of estrogen
may reduce the diminished bone mineral density associated with CAIS . 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 . Progestin
replacement therapy is seldom initiated, due to the absence of a uterus
. 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 .
It is no longer common practice to hide a diagnosis of CAIS from the affected individual or her family . Parents of children with CAIS need considerable support in planning and implementing disclosure for their child once the diagnosis has been established . 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 . In all cases, the assistance of a psychologist experienced in the subject is recommended .
, a segment of bowel, ileum
, peritoneum
, Interceed, buccal mucosa, amnion
, or dura mater
. Success of such methods should be determined by sexual function
, and not just by vaginal length, as has been done in the past . Ileal
or cecal
segments may be problematic because of a shorter mesentery
, which may produce tension on the neovagina, leading to stenosis
. The sigmoid
neovagina is thought to be self-lubricating, without the excess mucus
production associated with segments of small bowel . 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 . Other complications include bladder
and bowel injuries . Yearly exams are required as neovaginoplasty carries a risk of carcinoma
, although carcinoma of the neovagina is uncommon . Neither neovaginoplasty nor vaginal dilation should be performed before puberty
.
Patient groups
Androgen
Androgen, also called androgenic hormone or testoid, is the generic term for any natural or synthetic compound, usually a steroid hormone, that stimulates or controls the development and maintenance of male characteristics in vertebrates by binding to androgen receptors...
s. 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
Puberty
Puberty is the process of physical changes by which a child's body matures into an adult body capable of reproduction, as initiated by hormonal signals from the brain to the gonads; the ovaries in a girl, the testes in a boy...
, but does not significantly impair female genital or sexual development. As such, the insensitivity to androgens is only clinically significant when it occurs in genetic males (i.e. individuals with a Y chromosome
Y chromosome
The Y chromosome is one of the two sex-determining chromosomes in most mammals, including humans. In mammals, it contains the gene SRY, which triggers testis development if present. The human Y chromosome is composed of about 60 million base pairs...
, or more specifically, an SRY gene
SRY
SRY is a sex-determining gene on the Y chromosome in the therians .This intronless gene encodes a transcription factor that is a member of the SOX gene family of DNA-binding proteins...
). Clinical phenotypes in these individuals ranges from a full female habitus
Female body shape
Female body shape or figure is the cumulative product of a woman's skeletal structure and the quantity and distribution of muscle and fat on the body. There are, and have been, wide differences on what should be considered an ideal or preferred body shape, both for attractiveness and for health...
, despite the presence of a Y chromosome.
CAIS is one of three types of androgen insensitivity syndrome
Androgen insensitivity syndrome
Androgen insensitivity syndrome is a condition that results in the partial or complete inability of the cell to respond to androgens. The unresponsiveness of the cell to the presence of androgenic hormones can impair or prevent the masculinization of male genitalia in the developing fetus, as...
, 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
Mild androgen insensitivity syndrome
Mild androgen insensitivity syndrome is a condition that results in a mild impairment of the cell's ability to respond to androgens. The degree of impairment is sufficient to impair spermatogenesis and / or the development of secondary sexual characteristics at puberty in males, but does not...
(MAIS) is indicated when the external genitalia is that of a normal male, and partial androgen insensitivity syndrome
Partial androgen insensitivity syndrome
Partial androgen insensitivity syndrome is a condition that results in the partial inability of the cell to respond to androgens. The partial unresponsiveness of the cell to the presence of androgenic hormones impairs the masculinization of male genitalia in the developing fetus, as well as the...
(PAIS) is indicated when the external genitalia is partially, but not fully masculinized .
Androgen insensitivity syndrome is the largest single entity that leads to 46,XY undermasculinization .
Signs and symptoms
Individuals with complete androgen insensitivity syndrome (grades 6 and 7 on the Quigley scale) are born phenotypically femaleFemale body shape
Female body shape or figure is the cumulative product of a woman's skeletal structure and the quantity and distribution of muscle and fat on the body. There are, and have been, wide differences on what should be considered an ideal or preferred body shape, both for attractiveness and for health...
, without any signs of genital masculinization, despite having a 46,XY karyotype
Karyotype
A karyotype is the number and appearance of chromosomes in the nucleus of an eukaryotic cell. The term is also used for the complete set of chromosomes in a species, or an individual organism.p28...
. Symptoms of CAIS do not appear until puberty
Puberty
Puberty is the process of physical changes by which a child's body matures into an adult body capable of reproduction, as initiated by hormonal signals from the brain to the gonads; the ovaries in a girl, the testes in a boy...
, which may be slightly delayed , but is otherwise normal except for absent menses and diminished or absent secondary
Secondary sex characteristic
Secondary sex characteristics are features that distinguish the two sexes of a species, but that are not directly part of the reproductive system. They are believed to be the product of sexual selection for traits which give an individual an advantage over its rivals in courtship and aggressive...
terminal hair
Terminal hair
Terminal hairs are thick, long, and dark, as compared with vellus hair. During puberty, the increase in androgenic hormone levels causes vellus hair to be replaced with terminal hair in certain parts of the human body...
. Axillary hair (i.e. armpit hair) fails to develop in one third of all cases . External genitalia is normal, although the labia
Labia minora
The labia minora , also known as the inner labia, inner lips, or nymphae, are two flaps of skin on either side of the human vaginal opening, situated between the labia majora...
and clitoris
Clitoris
The clitoris is a sexual organ that is present only in female mammals. In humans, the visible button-like portion is located near the anterior junction of the labia minora, above the opening of the urethra and vagina. Unlike the penis, which is homologous to the clitoris, the clitoris does not...
are sometimes underdeveloped . The vaginal depth
Vagina
The vagina is a fibromuscular tubular tract leading from the uterus to the exterior of the body in female placental mammals and marsupials, or to the cloaca in female birds, monotremes, and some reptiles. Female insects and other invertebrates also have a vagina, which is the terminal part of the...
is widely variable, but is typically shorter than unaffected women ; one study of eight women with CAIS measured the average vaginal depth to be 5.9 cm (vs. 11.1 ± 1.0 cm for unaffected women ). In some extreme cases, the vagina has been reported to be aplastic
Aplasia
Aplasia is defined in general as "defective development or congenital absence of an organ or tissue." In the field of hematology, the term refers to "incomplete, retarded, or defective development, or cessation of the usual regenerative process."-Examples:*Acquired pure red cell aplasia*Aplasia...
(resembling a "dimple"), though the exact incidence of this is unknown .
The gonads in these women are not ovaries, but instead, are testes; during the embryonic stage of development
Human embryogenesis
Human embryology is the study of human development during the first eight weeks from gametogenesis pre-conception through fertilization up to and including the 8th week after implantation of the zygote in the uterus...
, testes form in an androgen-independent process that occurs due to the influence of the SRY gene
SRY
SRY is a sex-determining gene on the Y chromosome in the therians .This intronless gene encodes a transcription factor that is a member of the SOX gene family of DNA-binding proteins...
on the Y chromosome
Y chromosome
The Y chromosome is one of the two sex-determining chromosomes in most mammals, including humans. In mammals, it contains the gene SRY, which triggers testis development if present. The human Y chromosome is composed of about 60 million base pairs...
. They may be located intra-abdominally, at the internal inguinal ring, or may herniate
Inguinal hernia
An inguinal hernia is a protrusion of abdominal-cavity contents through the inguinal canal. They are very common , and their repair is one of the most frequently performed surgical operations....
into the labia majora
Labia majora
The labia majora are two prominent longitudinal cutaneous folds that extend downward and backward from the mons pubis to the perineum and form the lateral boundaries of the pudendal cleft, which contains the labia minora, interlabial sulci, clitoral hood, clitoral glans, frenulum clitoridis, the...
. Germ cells in the testes are arrested at an early stage and do not mature into sperm
Sperm
The term sperm is derived from the Greek word sperma and refers to the male reproductive cells. In the types of sexual reproduction known as anisogamy and oogamy, there is a marked difference in the size of the gametes with the smaller one being termed the "male" or sperm cell...
, since sensitivity to androgens is required in order for spermatogenesis
Spermatogenesis
Spermatogenesis is the process by which male primary germ cells undergo division, and produce a number of cells termed spermatogonia, from which the primary spermatocytes are derived. Each primary spermatocyte divides into two secondary spermatocytes, and each secondary spermatocyte into two...
to complete . Germ cell malignancy
Germ cell tumor
A germ cell tumor is a neoplasm derived from germ cells. Germ cell tumors can be cancerous or non-cancerous tumors. Germ cells normally occur inside the gonads...
risk, once thought to be relatively high, is now thought to be approximately 2% . Wolffian structures
Wolffian structures
In anatomy, Wolffian structures are male urogenital structures that include the epididymis, vas deferens, and seminal vesicles. They are often referred to in cases of androgen insensitivity syndrome.-See also:...
(the epididymides
Epididymis
The epididymis is part of the male reproductive system and is present in all male amniotes. It is a narrow, tightly-coiled tube connecting the efferent ducts from the rear of each testicle to its vas deferens. A similar, but probably non-homologous, structure is found in cartilaginous...
, vasa deferentia
Vas deferens
The vas deferens , also called ductus deferens, , is part of the male anatomy of many vertebrates; they transport sperm from the epididymis in anticipation of ejaculation....
, 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 . The prostate
Prostate
The prostate is a compound tubuloalveolar exocrine gland of the male reproductive system in most mammals....
, like the external male genitalia
Male external genitalia
The male external genitalia refers to the portion of the male reproductive system consisting of penis, urinary tract, and scrotum....
, cannot masculinize in the absence of androgen receptor
Androgen receptor
The androgen receptor , also known as NR3C4 , is a type of nuclear receptor that is activated by binding of either of the androgenic hormones testosterone or dihydrotestosterone in the cytoplasm and then translocating into the nucleus...
function, and thus remains in the female form .
The Müllerian system (the fallopian tubes, uterus
Uterus
The uterus or womb is a major female hormone-responsive reproductive sex organ of most mammals including humans. One end, the cervix, opens into the vagina, while the other is connected to one or both fallopian tubes, depending on the species...
, and upper portion of the vagina
Vagina
The vagina is a fibromuscular tubular tract leading from the uterus to the exterior of the body in female placental mammals and marsupials, or to the cloaca in female birds, monotremes, and some reptiles. Female insects and other invertebrates also have a vagina, which is the terminal part of the...
) typically regresses due to the presence of anti-Müllerian hormone
Anti-müllerian hormone
Anti-Müllerian hormone also known as AMH is a protein that, in humans, is encoded by the AMH gene. It inhibits the development of the Müllerian ducts in the male embryo. It has also been called Müllerian inhibiting factor , Müllerian-inhibiting hormone , and Müllerian-inhibiting substance...
originating from the Sertoli cells of the testes . These women are thus born without fallopian tubes, a cervix
Cervix
The cervix is the lower, narrow portion of the uterus where it joins with the top end of the vagina. It is cylindrical or conical in shape and protrudes through the upper anterior vaginal wall...
, or a uterus , and the vagina ends "blindly" in a pouch . Müllerian regression does not fully complete in approximately one third of all cases, resulting in Müllerian "remnants" . 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 . In an unrelated case, a fully developed uterus was found in a 22 year old adult with CAIS .
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 , larger teeth , minimal or no acne , well developed breasts , and a greater incidence of meibomian gland dysfunction (i.e. dry eye syndromes
Keratoconjunctivitis sicca
Keratoconjunctivitis sicca , also called keratitis sicca, xerophthalmia or dry eye syndrome is an eye disease caused by eye dryness, which, in turn, is caused by either decreased tear production or increased tear film evaporation. It is found in humans and some animals...
and light sensitivity
Photophobia
Photophobia is a symptom of abnormal intolerance to visual perception of light. As a medical symptom photophobia is not a morbid fear or phobia, but an experience of discomfort or pain to the eyes due to light exposure or by presence of actual physical photosensitivity of the eyes, though the term...
) .
Comorbidity
All forms of androgen insensitivity are associated with infertilityInfertility
Infertility primarily refers to the biological inability of a person to contribute to conception. Infertility may also refer to the state of a woman who is unable to carry a pregnancy to full term...
, though exceptions have been reported for both the mild and partial forms .
CAIS is associated with a decreased bone mineral density . Some have hypothesized that the decreased bone mineral density observed in women with CAIS is related to the timing of gonadectomy and inadequate estrogen
Estrogen
Estrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...
supplementation
Hormone replacement therapy (menopause)
Hormone replacement therapy is a system of medical treatment for surgically menopausal, perimenopausal and to a lesser extent postmenopausal women...
. However, recent studies show that bone mineral density is similar whether gonadectomy occurs before or after puberty
Puberty
Puberty is the process of physical changes by which a child's body matures into an adult body capable of reproduction, as initiated by hormonal signals from the brain to the gonads; the ovaries in a girl, the testes in a boy...
, and is decreased despite estrogen supplementation, leading some to hypothesize that the deficiency is directly attributable to the role of androgens in bone mineralization
Mineralization (biology)
In biology, mineralization refers to the process where an organic substance is converted to an inorganic substance.This may also be a normal biological process which takes place during the life of an organism such as the formation of bone tissue or egg shells, largely with calcium.This term may...
.
CAIS is also associated with an increased risk for gonadal tumors
Germ cell tumor
A germ cell tumor is a neoplasm derived from germ cells. Germ cell tumors can be cancerous or non-cancerous tumors. Germ cells normally occur inside the gonads...
(e.g. germ cell malignancy) in adulthood if gonadectomy is not performed . 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 . The incidence of gonadal tumors in childhood is thought to be relatively low; a recent review of the medical literature 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 .
Vaginal hypoplasia
Hypoplasia
Hypoplasia is underdevelopment or incomplete development of a tissue or organ. Although the term is not always used precisely, it properly refers to an inadequate or below-normal number of cells. Hypoplasia is similar to aplasia, but less severe. It is technically not the opposite of hyperplasia...
, a relatively frequent finding in CAIS and some forms of PAIS , is associated with sexual difficulties including vaginal penetration difficulties and dyspareunia
Dyspareunia
Dyspareunia is painful sexual intercourse, due to medical or psychological causes. The symptom is reported almost exclusively by women, although the problem can also occur in men. The causes are often reversible, even when long-standing, but self-perpetuating pain is a factor after the original...
.
At least one study indicates that individuals with an intersex
Intersex
Intersex, in humans and other animals, is the presence of intermediate or atypical combinations of physical features that usually distinguish female from male...
condition may be more prone to psychological difficulties, due at least in part to parental attitudes and behaviors , and concludes that preventative long-term psychological counseling
Psychotherapy
Psychotherapy is a general term referring to any form of therapeutic interaction or treatment contracted between a trained professional and a client or patient; family, couple or group...
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 .
Diagnosis
CAIS can only be diagnosed in normal phenotypic females . It is not usually suspected unless the menses fail to develop at puberty, or an inguinal herniaInguinal hernia
An inguinal hernia is a protrusion of abdominal-cavity contents through the inguinal canal. They are very common , and their repair is one of the most frequently performed surgical operations....
presents during premenarche
Menarche
Menarche is the first menstrual cycle, or first menstrual bleeding, in female human beings. From both social and medical perspectives it is often considered the central event of female puberty, as it signals the possibility of fertility....
. As many as 1-2% of prepubertal girls that present with an inguinal hernia will also have CAIS .
A diagnosis of CAIS or Swyer syndrome
Swyer syndrome
Swyer syndrome, or XY gonadal dysgenesis, 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...
can be made in utero
In utero
In utero is a Latin term literally meaning "in the womb". In biology, the phrase describes the state of an embryo or fetus. In legal contexts, the phrase is used to refer to unborn children. Under common law, unborn children are still considered to exist for property transfer purposes.-See also:*...
by comparing a karyotype
Karyotype
A karyotype is the number and appearance of chromosomes in the nucleus of an eukaryotic cell. The term is also used for the complete set of chromosomes in a species, or an individual organism.p28...
obtained by amniocentesis
Amniocentesis
Amniocentesis is a medical procedure used in prenatal diagnosis of chromosomal abnormalities and fetal infections, in which a small amount of amniotic fluid, which contains fetal tissues, is sampled from the amnion or amniotic sac surrounding a developing fetus, and the fetal DNA is examined for...
with the external genitalia of the fetus during a prenatal ultrasound
Ultrasound
Ultrasound is cyclic sound pressure with a frequency greater than the upper limit of human hearing. Ultrasound is thus not separated from "normal" sound based on differences in physical properties, only the fact that humans cannot hear it. Although this limit varies from person to person, it is...
. Many infants with CAIS do not experience the normal, spontaneous neonatal testosterone
Testosterone
Testosterone is a steroid hormone from the androgen group and is found in mammals, reptiles, birds, and other vertebrates. In mammals, testosterone is primarily secreted in the testes of males and the ovaries of females, although small amounts are also secreted by the adrenal glands...
surge, a fact which can be diagnostically exploited by obtaining baseline luteinizing hormone
Luteinizing hormone
Luteinizing hormone is a hormone produced by the anterior pituitary gland. In females, an acute rise of LH called the LH surge triggers ovulation and development of the corpus luteum. In males, where LH had also been called interstitial cell-stimulating hormone , it stimulates Leydig cell...
and testosterone measurements, followed by a human chorionic gonadotropin
Human chorionic gonadotropin
Human chorionic gonadotropin or human chorionic gonadotrophin is a glycoprotein hormone produced during pregnancy that is made by the developing embryo after conception and later by the syncytiotrophoblast .. Some tumors make this hormone; measured elevated levels when the patient is not...
(hGC) stimulation test .
The main differentials
Differential diagnosis
A differential diagnosis is a systematic diagnostic method used to identify the presence of an entity where multiple alternatives are possible , and may also refer to any of the included candidate alternatives A differential diagnosis (sometimes abbreviated DDx, ddx, DD, D/Dx, or ΔΔ) is a...
for CAIS are complete gonadal dysgenesis (Swyer syndrome
Swyer syndrome
Swyer syndrome, or XY gonadal dysgenesis, 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...
) and Müllerian agenesis (Mayer-Rokitansky-Kuster-Hauser syndrome or MRKH) . Both CAIS and Swyer syndrome are associated with a 46,XY karyotype
Karyotype
A karyotype is the number and appearance of chromosomes in the nucleus of an eukaryotic cell. The term is also used for the complete set of chromosomes in a species, or an individual organism.p28...
, whereas MRKH is not; MRKH can thus be ruled out by checking for the presence of a Y chromosome
Y chromosome
The Y chromosome is one of the two sex-determining chromosomes in most mammals, including humans. In mammals, it contains the gene SRY, which triggers testis development if present. The human Y chromosome is composed of about 60 million base pairs...
, which can be done either by fluorescence in situ hybridization (FISH) analysis or on full karyotype . Swyer syndrome is distinguished by poor breast development and shorter stature . The diagnosis of CAIS is confirmed when AR
Androgen receptor
The androgen receptor , also known as NR3C4 , is a type of nuclear receptor that is activated by binding of either of the androgenic hormones testosterone or dihydrotestosterone in the cytoplasm and then translocating into the nucleus...
gene sequencing
Gene sequencing
Gene Sequencing may refer to:* DNA sequencing* or a comprehensive variant of it: Full genome sequencing...
reveals a mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
, although up to 5% of individuals with CAIS do not have an AR mutation .
Up until the 1990s, a CAIS diagnosis was often hidden from the affected individual and / or family . It is current practice to disclose the genotype
Genotype
The genotype is the genetic makeup of a cell, an organism, or an individual usually with reference to a specific character under consideration...
at the time of diagnosis, particularly when the affected girl is at least of adolescent age . 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 .
Management
Management of AIS is currently limited to symptomatic managementSymptomatic treatment
Symptomatic treatment is any medical therapy of a disease that only affects its symptoms, not its cause, i.e., its etiology. It is usually aimed at reducing the signs and symptoms for the comfort and well-being of the patient, but it also may be useful in reducing organic consequences and sequelae...
; methods to correct a malfunctioning androgen receptor
Androgen receptor
The androgen receptor , also known as NR3C4 , is a type of nuclear receptor that is activated by binding of either of the androgenic hormones testosterone or dihydrotestosterone in the cytoplasm and then translocating into the nucleus...
protein that result from an AR gene mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
are not currently available. Areas of management include sex assignment
Sex assignment
Sex assignment refers to the assigning of the biological sex at the birth of a baby. In the majority of births, a relative, midwife, or physician inspects the genitalia when the baby is delivered, sees ordinary male or female genitalia, and declares, "it's a girl" or "it's a boy" without the...
, genitoplasty, gonadectomy in relation to tumor
Germ cell tumor
A germ cell tumor is a neoplasm derived from germ cells. Germ cell tumors can be cancerous or non-cancerous tumors. Germ cells normally occur inside the gonads...
risk, hormone replacement therapy
Hormone replacement therapy (menopause)
Hormone replacement therapy is a system of medical treatment for surgically menopausal, perimenopausal and to a lesser extent postmenopausal women...
, and genetic
Genetic counseling
Genetic counseling or traveling is the process by which patients or relatives, at risk of an inherited disorder, are advised of the consequences and nature of the disorder, the probability of developing or transmitting it, and the options open to them in management and family planning...
and psychological counseling
Psychotherapy
Psychotherapy is a general term referring to any form of therapeutic interaction or treatment contracted between a trained professional and a client or patient; family, couple or group...
.
Individuals with CAIS are raised as females . They are born phenotypically
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
female and almost always have a heterosexual female gender identity
Gender identity
A gender identity is the way in which an individual self-identifies with a gender category, for example, as being either a man or a woman, or in some cases being neither, which can be distinct from biological sex. Basic gender identity is usually formed by age three and is extremely difficult to...
; the incidence of homosexuality in women with CAIS is thought to be less than unaffected women . However, at least two case studies have reported male gender identity in individuals with CAIS .
Most cases of vaginal hypoplasia
Hypoplasia
Hypoplasia is underdevelopment or incomplete development of a tissue or organ. Although the term is not always used precisely, it properly refers to an inadequate or below-normal number of cells. Hypoplasia is similar to aplasia, but less severe. It is technically not the opposite of hyperplasia...
associated with CAIS can be corrected using non-surgical pressure dilation
Dilation
Dilation refers to an enlargement or expansion in bulk or extent, the opposite of contraction. It derives from the Latin dilatare, "to spread wide".In physiology:* Pupillary dilation, dilation of the pupil of the eye...
methods . The elastic nature of vaginal tissue, as demonstrated by its ability to accommodate the differences in size between a tampon
Tampon
A tampon is a mass of cotton or rayon or a mixture of the two inserted into a body cavity or wound to absorb bodilyfluid. The most common type in daily use is designed to be inserted into the vagina during menstruation to absorb the flow of menstrual fluid...
, a penis, and a baby's head , make dilation possible even in cases when the vaginal depth is significantly compromised . Treatment compliance
Compliance (medicine)
In medicine, compliance describes the degree to which a patient correctly follows medical advice...
is thought to be critical to achieve satisfactory results . Dilation can also be achieved via the Vecchietti procedure, which stretches vaginal tissues into a functional vagina using a traction
Traction
- Engineering :*Forces:** Traction , adhesive friction or force in the context of vehicle** Traction vector, in mechanics, the force per unit area on a surface, including normal and shear components...
device that is anchored to the abdominal wall, subperitoneal
Peritoneum
The peritoneum is the serous membrane that forms the lining of the abdominal cavity or the coelom — it covers most of the intra-abdominal organs — in amniotes and some invertebrates...
sutures, and a mold that is placed against the vaginal dimple . Vaginal stretching occurs by increasing the tension on the sutures, which is performed daily . The non-operative pressure dilation method is currently recommended as the first choice, since it is non-invasive, and highly successful . Vaginal dilation should not be performed before puberty
Puberty
Puberty is the process of physical changes by which a child's body matures into an adult body capable of reproduction, as initiated by hormonal signals from the brain to the gonads; the ovaries in a girl, the testes in a boy...
.
While it is recommended that women with CAIS eventually undergo gonadectomy to mitigate cancer risk, there are differing opinions regarding early versus late gonadectomy . The risk of malignant
Malignant
Malignancy is the tendency of a medical condition, especially tumors, to become progressively worse and to potentially result in death. Malignancy in cancers is characterized by anaplasia, invasiveness, and metastasis...
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 . However, only three cases of malignant germ cell tumors in prepubescent girls with CAIS have been reported in the last 100 years . The youngest of these girls was 14 years old . If gonadectomy is performed early, then puberty must be artificially induced using gradually increasing doses of estrogen
Estrogen
Estrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...
. If gonadectomy is performed late, then puberty will occur on its own, due to the aromatization of testosterone into estrogen
Aromatase
Aromatase is an enzyme responsible for a key step in the biosynthesis of estrogens. It is a member of the cytochrome P450 superfamily , which are monooxygenases that catalyze many reactions involved in steroidogenesis. In particular, aromatase is responsible for the aromatization of androgens into...
. Some choose to perform gonadectomy if and when inguinal hernia
Inguinal hernia
An inguinal hernia is a protrusion of abdominal-cavity contents through the inguinal canal. They are very common , and their repair is one of the most frequently performed surgical operations....
presents . Postoperative estrogen replacement therapy
Hormone replacement therapy (menopause)
Hormone replacement therapy is a system of medical treatment for surgically menopausal, perimenopausal and to a lesser extent postmenopausal women...
is critical to minimize bone mineral density deficiencies later in life .
Some have hypothesized that supraphysiological levels of estrogen
Estrogen
Estrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...
may reduce the diminished bone mineral density associated with CAIS . 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 . Progestin
Progestin
A progestin is a synthetic progestogen that has progestinic effects similar to progesterone. The two most common uses of progestins are for hormonal contraception , and to prevent endometrial hyperplasia from unopposed estrogen in hormone replacement therapy...
replacement therapy is seldom initiated, due to the absence of a uterus
Uterus
The uterus or womb is a major female hormone-responsive reproductive sex organ of most mammals including humans. One end, the cervix, opens into the vagina, while the other is connected to one or both fallopian tubes, depending on the species...
. Androgen replacement
Androgen replacement therapy
Androgen replacement therapy is a hormone treatment often prescribed to counter the effects of male Hypogonadism. It is also prescribed to lessen the effects or delay the onset of normal male aging...
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 .
It is no longer common practice to hide a diagnosis of CAIS from the affected individual or her family . Parents of children with CAIS need considerable support in planning and implementing disclosure for their child once the diagnosis has been established . 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 . In all cases, the assistance of a psychologist experienced in the subject is recommended .
Neovaginal Construction
Many surgical procedures have been developed to create a neovagina, as none of them is ideal . Surgical intervention should only be considered after non-surgical pressure dilation methods have failed to produce a satisfactory result . Neovaginoplasty can be performed using skin graftsSkin grafting
Skin grafting is a type of graft surgery involving the transplantation of skin. The transplanted tissue is called a skin graft.Skin grafting is often used to treat:*Extensive wounding or trauma*Burns...
, a segment of bowel, ileum
Ileum
The ileum is the final section of the small intestine in most higher vertebrates, including mammals, reptiles, and birds. In fish, the divisions of the small intestine are not as clear and the terms posterior intestine or distal intestine may be used instead of ileum.The ileum follows the duodenum...
, peritoneum
Peritoneum
The peritoneum is the serous membrane that forms the lining of the abdominal cavity or the coelom — it covers most of the intra-abdominal organs — in amniotes and some invertebrates...
, Interceed, buccal mucosa, amnion
Amnion
The amnion is a membrane building the amniotic sac that surrounds and protects an embryo. It is developed in reptiles, birds, and mammals, which are hence called “Amniota”; but not in amphibians and fish , which are consequently termed “Anamniota”. The primary role of this is the protection of the...
, or dura mater
Dura mater
The dura mater , or dura, is the outermost of the three layers of the meninges surrounding the brain and spinal cord. It is derived from Mesoderm. The other two meningeal layers are the pia mater and the arachnoid mater. The dura surrounds the brain and the spinal cord and is responsible for...
. Success of such methods should be determined by sexual function
Sexual function
Sexual function is a model developed at the Karolinska Institute in Stockholm, Sweden, defining different aspects of the assessment of sexual dysfunction comprises the following components....
, and not just by vaginal length, as has been done in the past . Ileal
Ileum
The ileum is the final section of the small intestine in most higher vertebrates, including mammals, reptiles, and birds. In fish, the divisions of the small intestine are not as clear and the terms posterior intestine or distal intestine may be used instead of ileum.The ileum follows the duodenum...
or cecal
Cecum
The cecum or caecum is a pouch, connecting the ileum with the ascending colon of the large intestine. It is separated from the ileum by the ileocecal valve or Bauhin's valve, and is considered to be the beginning of the large intestine. It is also separated from the colon by the cecocolic...
segments may be problematic because of a shorter mesentery
Mesentery
In anatomy, the mesentery is the double layer of peritoneum that suspends the jejunum and ileum from the posterior wall of the abdomen. Its meaning, however, is frequently extended to include double layers of peritoneum connecting various components of the abdominal cavity.-Mesentery :The...
, which may produce tension on the neovagina, leading to stenosis
Stenosis
A stenosis is an abnormal narrowing in a blood vessel or other tubular organ or structure.It is also sometimes called a stricture ....
. The sigmoid
Sigmoid colon
The sigmoid colon is the part of the large intestine that is closest to the rectum and anus. It forms a loop that averages about 40 cm...
neovagina is thought to be self-lubricating, without the excess mucus
Mucus
In vertebrates, mucus is a slippery secretion produced by, and covering, mucous membranes. Mucous fluid is typically produced from mucous cells found in mucous glands. Mucous cells secrete products that are rich in glycoproteins and water. Mucous fluid may also originate from mixed glands, which...
production associated with segments of small bowel . Vaginoplasty may create scarring at the introitus
Introitus
The introitus is an entrance that goes into a canal or hollow organ. Introitus is another name for the vaginal orifice.Introitus has also been used for classifying uterine prolapse:*1st degree prolapse: cervix is in the vagina...
(the vaginal opening), which requires additional surgery to correct. Vaginal dilators are required postoperatively to prevent vaginal stenosis from scarring . Other complications include bladder
Bladder
Bladder usually refers to an anatomical hollow organBladder may also refer to:-Biology:* Urinary bladder in humans** Urinary bladder ** Bladder control; see Urinary incontinence** Artificial urinary bladder, in humans...
and bowel injuries . Yearly exams are required as neovaginoplasty carries a risk of carcinoma
Carcinoma
Carcinoma is the medical term for the most common type of cancer occurring in humans. Put simply, a carcinoma is a cancer that begins in a tissue that lines the inner or outer surfaces of the body, and that generally arises from cells originating in the endodermal or ectodermal germ layer during...
, although carcinoma of the neovagina is uncommon . Neither neovaginoplasty nor vaginal dilation should be performed before puberty
Puberty
Puberty is the process of physical changes by which a child's body matures into an adult body capable of reproduction, as initiated by hormonal signals from the brain to the gonads; the ovaries in a girl, the testes in a boy...
.
External links
Information- An Australian parent/patient booklet on CAIS
- The Secret of My Sex news article
- Women With Male DNA All Female news article at ABCnews.com
Patient groups