Disorders of Sexual Differentiation Flashcards
How does normal gender and sexual differentiation occur?
The most commonly accepted paradigm, described by Jost, involves a stepwise process to gender and sexual development.
The primary determinant is the chromosomal gender, which is established at fertilization when the sperm provides an X or Y chromosome to the ovum’s X chromosome.
Chromosomal gender determines gonadal gender, with XX resulting in ovarian development and XY resulting in testicular formation.
Finally, the gonadal function determines the phenotypic gender. Although this paradigm is helpful to explain gender development, the simple Y = male, no Y = female equations are not always valid.
Testis-Determining Factor (TDF)
The testis determining factor (TDF) is located on the short arm of the Y chromosome near the centromere at the distal aspect of the Y-unique region.
TDF is a DNA-binding protein encoded by the SRY gene that is responsible for the initiation of male gender determination.
Interestingly, SRY appears to be expressed by the somatic cells from the urogenital ridge and not from germ cells.
Many other genes play a role in gender development.
SOX9 gene
Despite the presence of a functional SRY gene, the absence of the SOX9 gene results in a female phenotype in the majority of chromosomal males.
WT1 gene
The Wilms tumor gene (WT1) appears to play a key role not only in renal development, but also in testicular development.
Early alteration of WT1 function results in testicular agenesis, and later dysfunction results in aberrant testicular development (streak gonad or dysgerminomas).
This tumor suppressor gene has been implicated in Denys–Drash syndrome involving testicular (mixed gonadal dysgenesis) and renal (Wilms tumor) abnormalities.
Fushi-Tarzu factor-1 (FTZ-F1)
Fushi–Tarzu factor-1 (FTZ-F1) exerts its effect on gonadal development through its regulation of steroidogenic factor-1 (SF-1).
The SF1 gene is involved with steroid hormone production and the production of Müllerian-inhibitory substance (MIS) by the Sertoli cells of the testis that causes regression of the Müllerian ductal system.
Although FTZ-F1 and SF-1 are also expressed in ovarian tissues, the timing and intensity of their effect are critical for normal gonadal development.
DAX1 gene
Finally, the lack of an SRY gene alone does not impart normal female phenotypic and gonadal development. The DAX1 gene appears essential for the development of the ovary.
The DAX1 gene product appears to compete with the SRY gene product for a steroidogenic regulatory protein (StAR).
A dosage-sensitive element is also important.
Normally, the single SRY gene has a greater impact than a single DAX1 gene and causes upregulation of StAR.
However, in chromosomal abnormalities in which more than one DAX1 gene is present, downregulation of StAR occurs, testicular development is inhibited, and ovarian development is promoted.
As in the case of Turner syndrome, these primordial ovaries develop into streak gonads.
Likely, other genes are also important for normal ovarian development.
Development of the internal ductal structures depends on hormone secretion by the developing gonads.
In the absence of functioning testicular tissue, the female internal Müllerian duct structures develop.
The presence of a functioning testis results in male internal Wolffian duct development. This differentiation is mediated by the production of testosterone from the testis.
Along with MIS, testosterone promotes Wolffian duct development, which results in regression of the Müllerian duct structures. This is a paracrine effect and therefore results in ipsilateral gonadspecific ductal differentiation. This effect likely depends on high concentrations of androgen produced by the physically proximate gonad.
Decreased levels of MIS by an abnormal testis or streak gonad result in ipsilateral Müllerian development. This occurs despite regression of the Müllerian ducts on the contralateral side with normal testicular MIS production.
Conversely, systemic administration of androgen does not result in male ductal development in a female fetus.
Produced by Sertoli cells, MIS functions as a suppressor of Müllerian duct development and is a specific marker for functioning testicular tissue in infancy. In its absence, the Müllerian structures develop.
The concentration and timing of MIS secretion appear to be critical. Normally, secretion occurs during week 7 of gestation. By week 9, the Müllerian ducts become insensitive to MIS.
External genital development follows a similar path. In the absence of the testosterone metabolite dihydrotestosterone (DHT), the external genitalia develop into the female phenotype.
The male and female phenotypes are identical until week 7.
In the male, testosterone production by the testicular Leydig cells surges at 7 weeks and remains elevated until week 14 of gestation.
Testosterone is converted to DHT by 5α-reductase in the tissues of the genital skin and urogenital sinus.
The testosterone-binding receptor has much higher affinity for DHT than testosterone and serves to amplify the effect of testosterone on the developing external genitalia.
In the absence of 5α-reductase, the internal Wolffian ducts are preserved but the external structures are feminized.
After birth in males, neonatal testosterone levels surge in response to the loss of feedback inhibition by maternal estrogens and the subsequent rise in neonatal luteinizing hormone (LH).
Testosterone levels peak around the second to third month of life.
By 6 months, levels remain identical in males and females until puberty.
Androgen imprinting may occur on susceptible tissues, including genital organs and sensitive tissues in the brain related to male-type behaviors and gender orientation.
This early exposure may determine how these tissues respond to subsequent androgen exposure during puberty and adulthood.
H&A
What is the incidence of aberrant genital development?
Incidence estimates vary due to confusing terminology and varying DSD definitions.
The incidence of true ambiguous genitalia is approximately 1:4500–5000.
This incidence increases to 1:200–1:300 if patients with Klinefelter syndrome, Turner syndrome, hypospadias, or cryptorchidism are included.
The incidence of subjects with 46,X,Y disorders is approximately 1:20,000, with the leading causes including testicular or mixed gonadal dysgenesis.
For newborns with 46,XX DSD and ambiguous genitalia, congenital adrenal hyperplasia (CAH) is the most common cause, accounting for approximately 70% of cases.
The overall incidence is approximately 1 in 15,000 live births.
The rate is much higher in stillborns and in certain regional populations (Yupic Eskimos and the people of La Réunion, France).
H&A
What classification system is currently used for differences of sexual development?
Differences of sexual development (DSD), congenital conditions in which the development of the infant/child’s chromosomal, gonadal, and anatomic sex are atypical, are among the most fascinating conditions confronting the pediatric urologist, gynecologist, and surgeon.
Our understanding of these conditions and their causes continues to evolve, but gender assignment and the timing of reconstruction remain controversial.
Historically, the most commonly used classification system was the one proposed by Allen in 1976 based primarily on gonadal histology. This system categorized the most common DSD well, but did not accommodate less common syndromes easily. Also, the older intersex or hermaphrodite terminology has become offensive to some.
A newer classification released by the International Consensus Conference on Intersex has largely replaced Allen’s system.
This newer system incorporates an evolving understanding of the molecular basis of these disorders and replaces more offensive gender-based labels.
This classification system breaks down DSDs into three broad categories:
sex chromosome DSDs,
46,XY DSDs, and
46,XX DSDs.
The new terminology is used primarily in this text.
H&A
The majority of neonates with external genital ambiguity fall into what type of DSD?
46,XX DSD
The majority of neonates with external genital ambiguity fall into this category.
All patients have a 46,XX karyotype and exclusively ovarian tissue in nonpalpable gonads.
Simplistically, the cause of the gender ambiguity is an excess of androgen.
More than 95% are due to CAH, with the remainder resulting from maternal androgen exposure.
These patients have a normal female Müllerian ductal system with an upper vagina, uterus, and fallopian tubes.
They also have normal regression of the Wolffian ducts.
The level of virilization depends largely on the timing and magnitude of androgen exposure to the external genitalia.
The phenotype can range from mild clitoromegaly to a normal male appearance.
Virilization in CAH is due to the inability of the adrenal gland to form cortisol.
The precursors above the enzymatic defect are shunted into the mineralocorticoid or sex-steroid pathways.
Also, the end products generally have some, albeit weak, glucocorticoid function.
The lack of cortisol for negative feedback inhibition of adrenocorticotropic hormone (ACTH) production by the pituitary leaves this pathway unchecked.
Excess androgen is produced and is responsible for the virilization.
The corticosteroid synthetic and alternative pathways are shown in Figure 62.2.
The most common form of CAH is 21-hydroxylase deficiency (21-OHD), which accounts for more than 90% of CAH.
The 21-OHD gene has been mapped to the short arm of chromosome 6.
The variable location of the adrenal defect and relative function of the gene results in salt-wasting and non-saltwasting forms.
Type 1 results in virilization but no salt wasting. The gene defect affects only the fasciculata zone of the adrenal, and results in blocking cortisol production. However, the gene is normally expressed in the glomerulosa zone with preservation of mineralocorticoid production.
In type 2, also called the classic type, the gene abnormality affects both adrenal zones. Salt wasting results in dehydration and/or vascular collapse, and hyperkalemia develops because of the block in mineralocorticoid production.
11β-Hydroxylase deficiency (type 3) is a less common cause of CAH. This gene has been mapped to the long arm of chromosome 8. This abnormality results in virilization associated with hypertension due to the synthetic block being below deoxycorticosterone (DOC). DOC has potent mineralocorticoid function resulting in sodium resorption, fluid overload, hypertension, and hypokalemic acidosis.
Finally, 3β-hydroxylase deficiency (type 4) is a rare form of CAH. It results in severe salt wasting, and survival is unusual. It is the only type of CAH to occur in both genders.
Virilization of the female fetus can be caused by exogenous androgen exposure from the mother. This occurs primarily with the use of progesterone, commonly used as an adjunct to assist with fertility and in vitro fertilization.
Endogenous androgen exposure due to virilizing maternal ovarian tumors also has been reported, but these tumors are usually virilizing to the mother with the fetus being unaffected.
Diagnosis
The diagnosis of CAH is based on the previously described clinical and electrolyte abnormalities in addition to elevated 17-hydroxyprogesterone levels.
DOC and deoxycortisol levels also aid in determining which enzymatic defect is present.
The physical examination is notable for the absence of palpable gonads, the presence of a cervix on rectal examination, and bronzing of the skin.
Palpation of a gonad virtually excludes the diagnosis of 46,XX DSD.
The genitogram and an ultrasound (US) study mirror these findings, revealing Müllerian structures with a variable-length urogenital sinus.
Treatment
As all forms of CAH are inherited in an autosomal recessive manner, genetic counseling is recommended.
Families with a history of CAH should consider maternal treatment with dexamethasone before week 10 of gestation to eliminate or improve the level of fetal virilization.
Postnatally, cortisol replacement with hydrocortisone is the mainstay of therapy, with the addition of fluorhydrocortisone if salt wasting is present.
Supportive management of fluid and electrolyte abnormalities is best provided in a neonatal intensive care unit.
With regard to gender identity, the vast majority of patients with CAH (∼95%) identify as female and gender assignment is generally female given the 46,XX karyotype.
The ovaries are normal and have fertility potential.
Surgical reconstruction requires a feminizing genitoplasty and involves clitoroplasty, monsplasty, and vaginoplasty.
H&A
Which of DSD groups is the most heterogenous?
46,XY DSD
This group is the most heterogeneous in the newer classification system.
All patients have a 46,XY genotype and testicular tissue only.
The gonads are sometimes palpable.
The condition can be simplistically thought of as a deficit of either production or reception of androgen.
The androgen deficit may result from a defect in synthesis.
Several rare adrenal enzyme deficiencies have been implicated, including 3β-hydroxylase, 17α-hydroxylase, and 20,22-desmolase. All are involved in the steps from cholesterol to androstenedione and testosterone and are associated with severe CAH and often death.
3β-Hydroxylase and 20,22-desmolase deficiencies are associated with cortisol and aldosterone deficits with hyponatremia, hyperkalemia, and metabolic acidosis.
In 17α-hydroxylase deficiency, mineralocorticoid production is preserved, resulting in excess salt and water retention, hypertension, and hypokalemia.
In the male the phenotype is variable, ranging from the appearance of a proximal hypospadias with cryptorchidism to that of a phenotypic female with a blind-ending vagina.
Defects in 17,20-desmolase and 17β-hydroxysteroid oxidoreductase act at the testicular level to convert androstenedione to testosterone. Because the adrenal is unaffected, CAH does not occur.
The phenotype can be quite variable, but those with complete feminization can escape detection at birth and be reared as females.
Progressive virilization is related to excess gonadotropin production at puberty, which may partially compensate for the lack of testosterone synthesis.
Phallic growth and the development of male secondary sex characteristics create a conundrum with regard to gender reassignment when the diagnosis is made later in life.
Despite adequate production of androgen, receptor defects can render cells blind to the virilizing effects of the hormone. The phenotype is variable and depends on the degree of insensitivity of the receptor for androgen.
The extreme is normal female external genitalia resulting from complete androgen insensitivity syndrome (CAIS, also termed testicular feminization). The incidence of this syndrome is approximately 1 in 40,000. It usually results from a point mutation in the androgen receptor gene, located on the X chromosome.
Receptor defects seen in CAIS result in normal female external genitalia and a blind-ending vagina. Testes are present but may be nonpalpable. MIS production is intact, so no Müllerian ductal structures are present.
These patients usually are initially seen at puberty with amenorrhea, but can be encountered earlier with the finding of a testis at the time of inguinal hernia repair.
Partial androgen insensitivity is associated with a large spectrum of phenotypic variation (e.g., Gilbert–Dreyfus, Lub, and Reifenstein syndromes). It can be a sporadic or inherited condition, and gender assignment and treatment are individualized.
Testosterone is converted to DHT by 5α-reductase, type 2. DHT is a much more potent androgen with regard to virilization of the external genitalia and prostate. The 5 alpha-reductase deficiency phenotype is ambiguous, but virilization occurs at puberty related to the increased testosterone production and peripheral conversion by nongenital 5α-reductase, type 1. Unfortunately, the virilization is incomplete and a small phallus and infertility are likely.
Diagnosis
Metabolically, the diagnosis of CAH is made similarly to the 46,XX DSD patient, noting excess steroid levels above the enzymatic block and elevated levels of ACTH.
The physical examination confirms absence of a cervix on rectal examination, and bronzing of the skin may be present.
Palpation of a cryptorchid or descended testis is possible.
The genitogram and US mirror these findings, but a prominent utricle may be present that lacks a cervical impression at its apex.
In CAIS, testosterone levels are elevated postpubertally, but the diagnosis in the prepubertal child may require human chorionic gonadotropin (hCG) stimulation and genital skin fibroblast androgen receptor studies.
Receptor assays can delineate a quantitative versus qualitative receptor defect.
LH levels are elevated, related to the loss of testosterone feedback inhibition, which requires normal receptor hormone interaction.
5α-Reductase deficiency is confirmed by an elevated testosterone-to-DHT ratio and an abnormal 5α-reductase type 2 or SRD5A2 gene assay.
Treatment
In CAIS, the gender assignment is always female. CAIS patients who are assigned as female in infancy later identify themselves as female.
Because the androgen receptor defect is ubiquitous, virilization of the brain does not occur.
Classically, orchiectomy is recommended given the risk of malignant degeneration but is often deferred until after puberty.
The testis synthesizes estradiol, facilitating feminine development at puberty.
Orchiectomy before puberty necessitates hormone replacement for normal pubertal development.
More recently, preservation of the testes in phenotypic females identifying as female has become popular. Benefits of gonadal preservation may include bone health, psychosocial well-being, and other evolving effects.
The risk of malignancy has likely been overemphasized, and the risk of carcinoma in situ up to age 20 years is more likely similar to males with cryptorchidism (∼5%).
The argument ensues that surveillance is generally employed over prophylactic orchiectomy in this scenario, so why not for CAIS?
No uniform monitoring algorithm has been adopted, but a search for inguinal testes with US or magnetic resonance imaging for intra-abdominal testes has been proposed.
Tumor markers are not valuable for premalignant lesions, but there is potential for future markers of genetic susceptibility.
Gender assignment in partial androgen insensitivity syndrome (PAIS) is largely based on the response of the external genitalia to exogenous testosterone.
A significant virilization response argues for the male gender.
If there is no response, the female gender is favored.
This subgroup is the most variable and has the least consensus with regard to gender assignment. There are reports of gender reassignment at puberty. Dissatisfaction with the gender of rearing occurs in approximately 25% of PAIS patients, whether raised male or female.
In 5α-reductase deficiency syndrome, the brain is normally virilized and these individuals identify with the male gender. Thus, male gender assignment is recommended.
H&A
What is the management for Mullerian-Inhibitory Substance Deficiency?
MÜLLERIAN-INHIBITORY SUBSTANCE DEFICIENCY (HERNIA UTERINE INGUINALE)
MIS is produced by the Sertoli cells in the testis and causes regression of the Müllerian ductal structures.
In this rare syndrome of abnormal MIS production or MIS-receptor abnormality, Wolffian ductal development is unimpaired, but the Müllerian ducts also persist.
Because the infant has a normal male phenotype, this syndrome is rarely encountered in the neonatal period.
The most common presentation to the surgeon is that of finding a fallopian tube adjacent to an undescended testis in the hernia sac at the time of orchiopexy.
If this scenario is encountered, a biopsy of the gonad should be performed, the hernia should be repaired, and all structures left intact until completion of a full evaluation with karyotype and MIS levels.
Apparent males can also present with bilateral nonpalpable testes, and Müllerian structures are found at laparoscopy.
Abnormal MIS-receptor gene assays also can be helpful for verifying the diagnosis in those with a normal MIS level.
Subsequent management is primarily orchiopexy. This, however, can be difficult because the vas deferens can be closely adherent or ectopic to the fallopian tube or uterus.
Excision of discordant ductal structures can be attempted, but given the relatively low risk associated with leaving these structures, the risk of damage to the vas during this dissection outweighs the benefit of removal.
Despite normal testosterone levels, the patient often has impaired spermatogenesis.
H&A
What is the management for Leydig cell abnormalities?
As the Leydig cell is responsible for testosterone production in the testes, impaired testosterone production can also manifest from Leydig cell hypoplasia, agenesis, or abnormal Leydig cell gonadotropin receptors.
These disorders are rare.
Although the karyotype is 46,XY, the phenotype tends to be female, with a blind-ending vaginal pouch and the absence of internal Müllerian structures.
These patients usually are seen initially around puberty with amenorrhea and therefore are reared as female.
Management is similar to that for CAIS, with orchiectomy and estrogen replacement.
H&A
What is the management for Ovotesticular DSDs?
Ovotesticular DSD exists when both ovarian and testicular tissue are present.
The gonadal configuration also can be quite variable, with the ovary/ovotestis combination being most common in the United States, but any combination can occur.
Ovotestes are usually polar, with an ovary at one end and a testis at the other, but the distribution can be longitudinal, requiring deep longitudinal biopsy to sample the gonad adequately.
Because of the paracrine effect of the gonad, the ipsilateral internal duct structures correlate with the type of gonad present.
Ovotestes are associated with a variable duct structure, but usually fallopian tubes prevail.
A decisively Müllerian or Wolffian duct structure is usually found rather than an ipsilateral combination.
Ovotesticular DSD can be associated with a variety of karyotypes, with 46,XX being the most common, but different chromosomal content has been correlated with different races.
It is thought that a translocation of the SRY gene or associated genes to an X chromosome or autosome explains the development of testicular tissue in the 46,XX karyotype.
It is more difficult to explain ovarian tissue in a patient with a 46,XY karyotype.
Likely, key genes in ovarian development are present, but undetected, and complement the normal X chromosomal content. An unappreciated mosaicism also could have occurred.
The phenotype covers the entire spectrum, with ambiguity and asymmetry the rule, but with a tendency toward masculinization.
Although it is unusual for ovaries to be found in the labioscrotum, testes and ovotestes are often palpable.
Fertility has been described in those raised as female, but testicular fibrosis makes this unlikely in those raised as male.
Diagnosis
The diagnosis of ovotesticular DSD is suggested by a mosaic karyotype or ductal structures, but is confirmed by the presence of ovarian and testicular tissue on biopsy.
Treatment
Gender assignment in ovotesticular DSD is quite variable and should be based on the functional potential of the phenotype.
With either gender, the discordant gonads should be removed early in life.
Retained testicular tissue will cause virilization in females.
In males, the testicular tissue is preserved and orchiopexy is performed.
A 1–10% incidence of testicular tumors is found in males, predominantly gonadoblastomas and dysgerminomas, so long-term surveillance is needed.
Hypospadias repair also is required in males, and feminizing genitoplasty is performed in females.
Males tend to require hormonal replacement because of the progressive testicular fibrosis, but females usually do not.
Fertility is possible in those raised as female. However, females should be screened for testosterone levels, which can signal inadequate removal of testicular tissue.
H&A
What is the management for mixed gonadal dysgenesis?
Mixed gonadal dysgenesis (MGD) is the second most common form of neonatal ambiguous genitalia.
The patient will have a testis on one side and a streak gonad on the other, characterized microscopically by normal ovarian stroma without oocytes.
The internal duct structure mirrors the ipsilateral gonad, with the streak associated with a fallopian tube and uterus resulting from the lack of MIS.
The karyotype is generally a mosaic of 45,XO/46,XY, and the stigmata of Turner syndrome are variably present.
The phenotype is ambiguous, but masculinized, and the testis may be descended but more commonly is not.
The risk of a gonadal tumor, usually gonadoblastoma, is as high as 20%, and tumors can develop in either the testis or streak gonad. This may be mediated by the TSPY gene on the Y chromosome.
An increased risk of Wilms tumor also is present in MGD.
The Denys–Drash syndrome occurs in approximately 5% of patients with MGD and is classically described as ambiguous genitalia, Wilms tumor, and glomerulopathy, which is often associated with hypertension.
Diagnosis
The diagnosis is suggested by the physical stigmata of Turner syndrome on examination (webbed neck, shield chest) and 45,XO/46,XY karyotype.
The finding of a testis and streak gonad, however, confirms the diagnosis.
Treatment
Historically, the majority of patients with MGD have been raised as females because of the short stature conferred by Turner syndrome and the malignant risk of the retained testis.
Females undergo early gonadectomy and feminizing genitoplasty.
Males require early excision of the streak gonad, orchiopexy or orchiectomy, and hypospadias repair.
Infertility is the rule despite adequate testicular endocrine function.
Because of the increasing awareness regarding testosterone imprinting on the brain, more masculinized patients are being raised as males.
If individuals are raised as a male, close surveillance of the testis is necessary, unless elective orchiectomy and hormone replacement are chosen.
Testicular biopsy at the time of puberty to exclude dysgenetic elements has been recommended.
If carcinoma in situ is identified, low-dose radiation therapy is curative.
H&A
What is the management for pure gonadal dysgenesis?
Pure gonadal dysgenesis (PGD) is characterized by streak gonads bilaterally.
The external phenotype and internal duct structures are female.
These patients generally are seen at puberty with primary amenorrhea.
The chromosomal makeup is classically 46,XX.
PGD is an autosomally recessive trait, so genetic counseling is warranted. This implies that the condition can be caused by abnormalities in the X chromosome or supporting autosomal genes involved in gender differentiation.
The gonads do not carry risk of malignant degeneration.
Other conditions are also closely related to bilateral streak gonads. The chromosomal makeup is quite variable and can be 46,XY (XY sex reversal, Swyer syndrome, or male Turner syndrome), 45,XO, or a mosaic.
Variants with a Y chromosome differ in that they carry a high rate of malignancy in the retained streak gonads.
The phenotype is as described earlier, but these patients may be first seen in infancy with gonadoblastomas or dysgerminomas or with germ cell tumors that become more common in adolescence.
The stigmata of Turner syndrome are often present. Multiple chromosomal deletions and mutations have been described causing this syndrome.
Diagnosis
The finding of a female external phenotype and an internal duct structure with bilateral streak gonads confirms the diagnosis.
Follicle-stimulating hormone and LH levels are generally elevated, and estrogen and testosterone levels are decreased.
The diagnosis may be suggested by the physical stigmata of Turner syndrome on examination.
Treatment
In classic 46,XX PGD, the gonads can be left because there is no malignant potential.
If a Y chromosome is present, gonadectomy should be performed, as there is a high incidence of malignancy.
In either case, hormonal replacement at puberty is required because the streak gonads do not provide any endocrine function.
H&A
What are other syndromes of aberrant sexual differentiation?
OTHER SYNDROMES OF ABERRANT SEXUAL DIFFERENTIATION
Several syndromes do not fit neatly into the described classification systems.
1) Vanishing testis syndrome
Vanishing testis syndrome is characterized by a 46,XY karyotype but absent testes bilaterally.
This generally results in virilization to the point of normal external genitalia and internal duct structure but absent testes.
The testes were thought to have produced androgen at some point, resulting in masculinization, but subsequently vanished related to torsion or regression.
Patients are generally raised as boys, and hormonal supplementation at puberty is required.
2) Klinefelter syndrome
Klinefelter syndrome is characterized by a male karyotype containing two or more X chromosomes (47,XXY, 48,XXXY, etc.).
Although phenotypically male prepubertally, these patients acquire abnormal male secondary sexual characteristics (tall stature with disproportionately long legs, sparse facial hair, decreased muscle mass, and a feminine fat distribution), and infertility.
The testes are small and hard, with decreased androgen production and elevated estradiol levels related to primary hypergonadotropic hypogonadism.
Gynecomastia often occurs with an increased risk of breast cancer.
Fertility has been reported but requires assisted means, such as intracytoplasmic sperm injection (ICSI).
3) 46,XX testicular DSD
46,XX testicular DSD (XX sex reversal) is characterized by a male phenotype with a 46,XX karyotype.
Most commonly, this occurs from translocation of Y chromosomal material to the X chromosome, but it also can occur from mutation of the X chromosome or from mosaicism.
The phenotype and management are similar to those of Klinefelter syndrome, with the exception of shorter stature.
4) Mayer–Rokitansky–Küster–Hauser syndrome
Mayer–Rokitansky–Küster–Hauser syndrome is characterized by a 46,XX karyotype with normal female external genitalia but a short, blind-ending vagina.
Normal ovaries and fallopian tubes are present, but the uterus is generally rudimentary.
Patients are seen initially with primary amenorrhea, but may have cyclical pain related to functioning endometrium.
Treatment is geared toward vaginal reconstruction to allow menses or intercourse, or both.
H&A
What are important considerations in the evaluation of the newborn with ambiguous genitalia?
The diagnosis of ambiguous genitalia is extremely disconcerting to the family and should be addressed as a medical emergency.
Usually, genital ambiguity is obvious, but the finding of any degree of hypospadias, particularly in association with a nonpalpable testis, merits a DSD evaluation.
In this population, a high rate of DSD conditions is found despite the absence of classic ambiguity.
Table 62.2 indicates other abnormal physical examination findings that warrant consideration for DSD.
The family history may reveal maternal hormone exposure, previous fetal death, or a history of genital ambiguity.
The physical examination should focus on the genitalia. Assessment for palpable gonads is important, because a palpable gonad represents a testis or ovotestis and rules out 46,XX DSD, in which only ovaries are present, or PGD, in which only streak gonads are present.
If both gonads are palpable, this generally indicates 46,XY DSD.
One palpable gonad generally implies MGD or ovotesticular DSD.
Phallic stretched length, clitoral size, and the position of the urogenital sinus should be noted.
A rectal examination may reveal a palpable uterus.
The physical examination should include assessment for the stigmata of Turner syndrome associated with MGD and PGD.
Bronzing of the areola or scrotum can suggest elevated ACTH production in CAH.
The initial metabolic evaluation should include a karyotype or fluorescent in situ hybridization to identify X and Y chromosomes.
17-OH progesterone levels should be obtained after 3 or 4 days of life, by which time spurious elevations resulting from the stress related to birth have subsided.
Electrolyte levels should be monitored closely in the interim to identify salt wasting with CAH.
Testosterone and DHT levels are important for evaluating 5α-reductase deficiency.
An elevated LH level and a low MIS level suggest testis dysgenesis or absence.
ACTH or hCG stimulation tests can be performed but are more controversial.
Genetic evaluation for DSDs have always involved a karyotype. Historically, due to cost and the relative difficulty in sequencing, previous diagnostic evaluations have relied heavily on biochemical and phenotypic features.
However, for patients with 46,XY DSD or 46,XX who have ovotesticular or testicular disease, diagnosis may be difficult using such approaches.
With the advent of next-generation sequencing, more widespread genetic testing for DSD has gained momentum.
Currently, more than 80 genes either play a role in sexual development or have led to DSD development.
An in-depth review of some of the more common genes involved in DSD is available.
A recent review of studies from 2015 and 2016 using more nontargeted genetic testing approaches found that 35% of patients with 46,XY received a genetic diagnosis.
This increased genetic diagnostic rate allows for better clarification of a phenotypically diverse population.
The Society of Endocrinology in the United Kingdom has developed an algorithm for genetic testing that includes karyotype followed by microarray, followed either by single-gene testing or panel testing, finally followed by whole-exome or wholegenome sequencing if no diagnosis is found with initial testing.
Although these tests improve the molecular diagnostic rate, the effect it has on treatment for patients with DSDs is less clear, and we will likely continue to learn more as larger groups of patients are evaluated.
Early imaging studies include pelvic US, which should identify a uterus if one is present. Although a gonad may be seen, US is not useful in differentiating a testis, ovotestis, or ovary.
A genitogram performed by retrograde contrast injection into the urogenital sinus is helpful in identifying the level of confluence of a vagina and urethra and its relation to the urethral sphincter.
Gonadal biopsy is often required for diagnostic purposes, but the diagnosis of CAH can be made by metabolic evaluation alone.
Endoscopy is not usually required for diagnosis, but is essential in characterizing the internal duct structure, the level of confluence of the urogenital sinus, and planning for and performing the reconstructive procedures.
The gender-assignment team should include a pediatric urologist/surgeon, endocrinologist, geneticist, neonatologist, psychologist, and social worker, who together evaluate all newborns with ambiguous genitalia.
This information is synthesized by the team and presented to the parents in a combined care conference.
The goals of gender assignment and management should include preservation of sexual function and any reproductive potential with the least number of operations, appropriate gender appearance with a stable gender identity, and psychosocial well-being.
H&A
What are important considerations for fertility potential and preservation in DSD patients?
A discussion about fertility potential is an essential part of the care of individuals with DSD.
Various factors make reproduction a challenge, including gonadal failure, impaired gamete production, anatomic barriers, and the assumption of infertility as a result of discordance between gender identity and phenotypic gender.
Traditional views of fertility potential suggest that
(1) donor oocytes may make pregnancy a possibility for women with testicular dysgenesis but the absence of a uterus impairs fertility and
(2) infertility results from oligospermia or azoospermia in males with DSD.
Assisted reproductive technology, such as ICSI, has resulted in fertility in a few patients with DSD.
However, in a recent study, the identification of germ cells in the majority of studied individuals with DSD suggests a higher potential for fertility than previously thought.
In this retrospective review of histologic samples of gonadal tissue from 44 patients with DSD, germ cells were present in 68%, including all patients with CAIS, MGD, and ovotesticular DSD.
Of those with streak gonads, 15% had germ cells present.
The authors also reported an inverse correlation between the number of germ cells and age in patients with DSD.
Although cryopreservation of prepubertal gonadal tissue and in vitro ovarian follicle and sperm maturation for future attempts at reproduction remain experimental and are associated with the risk of aneuploidy in the offspring, such technology offers a higher potential for fertility preservation in individuals with DSD.
In addition, shifting traditional views regarding the congruency between gamete and gender identity could allow for the ability of some individuals with DSD to have biological offspring.
Another consideration is the timing of fertility preservation. Although delaying gonadectomy allows individuals with DSD to make autonomous decisions regarding gender identity, such a decision may decrease fertility potential as with patients with CAIS.
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What are considerations for the psychosexual development of children with DSDs?
Gender assignment for children with DSD is a critical decision with lifelong impact for both the child and family.
Gender dysphoria occurs more frequently in individuals with DSD as compared with the general population.
The goal is congruence between initial gender assignment and the child’s eventual gender identity to prevent future distress related to gender dysphoria.
The degree of contribution of hormonal influences versus socialization on the development of gender identity remains a topic of ongoing research.
Money’s assumption of gender neutrality at birth has recently been challenged as the effect of prenatal androgen exposure on the psychosexual development of individuals with DSD has become a focus.
Data now suggest that although early exposure to androgens has a strong effect on gender roles (i.e., masculine play in childhood), social influences such as the parents’ chosen gender of rearing, learning, and socialization are better predictors of gender identity in most forms of DSD.
Exceptions exist, however, as with genetic males with 5α-RD2 or 17βHSD-3 deficiency who tend to develop male gender identity despite female rearing.
Congruence between the sex of rearing and gender identity is associated with positive psychological development in individuals with DSD, whereas discordance between sex of rearing and gender roles seems less important.
Thus, it should be emphasized that every child with DSD should be treated individually.
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What are considerations regarding reconstructive genital surgical procedures?
For more than 20 years, largely based on the work of John Money and the “John/Joan Case,” the overwhelming bias was that gender identity was largely inducible and loosely dependent on chromosomal constitution.
The focus was on one of two twin boys who was reassigned to the female gender early in life after a demasculinizing circumcision injury.
The child reportedly developed normally from a psychosocial standpoint and adapted well to life as a girl.
Only with extended follow-up into adulthood was it discovered that the individual converted back to the male gender after severe dissatisfaction with a female identity (including attempted suicide).
This rattled the fundamental concepts on which gender assignment had been based for decades and brought to the forefront a tremendous controversy regarding the appropriate management of children with ambiguous genitalia and gender reassignment.
As reconstruction is rarely done in response to any lifethreatening issues, support groups for individuals with DSD have advocated delaying any reconstruction until the child can express his or her wishes regarding gender assignment.
Although this would decrease the likelihood of a mismatch between physical and psychological gender, the period of genital ambiguity could be quite challenging for the child and family in our society.
Despite the controversy, the International Consensus Panel on Intersex stated that the evidence is currently insufficient to abandon the practice of early genital reconstruction.
However, the advantages and disadvantages of early genital reconstruction must be discussed thoroughly with the family before embarking on any reconstructive operations.
In a recent study, a consortium of 10 children’s hospitals reported that despite counseling families thoroughly on this issue, over 95% chose early surgical reconstruction.
Outcomes literature regarding the well-being of DSD patients with and without surgical intervention is in its infancy.
In the report from the consortium of 10 children’s hospitals mentioned previously, there seemed to be an improvement in multiple distress variables after reconstructive genitoplasty.
Some element of decisional regret was noted in approximately a quarter of families and was associated with higher levels of preoperative illness uncertainty and educational status rather than the gender of rearing or surgical complications.
In general, if genital reconstruction is thought to be appropriate, it is planned in the first 3–6 months of life.
For feminizing reconstruction, the vaginal tissue is thicker as a result of maternal hormonal influence and the distance from the vagina to perineum is shorter at this age.
Because parents have a great degree of anxiety surrounding the gender of their child, early repair may help reduce this anxiety and encourage parent/child bonding.
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What are considerations for reconstructive female gender assignment?
Feminizing genitoplasty includes three major components: monsplasty, clitoroplasty, and vaginoplasty.
The timing of the vaginoplasty depends on the level of the confluence of the urogenital sinus.
For a low confluence, the vaginoplasty is performed in the neonatal period with the monsplasty and clitoroplasty.
Even with a high confluence, the vaginoplasty can be performed with the monsplasty and clitoroplasty in the newborn.
However, because vaginal dilation is often necessary after repair, it may be better to defer the vaginoplasty until the patient is peripubertal and more capable and interested in this requirement.
Cystoscopy is invaluable for this assessment.
We generally insert a Fogarty balloon catheter in the vagina and a catheter in the urethra and bladder to define the confluence during the dissection.
The procedure is initiated by placing a traction suture in the glans.
A dorsolateral circumcising incision is made, leaving a 4- to 5-mm distal preputial cuff, much like is done in a hypospadias repair.
The lateral borders of the mucosalized plate are incised, taking this back adjacent to the urogenital sinus.
The shaft of the phallus is then degloved of skin superficial to the Buck fascia.
Fascial incisions are then made lateral to the neurovascular bundles.
A plane is created just beneath the Buck fascia from the level just proximal to the glans back to the pubic symphysis.
The mucosalized plate is elevated on the ventrum and preserved to naturally fill the void between the urethral meatus and clitoris.
The dorsal pedicles, including the neurovascular bundles, are preserved. The base of the corporeal bodies are suture ligated at the level of the pubic symphysis, and the distal corporeal tissue is excised.
An alternative technique preserving the corporeal bodies has been described to maintain the potential for reversibility, but long-term functional outcome is unknown at this time.
No clitoral reduction is performed, to avoid nerve injury. It can be recessed and has a quite normal appearance in adulthood. The clitoris is anchored to the corporal stumps to secure its position, being sure not to compromise the dorsal neurovascular pedicle.
A posterior inverted U-shaped flap is then made from the level of the ischial tuberosities to just posterior to the urogenital meatus.
For a very low confluence, the dissection is carried along the posterior aspect of the urogenital sinus to the level of the confluence, the posterior wall is incised until the vaginal introitus is normal in caliber, and the U-flap is advanced to complete the posterior vaginal wall. With higher confluences, total urogenital mobilization is favored.
For total urogenital mobilization, the urogenital sinus is incised circumferentially and mobilized as one unit to the level of the confluence.
At this point, the vagina can be carefully separated from the urethra under direct vision and the defect in the urethra is closed.
The urogenital sinus can be incised in the ventral and dorsal midline and rotated posterolaterally to lengthen the distal vagina.
Using this technique, a long distance to the perineum can be bridged.
Total urogenital mobilization is attractive as one can approach even the high urogenital confluences in the neonatal period without vaginal substitution or grafting, but the family must be appropriately cautioned.
Although early results are favorable, descent of the bladder neck is counterintuitive when considering our knowledge of adult female stress incontinence, and long-term continence could be an issue.
To complete the monsplasty, the dorsal phallic shaft skin is incised vertically, a preputial hood is formed for the clitoris, and the majority of this tissue is used to construct the labia minor with V-shaped advancement flaps.
Other techniques for the high urogenital sinus include a posterior approach that requires incising the rectum and an anterior transvesical approach.
In some patients with a high urogenital confluence, vaginal reconstruction is delayed until the peripubertal period, just before menarche.
The techniques described are still used, but in some patients, especially those who are obese, these methods are insufficient. In such cases, vaginal substitution with a colonic segment is preferred, but ileal substitutions and split-thickness skin grafts also have been used.
The benefit of vascularized bowel substitution is less vaginal stenosis and the natural formation of lubricating mucus, but this may require wearing a pad if there is excessive mucus production.
Colonic segments appear to have a lower rate of stenosis than do ileal segments.
Conversely, skin grafts have a tendency to become stenotic and may require frequent dilation and revision, but long-term satisfaction also has been reported.
The barrier function to sexually transmitted diseases is likely superior with skin grafts when compared with intestine.
A newer technique is the use of buccal mucosa as a graft created over a vaginal form. This approach is promising in that this tissue is abundant, has excellent tissue match characteristics, and is a familiar substrate to pediatric urologists as it is used in urethral reconstruction.
If a rudimentary vagina or depression exists, sequential dilation with the technique described by Frank and modified to a dilating seat by Ingram may be successful.
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