Differences (Disorders) of Sex Development (DSDs)

Differences (disorders) of sex development (DSDs), formerly termed intersex conditions, are seen in infants who are born with ambiguous or abnormal genitalia and may have indeterminate phenotypic sex. In most cases today, clinicians can promptly make an accurate diagnosis and counsel parents on therapeutic options. However, the paradigm of early gender assignment has been challenged by the results of clinical and basic science research, which show that gender identity development likely begins in utero and may not be the same as chromosomal or phenotypic sex.

Whereas surgical genital reconstruction has been widely applied to infants with DSDs in the past, the growing understanding of the psychological and social implications of gender assignment has shifted the paradigm away from early reconstruction in some cases. This article focuses on newborn evaluation and the differential diagnoses in children with DSDs, including children with ambiguous genitalia. ^{[1, 2]}

Classification

In 2006, the Lawson Wilkins Pediatric Endocrine Society (LWPES) and the European Society for Paediatric Endocrinology (ESPE) published proposed changes to the previously used nomenclature and definitions of disorders in which the development of chromosomal, gonadal, or phenotypic sex is atypical. ^{[3, 4]} The rationale behind these proposals was to change the terminology to reflect advances in the understanding of the pathophysiology of these disorders while being sensitive to the needs and concerns of patients affected by them. ^{[5, 6]}

The previous terminology and the revised LWPES-ESPE nomenclature are compared in Table 1 below. The LWPES-ESPE terminology mainly reflects the chromosomal sex or the gonadal tissue associated with the disorder.

Table 1. Previous Terminology and Revised Nomenclature of Disorders of Sex Development (Open Table in a new window)

As examples, classifications of sex chromosome DSD include the following:

• 45,X ( Turner syndrome and variants)
• 47,XXY ( Klinefelter syndrome and variants)
• 45,X/46,XY (mixed gonadal dysgenesis, ovotesticular DSD)
• 46,XX/46,XY (chimeric, ovotesticular DSD)

Classifications of 46,XY DSD include the following:

• Disorders of testicular development (complete and partial gonadal dysgenesis, gonadal regression, ovotesticular DSD)
• Disorders of androgen synthesis (Leydig cell agenesis, Leydig cell unresponsiveness, androgen biosynthesis defect)
• Defect of androgen action (complete and partial  androgen insensitivity)
• Disorders of antimüllerian hormone (AMH) or its receptors
• Other conditions (severe  hypospadias,  cloacal exstrophy)

Classifications of 46,XX DSD include the following:

• Disorders of ovarian development (ovotesticular DSD, testicular DSD, gonadal dysgenesis)
• Androgen excess (fetal [eg,  congenital adrenal hyperplasia (CAH)], fetoplacental, maternal)
• Other conditions (müllerian agenesis, vaginal atresia, cloacal exstrophy)

Adequate comprehension of normal and abnormal sexual differentiation is essential to understanding DSDs. A summary of current knowledge regarding the embryology and classification of these conditions provides an appropriate introduction to the topic.

Embryology of sexual differentiation

Phenotypic sex determination begins with genetic sex and follows a logical cascade: Chromosomal sex determines gonadal sex, which determines phenotypic sex. The type of gonad present determines the differentiation/regression of the internal ducts (ie, müllerian and wolffian ducts) and ultimately determines the phenotypic sex. Gender identity is determined not only by the phenotypic appearance of the individual but also by the brain's antenatal and postnatal development as influenced by the environment.

Gonadal differentiation

During the second month of fetal life, the indifferent gonad is guided to develop into a testis by genetic information present on the short arm of the Y chromosome. Testis-determining factor (TDF) is a 35-kilobase pair (kbp) sequence on the 11.3 subband of the Y chromosome, an area termed the sex-determining region of the Y chromosome (SRY). When this region is absent or altered, the indifferent gonad develops into an ovary.

The existence of patients with 46,XX testicular DSD, who have testicular tissue in the absence of an obvious Y chromosome or SRY genetic material, clearly requires other genetic explanations. Other genes important to testicular development include DAX1 on the X chromosome, SF1 on band 9q33, WT1 on band 11p13, SOX9 on bands 17q24-q25, and AMH on band 19q13.3. Fetal ovaries develop when the TDF gene (or genes) is absent.

Differentiation of internal ducts

Development of the internal ducts results from a paracrine effect from the ipsilateral gonad. Jost's classic research with rabbits greatly clarified the gonad's role in controlling the subsequent development of internal sex ducts and external genital phenotype. ^[7]

When testicular tissue is absent, the fetus morphologically begins and completes the internal sex duct development and external phenotypic development of a female. When testicular tissue is present, two produced substances appear to be critical for the development of male internal sex ducts and an external male phenotype: testosterone and müllerian-inhibiting substance (MIS; ie, AMH).

Testosterone is produced by testicular Leydig cells and induces the primordial wolffian (mesonephric) duct to develop into the epididymis, vas deferens, and seminal vesicle.

A spatial relation is important in the effect of testosterone. Wolffian structures located closest to the source of testosterone undergo the greatest degree of male differentiation. Thus, patients with ovotesticular DSDs often have a degree of wolffian development near testicular tissue, even when joined with an ovary as an ovotestis. No wolffian development is expected in association with a streak gonad or a non-testosterone-producing dysgenetic testis.

High local testosterone levels (paracrine effect) appear to be necessary for wolffian duct differentiation because maternal ingestion of androgens does not cause male internal differentiation in a female fetus, nor does this differentiation occur in females with CAH (also termed adrenogenital syndrome).

MIS (AMH) is produced by the Sertoli cells of the testis and is critical to normal male internal duct development. MIS is a 15-kd protein that is secreted by the testis beginning in fetal week 8. Its prime role is to repress the passive development of the müllerian ducts (eg, fallopian tubes, uterus, upper vagina). In a male fetus with normal testicular function, MIS represses müllerian duct development, whereas testosterone stimulates wolffian duct development.

The influences of testosterone and estrogen apparently modulate but do not isolate the role of MIS. Local testosterone production appears to enhance the inhibition of müllerian duct development produced by MIS, whereas estrogens may interfere with MIS action, resulting in a degree of müllerian duct development. This suggests that müllerian development may be more complex than was initially appreciated, and the research helps explain the variable internal sex duct anatomy that occurs in some of the more complex DSDs.

Differentiation of external genitalia

The external genitalia of male and female sexes are identical during the first 7 weeks of gestation. Without the hormonal action of the androgens testosterone and dihydrotestosterone (DHT), external genitalia appear phenotypically female.

In the gonadal male, differentiation toward the male phenotype actively occurs over the next 8 weeks. This differentiation is moderated by testosterone, which is converted to 5-DHT by the action of an enzyme, 5-alpha reductase, present within the cytoplasm of cells of the external genitalia and the urogenital sinus. DHT is bound to cytosol androgen receptors within the cytoplasm and is subsequently transported to the nucleus, where it leads to translation and transcription of genetic material.

In turn, these actions lead to normal male external genital development from primordial parts, forming the scrotum from the genital swellings, forming the shaft of the penis from the folds, and forming the glans penis from the tubercle. The prostate develops from the urogenital sinus.

Incomplete masculinization occurs when testosterone fails to convert to DHT or when DHT fails to act within the cytoplasm or nucleus of the cells of the external genitalia and urogenital sinus. The timing of this testosterone-related developmental change begins at approximately 6 weeks of gestation with a testosterone rise in response to a surge of luteinizing hormone (LH).

Testosterone levels remain elevated until week 14. Most phenotypic differentiation occurs during this period. After week 14, fetal testosterone levels settle at a lower level and are maintained more by maternal stimulation through human chorionic gonadotropin (hCG) than by LH. Testosterone's continued action during the latter phases of gestation is responsible for the continued growth of the phallus, which is directly responsive to testosterone and to DHT.

46,XX DSDs

46,XX DSDs can be caused by CAH or maternal androgens.

Congenital adrenal hyperplasia

Overall, CAH is the most frequent cause of ambiguous genitalia in the newborn, constituting approximately 60% of all DSDs. Excessive production of adrenal androgens results in a gonadal female with a virilized phenotype (46,XX DSD, formerly termed female pseudohermaphroditism).

The basic biochemical defect is an enzymatic block that prevents sufficient cortisol production. Biofeedback via the pituitary gland causes the precursor to accumulate above the block. Metabolic byproducts are shifted towards the production of adrenal androgens. Clinical manifestations of CAH depend on which enzymatic defect is present.

CAH may result from several metabolic defects. In 90% of patients with CAH, the block is at the 21-hydroxylation enzyme (21-hydroxylase deficiency). This leads to glucocorticoid and mineralocorticoid deficiency with a compensatory increase in the secretion of adrenocorticotropic hormone (ACTH) secretion and concomitant buildup of androgenic byproducts, which causes masculinization of a female fetus. The result is a female infant with varying degrees of virilization.

Biochemically, 75% of patients have salt-wasting nephropathy. Before this condition was commonly recognized, as many as one third of patients presented with evidence of vascular collapse. The 21-hydroxylase defect is inherited as an autosomal recessive trait closely linked to the human leukocyte antigen (HLA) locus on chromosome 6. The transmitted trait may have two varieties, which helps account for the clinical heterogenicity seen in patients with salt-wasting nephropathy.

Another cause of CAH is 11-hydroxylase deficiency. Patients who have CAH with 11-hydroxylase deficiency accumulate deoxycorticosterone (DOC) and 11-deoxycortisol. This form of the syndrome exhibits salt retention and hypertension because DOC is a potent mineralocorticoid. This enzymatic deficiency is suspected in a 46,XX child with ambiguous genitalia in whom the 17-OHP level is only mildly elevated. The diagnosis can be confirmed by a steroid screen of the serum.

A less frequently seen version of CAH is caused by 3-beta-hydroxysteroid dehydrogenase deficiency. This version causes less severe virilization of a female infant than the virilization caused by 21-hydroxylase or 11-hydroxylase deficiency. The buildup of pregneninolone, which is subject to hepatic conversion into testosterone, produces virilization.

Prompt diagnosis of DSD secondary to CAH is important. The diagnosis is suspected antenatally when there is discordance between the phenotypic sex diagnosed on antenatal ultrasonography (US) and the female karyotype on fetal DNA testing. The diagnosis is confirmed by noting an elevated amniotic fluid level of 17-hydroxyprogesterone (17-OHP) during the second trimester or by HLA typing of the amniotic cells.

Following birth, CAH is diagnosed more often during the evaluation of a 46,XX child with ambiguous genitalia and nonpalpable gonads. Patients with CAH have variations in the degree of phallic enlargement, the extent of genital fold fusion, and the size and level of entry of the vagina into the urogenital sinus. Although the degree of virilization seen in CAH can be extreme, internal müllerian structures are consistently present.

Rectal examination, retrograde genitography, or US reveals the presence of internal müllerian structures. Newborn screening has reliably increased the rate of diagnosis and shortened the time to achieving it, especially in males with salt-wasting and simple virilizing forms. The diagnosis is biochemically confirmed by an elevated serum level of 17-OHP. The reference range for 17-OHP in the newborn cord blood can be as high as 900-5000 ng/dL, but the serum level rapidly decreases by day 2 or 3 of life. A repeat elevated serum value exceeding 500 ng/dL at this point makes the diagnosis highly likely.

It should be kept in mind that 17-OHP levels may be markedly elevated in the 11-hydroxylase form of CAH, as well as in the rare child with the 3-beta-hydroxysteroid dehydrogenase form. Serum levels of dehydroepiandrosterone or its sulfate metabolite are also characteristically elevated. In these children, endocrine stabilization must be individualized, a process that usually takes several weeks.

It should be kept in mind that 3-beta-hydroxysteroid dehydrogenase deficiency is the only common form of CAH that can also cause ambiguity in a genetic male. This ambiguity occurs because the enzyme defect is present in both the adrenal glands and the testes, leading to inadequate production of testosterone in utero.

Maternal androgens

In rare cases, 46,XX DSDs may be drug-induced. Virilization of a female fetus may occur if progestational agents or androgens are used during the first trimester of pregnancy. After the first trimester, these drugs cause only phallic enlargement without labioscrotal fusion. The incriminated drugs were formerly administered to avoid spontaneous miscarriages in patients who had a history of habitual abortion or to treat endometriosis.

Endocrine abnormality in the mother as a source of virilizing hormones is even rarer because these abnormalities, if initially present, usually prevent the development of a pregnancy. However, various ovarian tumors (eg, arrhenoblastomas, Krukenberg tumors, luteomas, lipoid tumors of the ovary, and stromal cell tumors) reportedly have produced virilization of a female fetus.

Aromatase deficiency is a rarer cause of virilization of the female fetus. Normally, weak androgens produced by the fetal adrenal gland are converted to estrogens by placental aromatase. Mutations of the aromatase gene can result in virilization of the mother and female fetus during pregnancy. Maternal virilization resolves postnatally, but it recurs in subsequent pregnancies.

46,XY DSDs

Common causes of 46,XY DSDs include deficient biosynthesis of testosterone, complete androgen insensitivity syndrome (also known as testicular feminization syndrome), partial androgen insensitivity syndrome, 5-alpha-reductase deficiency, and isolated MIS deficiency (also known as persistent müllerian duct syndrome [PMDS]).

Deficient testosterone biosynthesis

Production of testosterone from cholesterol involves five enzymatic steps, and defects have been identified at each step. Of these five enzymes, three (cholesterol side chain cleavage enzyme, 3-beta-hydroxysteroid dehydrogenase, and 17-alpha hydroxylase) are shared with the adrenal glands, and their deficiency leads to ambiguous genitalia and symptoms of CAH. Both 17,20 desmolase and 17-ketosteroid reductase occur only as part of normal androgen synthesis; thus, their defects, while associated with genital abnormalities, are not associated with CAH.

Theoretically, biochemical diagnosis of these syndromes is possible, but as a practical matter, diagnosis usually is not feasible, because few centers offer the research-based endocrinologic assays necessary to identify the buildup of precursor products. During the newborn period, these patients present as 46,XY gonadal males with poor virilization and ambiguous genitalia. The genitalia respond to exogenously administered testosterone. Children with CAH manifestations also require treatment with steroid and mineralocorticoid replacement.

Genetic counseling is desirable because 17-alpha hydroxylase and 3-beta-hydroxysteroid dehydrogenase deficiencies are transmitted as autosomal recessive traits.

Additional rare causes for deficiencies in testosterone production include Leydig cell agenesis, Leydig cell hypoplasia, abnormal Leydig cell gonadotropin receptors, and delayed receptor maturation.

Complete androgen insensitivity syndrome

Complete androgen insensitivity syndrome (testicular feminization syndrome) involves a failure of the end organs (external genitalia and prostate) in a 46,XY gonadal male fetus to respond to appropriately produced levels of dihydrotestosterone (DHT), resulting in testicular feminization.

The basic pathophysiology of the lack of androgen effect on the genitalia has come to be understood more fully. Some patients are receptor-negative; their cytosol receptors cannot bind DHT. Others are receptor-positive; their receptors apparently permit DHT binding, but DHT does not lead to normal differentiation toward the male phenotype. An assay of genital skin fibroblasts elucidates the difference between receptor-negative and receptor-positive types.

Inheritance appears to be X-linked. Complete androgen insensitivity is diagnosed in infancy if a child with phenotypic female external genitalia has palpable gonads (testes) on physical examination or if testes were discovered in a phenotypic female during hernia repair. Patients with complete androgen insensitivity have a 46,XY karyotype, bilateral testes, female external genitalia, and no müllerian derivatives.

Endocrine evaluation in the neonatal period demonstrates normal male levels of testosterone and DHT. At puberty, gonadotropin levels rise, leading to increased levels of testosterone, which is peripherally converted to estradiol, resulting in feminization and breast development.

Inguinal hernias are common in testicular feminization (50% frequency), and the condition is occasionally diagnosed when a gonad is present in the hernia and a fallopian tube cannot be seen during inguinal herniorrhaphy of a phenotypic female. Failure to identify an internal müllerian structure in a phenotypic female with an inguinal hernia should always raise the possibility of testicular feminization. If the condition is not detected in this fashion, the diagnosis usually is not made until puberty, when the patient presents with amenorrhea.

Although these patients have a normal female phenotype, they have deficient axillary and pubic hair as they go into puberty, and their breasts, though well formed, characteristically are deficient in stroma. Their external genitalia are unequivocally female; however, the vagina is short, with a blind ending.

Despite a 46,XY karyotype and gonads with the typical appearance of testes (perhaps altered similarly to those of patients with cryptorchidism), a feminine gender assignment is unquestionable because of the completely feminine phenotype and because end-organ failure prevents endocrinologically produced masculinization. Confirmation of the diagnosis is crucial because the syndrome is associated with a 1-2% risk of gonadal malignancies, usually gonadoblastoma or seminoma. Sertoli cell, Leydig cell tumors, and malignant transformation of tubular cell adenomas have been reported.

Disagreement exists on the best timing for gonadectomy. Some experts prefer to leave testes in situ until puberty is complete so as to benefit from estradiol produced by the testes, which is important for the development of the female phenotype. This opinion is supported by the extremely low risk of gonadal malignancy before puberty. The youngest age at the incidence of gonadal malignancy was 14 years. In contrast, others have preferred to remove the testes early because morbidity is minimal in a young child.

Pubertal changes are easily induced with hormone replacement, a requirement for all patients following gonadectomy. Although a vaginoplasty may be required later, many of these patients have an adequate vagina, requiring no therapy or possibly only vaginal dilation.

Partial androgen insensitivity syndrome

An incomplete form of androgen insensitivity also occurs. These patients demonstrate a spectrum of external genitalia ranging from very feminine (eg, Lubs syndrome) to increasingly masculine (eg, Gilbert-Dreyfus syndrome) to most masculine (eg, Reifenstein syndrome).

A diagnosis of incomplete androgen insensitivity is suggested by elevated LH levels, with reference-range levels of plasma DHT and 5-alpha-reductase activity in genital skin fibroblasts. Exogenously administered androgens do not cause adequate virilization; therefore, incomplete androgen insensitivity raises questions regarding the preferred sex in which to rear the child.

Management is individualized according to the degree of virilization and genital ambiguity. Patients assigned a female gender require gonadectomy, surgical reconstruction, and estrogen-progestin replacement at puberty. Those assigned a male gender require genital reconstruction of hypospadias, treatment of cryptorchidism, and reduction of gynecomastia. The risk of gonadal tumors is higher than with complete androgen insensitivity syndrome.

5-Alpha-reductase deficiency

A 46,XY fetus with normal testes but without the enzyme 5-alpha reductase in the cells of the external genitalia and urogenital sinus cannot produce DHT. Consequently, the fetus is born with minimally virilized external genitalia (eg, pseudovagina, perineoscrotal hypospadias), though there is usually some degree of phallic enlargement, reflecting the direct action of testosterone.

One characteristic feature of patients with 5-alpha reductase deficiency is improved virilization at puberty, presumably caused by the direct action of testosterone on the phallus. At puberty, penile growth is increased, and the individual develops a masculine voice and muscle mass. The only characteristics that do not develop are those that depend on DHT (eg, prostatic enlargement, facial hair, acne). A spectrum of 5-alpha-reductase deficiency apparently occurs in different pedigrees, which probably accounts for some of the variation in the phenotypes seen in infancy.

Diagnosis of this deficiency can be confirmed in a patient with a 46,XY karyotype by the presence of a high ratio of serum testosterone to DHT. During the first 60 days of life, infants experience a surge of LH that obviates the need to carry out human chorionic gonadotropin (hCG) stimulation, which may be useful to exaggerate the testosterone-to-DHT ratio characteristic of this syndrome. The reference-range testosterone-to-DHT ratio is 8-16:1, whereas patients with 5-alpha-reductase deficiency characteristically have a ratio greater than 35:1.

Urinary metabolites of testosterone and DHT can be used to establish the diagnosis in a similar fashion. Imperato-McGinley et al ^[8] and Saenger et al ^[9] demonstrated that cultured skin fibroblasts exhibit decreased 5-alpha-reductase activity.

Gender assignment in these patients has been the subject of considerable debate because of the major virilization that occurs at puberty. Glassberg argued that all such patients should be raised as males. ^[10] Others disagree and concur with Saenger that only the most extremely virilized infant should receive a male assignment.

The surgical results of a masculinizing operation in a mildly virilized infant are poor, and the burden of growing up with inadequate genitalia hardly seems justified. Accordingly, gonadectomy and feminizing genitoplasty are sometimes considered for poorly virilized patients. Individuals with unambiguous female external genitalia or extremely small phallic size can be assigned a female gender. In these patients, gonadectomy should be performed before puberty to prevent virilization. 

Isolated deficiency of MIS

Isolated MIS deficiency (PMDS) is a rare syndrome and usually does not present in the newborn period, because the genitalia appear to be those of a male with undescended testes. The syndrome is fascinating because the phenotypic findings are exactly those expected in a 46,XY genetic and gonadal male in whom the isolated defect in the testis is a complete failure to produce MIS.

These patients have normal male external genitalia with unilateral or bilateral undescended testes, bilateral fallopian tubes, a uterus, and a vagina draining into a prostatic utricle. The most common presentation is a phenotypic male with an inguinal hernia on one side and an impalpable contralateral gonad. Herniorrhaphy reveals a uterus and a fallopian tube in the hernia sac. Because the testis produces reference-range levels of testosterone, a vas deferens presents bilaterally, usually running close to the uterus; therefore, damage to the vas is likely when müllerian remnants are excised. At times, the vas deferens ends blindly.

Appropriate surgical management is straightforward and includes orchiopexy for undescended testes. Attempts to excise müllerian remnants may incur damage to the adjacent vas. The incidence of malignancy, as compared with that in the usual cryptorchid testis, is unknown. Removal of müllerian remnants is unnecessary, given that the remnants rarely produce symptoms and that malignant transformation has been limited to case reports.

Ovotesticular DSDs

Both ovarian and testicular tissues are present in ovotesticular DSD (formerly termed true hermaphroditism), an uncommon cause of genital ambiguity in North America, accounting for fewer than 10% of DSD cases. The appearance of the genitalia varies widely in this condition. Although ambiguity is the rule, the tendency is toward masculinization.

The most common karyotype is 46,XX, though mosaicism is common. A translocation of the gene coding for HY antigen from a Y chromosome to either an X chromosome or an autosome presumably explains the testicular material in a patient with a 46,XX karyotype. More difficult to understand is how a patient with a 46,XY karyotype can have ovarian tissue, given that two X chromosomes are believed to be necessary for normal ovarian development. Possibly, unidentified XX cell lines are present in these patients.

Gonadal findings may include any combination of ovary, testis, or ovotestis. An ovotestis is most common and is found in approximately two thirds of patients. When an ovotestis is present, one third of the patients exhibit bilateral ovotestes. A palpable gonad is present in 61% of patients; of these, 60% are found to be an ovotestis.

In 80% of patients with ovotestes, testicular and ovarian tissues are aligned in an end-to-end fashion, emphasizing the need for a long longitudinal biopsy. In 20% of patients with ovotestes, testicular tissue is found in the hilar region of the gonad, reemphasizing the need for an adequate and deep biopsy. Ovarian tissue is usually more developed and possibly has fertility potential, whereas testicular tissue is dysgenetic and is associated with malignancy risk.

An ovary, when found, is situated most commonly in the normal anatomic intra-abdominal position, though Van Niekerk reported an ovary in the hemiscrotum. ^[11]  The least common gonad in ovotesticular DSD is the testis; when present, a testis is found approximately two thirds of the time in the scrotum, emphasizing that normal testicular tissue is most likely to descend fully.

Ovotestes may present with either a fallopian tube or a vas deferens but usually not with both. If a fallopian tube has a fimbriated end, the end is closed in most patients, perhaps contributing to the usual lack of fertility. Although fertility is rare in this setting, it has been reported. Gonadal tumors also are rare but have been reported.

Gonadal dysgenesis

Gonadal dysgenesis can be either partial or pure.

Partial gonadal dysgenesis

Partial gonadal dysgenesis can be classified either as 46,XY DSD or as sex chromosome DSD if there is mosaicism (45,X/46,XY). These conditions represent a spectrum of disorders in which the gonads are abnormally developed. Typically, at least one gonad is either dysgenetic or a streak. For example, in mixed gonadal dysgenesis (MGD), a streak gonad is usually present on one side and a testis (usually dysgenetic) on the opposite side.

In 1967, Federman used the term dysgenetic male pseudohermaphroditism (DMP) to describe patients with bilaterally dysgenetic testes and incomplete virilization of the internal sex ducts and external genitalia. Federman indicated the similarities in karyotype, gonadal histology, and phenotype that this group shares with patients with MGD and those with ovotesticular DSD. ^[12]

A dysgenetic testis histologically demonstrates immature and hypoplastic testicular tubules in a stroma similar to that seen in streak gonads and may help to explain the similarities of these syndromes. Federman described a spectrum of faulty testicular differentiation, with streak gonad at the extreme end of the spectrum and dysgenetic testis lying between streak gonad and a normal testis.

Patients with MGD have a streak gonad on one side with a contralateral dysgenetic testis, variable degrees of virilization, and persistent mullerian structures, at least on the side of the streak gonad. Most patients with MGD have a mosaic karyotype, 45,X/46,XY. A characteristic of patients with a 45,X karyotype is short stature. Patients who have no internal müllerian remnants usually have no 45,X component.

The risk of gonadal malignancy is increased when a Y chromosome is present in the karyotype. In MGD, 25% of gonads, including streak gonads, are expected to undergo malignant change, most often to gonadoblastoma, unless the patient has a gonadectomy before adulthood. In addition to gonadoblastomas, seminomas, and embryonal cell carcinomas may develop. A small series reported that 15-30% of DMP patients had gonadal malignancies, most often a gonadoblastoma. Manuel et al reported the incidence of gonadoblastoma or dysgerminoma to be 46% by the age of 40 years. ^[13]  

Early gonadectomy appears wise because tumors may arise in the first decade in both MGD and DMP. It is important to keep in mind that patients with MGD have an increased risk of Wilms tumor. Proper screening of Wilms tumor should be part of their care.

Gender assignment for patients with DMP and MGD remains under debate. For example, Glassberg argued for assigning a male gender to patients who are sufficiently virilized. ^[10] However, Rajfer and Walsh preferred an elective feminine gender assignment for patients with MGD because of the high incidence of inadequate external virilization and the high risk of gonadal malignancy. ^[14]

Estrogen support is required if these patients are assigned a female gender. Estrogen therapy should be combined with a progestational agent if a uterus is present to lower the risk of endometrial carcinoma,

Pure gonadal dysgenesis

This class of DSD, with bilateral streak gonads appearing as ovarian stroma without oocytes, usually goes unrecognized in newborns because the phenotype is typically completely female. Patients tend to present at puberty, at which point they do not undergo normal pubertal changes. Girls with Turner syndrome (45,XO) may be diagnosed earlier by noting the characteristic associated somatic features of short stature, webbed neck, and wide-spaced nipples. Neither Turner syndrome nor the 46, XX type of pure gonadal dysgenesis appears to be associated with an increased risk of gonadal malignancy unless a Y chromosome is present in the mosaic forms.

Therapy in these children is primarily limited to appropriate estrogen and progesterone replacement and growth hormone support. Prophylactic gonadectomy is advised in the Y mosaic Turner syndrome because the risk of gonadoblastoma is estimated to be 12%. ^[15]

The 46,XY type of pure gonadal dysgenesis poses a different problem because the bilateral streak gonads carry a significant potential for malignancy. Nearly one third of patients develop a dysgerminoma or gonadoblastoma; therefore, gonadectomy becomes important as soon as the diagnosis is recognized followed by cyclic hormone replacement with estrogen and progestins

Pure gonadal dysgenesis syndromes represent opportunities for genetic counseling. Turner syndrome appears sporadically, suggesting a postzygotic error; however, the 46,XX type of pure gonadal dysgenesis appears to have an autosomal recessive transmission, and the 46,XY type is apparently an X-linked recessive trait.

DSDs vary in frequency, depending on their etiology. CAH is the most common cause of DSDs, with a reported incidence ranging from 1 in 5000 to 1 in 15,000 in the United States and Europe. The frequency is highest in neonates of European Jewish, Hispanic, Slavic, or Italian descent or the Alaskan Eskimo population. ^[16]  MGD is the second most common cause of DSDs. In a series from the Children’s Hospital of Boston DSDs were found in 50% of children with hypospadias with unilateral or bilateral nonpalpable cryptorchid testes. ^[17] Therefore, clinicians should suspect the possibility of a DSD in patients with both hypospadias and cryptorchidism.

Age- and sex-related demographics

DSDs typically are diagnosed at birth in infants with ambiguous genitalia. Disorders associated with phenotypic males and females may be diagnosed much later. The classic presentation of MIS deficiency is a boy with a hernia on one side and an impalpable contralateral gonad. At the time of surgery, a uterus and fallopian tubes are noted along with normal wolffian structures. Diagnosis in 46,XY phenotypic females with complete androgen insensitivity usually occurs after puberty during an evaluation for primary amenorrhea.

Among all causes of DSDs, only salt-wasting CAH is considered a true medical emergency. Salt-wasting nephropathy occurs in 75% of infants born with CAH, the most common cause of ambiguous genitalia. If unrecognized, the resulting hypotension can cause vascular collapse and death. Male infants with this syndrome may be phenotypically normal, and the diagnosis may be missed.

Other causes of DSDs are not considered medical emergencies. Time pressure should be avoided. Modern treatment of infants with ambiguous genitalia involves a team-oriented approach. This gender-assignment team usually involves neonatologists, geneticists, endocrinologists, surgeons, counselors, and ethicists. The goal is to provide appropriate medical support and counseling regarding care and therapy. Management decisions should only be made after all the available information is explained to the family and thoroughly discussed with the multidisciplinary team. The topic of early gender reassignment remains contentious.

Parents of children with DSDs are often overwhelmed and confused by their child's condition. The family should be offered congratulations and support. Gender-neutral terminology (eg, "your baby”) should be used.  Although gender assignment and naming of the child are pressing issues, these actions should not be unduly rushed. Parents should be provided with as much information as possible so that they can make informed decisions. Time pressure should be avoided. Certain legislations, such as the German Law, demand that the legal gender of a child born with ambiguous genitalia be left open at birth.

Adequate counseling and support for parents should include education regarding sexual development in utero (including brain imprinting of gender identity), genetic counseling, and ethical considerations of the child's rights to make decisions regarding gender. All communications to the parents must be in the form of a proposal. Parents must clearly understand that the care of DSD patients is a dynamic process in which different disciplines are involved. ^[18]

Communication and information-giving should be gradual and repeated because information must be imparted repeatedly for the often complex and new information on the person’s own body status, diagnostic interventions, and diagnostic results to be fully grasped. All communications must be documented, and a copy of any information provided should be handed out to the parents. Children and adolescents born with DSDs should be gradually informed about their condition. They should be allowed to grow up accepting their bodies and conditions and achieving the best quality of life possible.