Disorders of Sex Development

Updated: Jul 17, 2017
  • Author: Joel Hutcheson, MD; Chief Editor: Marc Cendron, MD  more...
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Overview

Practice Essentials

Key points in the management of disorders of sex development (DSDs) include the following:

  • Infants born with ambiguous or abnormal genitalia may have indeterminate phenotypic sex
  • DSDs, formerly termed intersex conditions, are classified on the basis of genetics and the state of the gonads
  • DSDs may be caused by virilization of a child with 46,XX or undervirilization of a child with 46,XY
  • Some individuals with DSDs have genetic mosaicism and may have abnormal gonads (streak ovary, ovotestis, dysgenetic testis).
  • Congenital adrenal hyperplasia (CAH) is the most common cause of DSD
  • The incidence of CAH is 1 in 15,000
  • The most common cause of CAH is 21-hydroxlase deficiency resulting in virilization of a child with 46,XX
  • Prompt diagnosis of the underlying cause of DSD is essential; 75% of those with 21-hydroxlase deficiency have salt-wasting nephropathy
  • Gender identity is not necessarily the same as phenotypic or chromosomal sex
  • Gender assignment of a child with DSD is best made after parents have been counseled by a gender medicine team
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Background

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. The ability to diagnose these conditions has advanced rapidly. 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 DSD 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 nomenclature 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.

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 Sexual Development (Open Table in a new window)

Previous Revised
Female pseudohermaphrodite 46,XX DSD
Male pseudohermaphrodite 46,XY DSD
True hermaphrodite Ovotesticular DSD
XX male 46,XX testicular DSD
XY sex reversal 46,XY complete gonadal dysgenesis

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)
  • Disorders of androgen synthesis (complete and partial androgen insensitivity, disorders of antimüllerian hormone [AMH]/receptor, androgen biosynthesis defect)
  • Other (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 ( vaginal atresia, cloacal exstrophy)
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Pathophysiology

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 prenatal 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 subsequent development of internal sex ducts and external genital phenotype. [5]

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 development of male internal sex ducts and an external male phenotype: testosterone and müllerian-inhibiting substance (MIS) or 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. It prime role is to repress 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 both 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 the 14th week, 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 continued growth of the phallus, which is directly responsive to testosterone and to DHT.

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Etiology

The more common causes of DSDs are described below.

46,XX disorders of sexual development

Congenital adrenal hyperplasia

Overall, CAH is the most frequent cause of ambiguous genitalia in the newborn, constituting approximately 60% of all DSDs. Excessive androstenedione production 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. Clinical manifestation of CAH depends on which enzymatic defect is present.

CAH presents a spectrum of abnormalities, including the degree of phallic enlargement, the extent of urethral 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. In these children, endocrine stabilization must be individualized, a process that usually takes several weeks.

CAH may result from several metabolic defects, one of which is 21-hydroxylase deficiency. In 90% of patients with CAH, the block is at the 21-hydroxylation enzyme. This leads to a mineralocorticoid deficiency and a 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.

Prompt diagnosis of DSDs secondary to CAH is important. Prenatal diagnosis is confirmed by noting an elevated amniotic fluid level of 17-hydroxyprogesterone (17-OHP) during the second trimester or by HLA typing of amniotic cells. CAH is diagnosed more often following birth during evaluation of a 46,XX child with ambiguous genitalia, when rectal examination, retrograde genitography, or ultrasonography reveals evidence of an internal müllerian structure in the form of a cervix.

Diagnosis is confirmed by an elevated serum level of 17-OHP. Reference range newborn cord blood levels of 17-OHP can be as high as 900-5000 ng/dL, but the serum level rapidly decreases by the second or third day 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.

Another cause of CAH is 11-hydroxylase deficiency. Patients who have CAH with 11-hydroxylase block accumulate deoxycorticosterone (DOC) and 11-deoxycortisol. This form of the syndrome exhibits salt retention and hypertension because DOC is a potent mineralocorticoid. Suspect this diagnosis in a 46,XX child with ambiguous genitalia in whom the 17-OHP level is elevated only mildly. 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 the virilization.

Patients can present with a salt-losing crisis caused by deficient mineralocorticoid production, similar to that occurring with 21-hydroxylase deficiency. The diagnosis can be confirmed by identifying an elevated serum level of dehydroepiandrosterone or its sulfate metabolite.

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 the 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

Although rare, 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.

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

Ovotesticular disorders of sexual development

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 problematic is how a patient with a 46,XY karyotype can have ovarian tissue, given that two X chromosomes are believed to be necessary to normal ovarian development. Possibly, unidentified XX cell lines are present in these patients.

Gonadal findings may be 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 testicle, when present, is more likely to exist on the right (57.4%), and an ovary, when present, is more common on the left (62%). 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.

An ovary, when found, is situated most commonly in the normal anatomic intra-abdominal position, though Van Niekerk reported an ovary in the right hemiscrotum. [6] 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.

46,XY disorders of sexual development

Isolated deficiency of MIS

Isolated MIS deficiency 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 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.

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 fallopian tube in the hernia sac. Since 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 excising müllerian remnants. At times, the vas deferens ends blindly.

Appropriate surgical management attempts to bring the testes into the scrotum based on the rationale that testis tumors may occur later, emphasizing the need to remove any testicular tissue that cannot be palpated. Incidence of malignancy is unknown compared to the usual cryptorchid testis. Removal of müllerian remnants is unnecessary, since the remnants rarely produce symptoms and have no reported history of subsequent malignancy

46,XY DSD (formerly termed male pseudohermaphroditism) occasionally occurs in families. Confined to males expressing the characteristic, inheritance may be either X-linked recessive or autosomal dominant. Genetic counseling is important.

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 (ie, 20-alpha hydroxylase, 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, so 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

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

Currently, the basic pathophysiology of the lack of androgen effect on the genitalia is understood more fully. Some patients are receptor-negative; their cytosol receptors cannot bind DHT. Another variant is receptor-positive, in which receptors apparently permit DHT binding, but DHT does not lead to normal differentiation toward the male phenotype. Assays of genital skin fibroblasts elucidate the difference between receptor-negative and receptor-positive types.

Inheritance appears to be X-linked. Complete androgen insensitivity presents in infancy only if the child has a shallow blind-ending vagina, reflecting the lack of internal müllerian development expected in an XY patient whose testes manufacture MIS at reference range levels.

Inguinal hernias are common in testicular feminization, and an occasional case is detected during inguinal herniorrhaphy when a gonad is present in the hernia and a fallopian tube cannot be seen.

Failure to identify an internal müllerian structure in a phenotypic female with an inguinal hernia should always raise the possibility of testicular feminization. If not detected in this fashion, diagnosis usually is not made until puberty, when the patient presents with amenorrhea. Although these characteristics are not noted early in life, these girls exhibit a body hair deficiency as they age, and their breasts, although well formed, characteristically are deficient in stroma.

Despite a 46,XY karyotype and gonads with the typical appearance of testes (perhaps altered similarly to those 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 significant incidence of gonadal malignancies.

Malignant tumors are termed germinomas or, more properly, seminomas because the tumors arise in a testis. The youngest reported age of occurrence was 14 years. Overall frequency of gonadal malignancies is approximately 6%, with incidence rising to more than 30% by age 50 years. Sertoli cell and Leydig cell tumors have been reported. Tubular cell adenomas, also fairly frequent, have a potential for malignancy because neoplastic transformation has been reported.

Disagreement exists on the best timing for gonadectomy. Scully recommends gonad removal after puberty. (Puberty occurs normally because the girl's complete pituitary is androgen insensitive.) In contrast, the author's experience at The Children's Hospital of Philadelphia has been to remove testes early because morbidity is minimal in a young child.

Pubertal changes are induced easily with hormone replacement, a requirement for all patients following gonadectomy. Although a vaginoplasty later may be required, many of the girls 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 little question regarding the preferred sex with which to rear the child. An early gonadectomy and feminizing genitoplasty are recommended in infancy.

5-Alpha-reductase deficiency

A 46,XY fetus with normal testes but lacking the enzyme 5-alpha reductase in the cells of the external genitalia and urogenital sinus cannot produce DHT. Therefore, the fetus is born with minimally virilized external genitalia (eg, pseudovaginal perineoscrotal hypospadias), though the fetus usually has a degree of phallic enlargement, reflecting the direct action of testosterone.

The striking feature in these patients is the extreme virilization at puberty, presumably caused by direct action of testosterone on the phallus. At puberty, penile growth is dramatic, 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, while 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 [7] and Saenger et al [8] demonstrated that cultured skin fibroblasts demonstrate decreased 5-alpha-reductase activity.

Gender assignment in these patients has been debated because of the major virilization that occurs at puberty. Glassberg has argued that all patients should be raised as males. [9] The authors disagree and generally concur with Saenger that only the most extremely virilized infant should receive a male assignment. 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. The authors usually recommend gonadectomy and feminizing genitoplasty.

Partial gonadal dysgenesis

Partial gonadal dysgenesis can be classified as either 46,XY DSD or sex chromosome DSD if there is mosaicism (45,X/46,XY). These 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. [10]

A dysgenetic testis histologically demonstrates immature and hypoplastic testicular tubules in a stroma characteristic of ovarian tissue but that lacks oocytes. This stroma has the appearance of 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 one 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 testis. Although the degree of virilization varies, all patients have a vagina and a uterus, and most have a fallopian tube, at least on the side of the streak.

Most patients with MGD have a mosaic karyotype, 45,X/46,XY. A characteristic of patients with an 45,X karyotype is short stature. Patients who have no internal müllerian remnants usually have no 45,X component.

Gonadal malignancy is a risk when a Y chromosome is present in the karyotype. In MGD, 25% of gonads, including streak gonads, can be 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 malignancies, most often a gonadoblastoma. Early gonadectomy appears wise because tumors may arise in the first decade in both syndromes.

Gender assignment for patients with DMP and MGD remains under debate. For example, Glassberg, noting that no case has been reported of a tumor developing in a fully descended testis in a patient with either MGD or DMP, argues for assigning male gender to patients who are sufficiently virilized. [9] However, Rajfer and Walsh prefer an elective feminine gender assignment for patients with MGD because a uterus and vagina always are present and one half of patients are markedly short and have a high incidence of inadequate external virilization. [11]

Estrogen support is required if these patients are raised as females. If the uterus remains in place, remember that unopposed estrogen can increase incidence of endometrial carcinoma; thus, these patients must be cycled with a combination of estrogen and a progestational agent.

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 detected earlier by noting the characteristic associated anomalies of short stature, webbing of the neck, and wide-spaced nipples. Neither Turner syndrome nor the 46,XX type of pure gonadal dysgenesis appear to be associated with increased risk of gonadal malignancy. Therapy in these children (from an intersex standpoint) is primarily limited to appropriate estrogen and progesterone support.

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.

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.

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Epidemiology

United States statistics

DSDs vary in frequency, depending on their etiology. CAH is the most common cause of ambiguous genitalia in the newborn. Mixed gonadal dysgenesis (MGD) is the second most common cause of DSDs.

Hypospadias occurs at a rate of 1 case per 300 live male births; in fewer than 1% of patients, hypospadias occurs in combination with undescended testes. A large series at Children's Hospital in Boston found DSDs in 50% of children with hypospadias and unilateral or bilateral cryptorchidism in which the gonads were impalpable. [12] Clinicians should suspect the possibility of a DSD in patients with both hypospadias and cryptorchidism.

International statistics

Analysis of worldwide infant screening of 6.5 million newborns found the incidence of CAH to be 1 case per 15,000 live births. Frequency was highest in neonates of European Jewish, Hispanic, Slavic, or Italian descent.

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.

DSDs may result in individuals who do not conform to traditional male or female classifications.

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Prognosis

Infants born with ambiguous genitalia represent a true medical and social 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.

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. The topic of early gender reassignment is currently under debate.

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Patient Education

Parents of children with DSD are often overwhelmed and confused by their child's condition. 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. Adequate counseling and support for parents includes 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.

Thus, the ideal management method is a team approach that includes neonatologists, geneticists, endocrinologists, surgeons, counselors, and ethicists.

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