AUTHOR INFORMATION

Section 1 of 11

Authored by Joel Hutcheson, MD, Consulting Staff, Departments of Surgery and Urology, Pediatric Surgical Associates

Coauthored by Howard M Snyder III, MD, Professor, Department of Surgery, Division of Pediatric Urology, University of Pennsylvania School of Medicine

Joel Hutcheson, MD, is a member of the following medical societies: American Academy of Pediatrics, and American Urological Association

Edited by M David Bomalaski, MD, FAAP, Chief of Medical Staff, 3rd Medical Group, Elmendorf Air Force Base; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Harry P Koo, MD, Chairman of Urology Division and Director of Pediatric Urology, Virginia Commonwealth University; Professor of Surgery, VCU School of Medicine, Medical College of Virginia; Director of Urology, Children's Hospital of Richmond; Paul D Petry, DO, FACOP, FAAP, Clinical Assistant Professor of Pediatrics, University of North Dakota, School of Medicine and Health Sciences; Consulting Staff, Altru Health System; and William J Cromie, MD, MBA, President and Chief Executive Officer, Department of Health Care, Capital District Physicians' Health Plan

Author's Email:	Joel Hutcheson, MD
Editor's Email:	M David Bomalaski, MD, FAAP

eMedicine Journal, May 26 2006, VOLUME 7, Number 5

INTRODUCTION

Section 2 of 11

Background: Intersex conditions are among the most fascinating conditions encountered by the clinician. The ability to diagnose infants born with intersex conditions has advanced rapidly in recent years. 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. While the techniques of surgical genital reconstruction have been mastered, the 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 diagnosis in children with intersex conditions, including children with ambiguous genitalia.

Traditional intersex classifications

For convenience, intersex conditions traditionally have been divided into the following 5 simplified classifications based on the differentiation of the gonad:

• Female pseudohermaphrodite - Two ovaries

• Male pseudohermaphrodite - Two testes

• True hermaphrodite - Ovary and/or testis and/or ovotestis

• Mixed gonadal dysgenesis - Testis plus streak gonad

• Pure gonadal dysgenesis - Bilateral streak gonads

(A streak gonad is dysgenetic and resembles ovarian stromal tissue. No germ cells are present.)

The internal ducts and external genitalia may vary in development, since the presence of apparently male or female gonads does not necessarily correlate with the patient's gender identity.

Pathophysiology: Adequate comprehension of normal and abnormal sexual differentiation is essential to understanding intersex disorders. A summary of current knowledge regarding the embryology and classification of intersex states provides an appropriate introduction to the topic.

Embryology of sexual differentiation

Overview

Phenotypic sex determination begins with genetic sex and follows a logical cascade as follows: 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.

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 XX sex-reversed males 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.

When testicular tissue is not present, the fetus morphologically begins and completes the internal sex duct development and external phenotypic development of a female. When testicular tissue is present, 2 produced substances appear to be critical for development of male internal sex ducts and an external male phenotype, namely, testosterone and müllerian-inhibiting substance (MIS) or antimüllerian hormone (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 factor is important in the effect of testosterone. Wolffian structures located closest to the source of testosterone undergo the greatest degree of male differentiation. Thus, a true hermaphrodite often has 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 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 congenital adrenal hyperplasia (CAH), also termed adrenogenital syndrome.

MIS is produced by the Sertoli cells of the testis and is critical to normal male internal duct development. MIS is a protein with a molecular weight of 15,000 d that is secreted by the testis beginning in the eighth fetal week. The prime role of MIS 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, while 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, while estrogens may interfere with MIS action, resulting in a degree of müllerian duct development. This type of research suggests that müllerian development may be more complex than initially appreciated, and the research helps explain the variable internal sex duct anatomy that occurs in some of the more complex intersex states.

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 subsequently is 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 the 14th week. 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.

Frequency:

• In the US: Intersex conditions vary in frequency. CAH is the most common cause of ambiguous genitalia in the newborn. Mixed gonadal dysgenesis (MGD) is the second most common cause of intersex conditions. 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 Boston found intersex conditions in 50% of children with hypospadias and unilateral or bilateral cryptorchidism in which the gonads were impalpable. Clinicians should suspect the possibility of an intersex condition if hypospadias and cryptorchidism occur in the same patient.

• Internationally: 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.

Mortality/Morbidity:

• Medical aspects: Infants born with ambiguous genitalia present 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.

• Social aspects: 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.

Sex: By definition, intersex conditions result in individuals who do not conform to traditional male or female classifications.

Age: Intersex disorders typically are diagnosed at birth in infants with ambiguous genitalia. Intersex 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.

CLINICAL

Section 3 of 11

History: Evaluation of a newborn with ambiguous genitalia requires a team effort. The most common intersex condition, CAH, results in virilization of a 46,XX female. The clinician's challenge is to distinguish CAH from other less common causes. A detailed family history is essential and should include the following:

• A family history of genital ambiguity, infertility, or unexpected changes at puberty may suggest a genetically transmitted trait.



• Recessive traits tend to occur in siblings, while X-linked abnormalities tend to appear in males who are scattered sporadically across the family history.



• A history of early death of infants in a family may suggest a previously missed adrenogenital deficiency.



• Maternal drug ingestion is important, particularly during the first trimester, when ambiguity may be produced exogenously in a gonadal female.



• Although extremely rare, a history of maternal virilization may suggest an androgen-producing maternal tumor.

Physical: Certain physical characteristics may suggest the directions toward which a successful investigation might be pursued.

• External genitalia examination


• • Note the size and degree of differentiation of the phallus, since variations may represent clitoromegaly or hypospadias.
  
  
  
  • Note the position of the urethral meatus.
  
  
  
  • Labioscrotal folds may be separated or folds may be fused at the midline, giving an appearance of a scrotum.
  
  
  
  • Rugose scrotal or labioscrotal folds with increased pigmentation suggest the possibility of increased corticotropin levels as part of adrenogenital syndrome.
  
  
  
• Gonadal examination


• • Documentation of palpable gonads is important. Although ovotestes have been reported to descend completely into the bottom of labioscrotal folds, in most patients, only testicular material descends fully.
  
  
  
  • If examination reveals palpable inguinal gonads, diagnoses of a gonadal female, Turner syndrome, and pure gonadal dysgenesis can be eliminated.
  
  
  
  • Impalpable gonads, even in an apparently fully virilized infant, should raise the possibility of a severely virilized female pseudohermaphrodite with CAH.
  
  
  
• Rectal examination


• • Rectal examination may reveal the cervix and uterus, confirming internal müllerian structures.
  
  
  
  • The uterus is relatively enlarged in a newborn because of the effects of maternal estrogen, permitting easy identification.
  
  
  

Causes: The more common causes of each of the 5 categories of intersex disorders are described.

Female pseudohermaphrodite

• Overall, CAH is the most frequent cause of ambiguous genitalia in the newborn, constituting approximately 60% of all intersex cases. CAH produces a female pseudohermaphrodite, which is a gonadal female with a virilized phenotype.

• 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 present consistently. In these children, endocrine stabilization must be individualized, a process that usually takes several weeks.

• CAH may result from the following:
  • 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. Prior to common recognition of this condition, 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 2 varieties, which helps account for the clinical heterogenicity seen in patients with salt-wasting nephropathy.

    • 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 or retrograde genitogram reveals evidence of an internal müllerian structure in the form of a cervix.

    • Diagnosis is confirmed by an elevated serum level of 17-OHP. While reference range newborn cord blood levels of 17-OHP can be as high as 900-5000 ng/dL, 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.

    • Remember 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 of CAH.

  • 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.

  • 3-Beta-hydroxysteroid dehydrogenase deficiency
    • 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. Confirm the diagnosis by identifying an elevated serum level of dehydroepiandrosterone or its sulfate metabolite.

    • Keep in mind that 3-beta-hydroxysteroid dehydrogenase deficiency is the only common form of CAH that also can 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, female pseudohermaphroditism 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 formerly were 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 more rare because these abnormalities, if initially present, usually prevent development of a pregnancy. However, a variety of ovarian tumors (eg, arrhenoblastomas, Krukenberg tumors, luteomas, lipoid tumors of the ovary, stromal cell tumors) reportedly have produced virilization of a female fetus.

True hermaphrodite

• Both ovarian and testicular tissues are present in true hermaphroditism. True hermaphroditism is an uncommon cause of genital ambiguity in North America, accounting for fewer than 10% of intersex cases.

• Appearance of the genitalia varies widely in this condition, and while ambiguity is the rule, the tendency is towards masculinization.

• The most common karyotype is 46,XX, although 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 true hermaphrodite with a 46,XY karyotype can have ovarian tissue, since 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, although Van Niekerk reported an ovary in the right hemiscrotum. The least common gonad in true hermaphroditism 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 both. If a fallopian tube has a fimbriated end, the end is closed in most patients, perhaps contributing to the usual lack of fertility. While rare, fertility has been reported. Gonadal tumors also are rare but have been reported.

Male pseudohermaphrodite

• 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.

  • Male pseudohermaphrodism 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 5 enzymatic steps, and defects have been identified at each step. Of these 5 enzymes, 3 (ie, 20-alpha hydroxylase, 3-beta-hydroxysteroid dehydrogenase, 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.

• Androgen insensitivity (causing testicular feminization)
  • 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 DHT.

  • 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.

  • An incomplete form of androgen insensitivity also occurs. These patients demonstrate a spectrum of syndromes 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), although 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 5-alpha-reductase 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 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 and Saenger et al 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. The authors of this article 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 to the child of growing up with inadequate genitalia hardly seems justified. The authors usually recommend gonadectomy and feminizing genitoplasty.

Mixed gonadal dysgenesis

MGD and dysgenetic male pseudohermaphroditism are considered together because of the similarities found in these two causes of ambiguous genitalia.

• 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 with true hermaphroditism.

• A postulated common thread in these two groups of patients is a defect in the sex chromosomes that causes abnormal testicular differentiation, resulting in incomplete virilization and, consequently, ambiguous genitalia. Precisely defined, DMP is an intersex state characterized by bilaterally dysgenetic testes with persistent internal müllerian duct structures, cryptorchidism, and incomplete external virilization. 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 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 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, XO/XY. A characteristic of patients with an XO karyotype is short stature. Patients with DMP are more likely to have a 46,XY karyotype. Internal müllerian remnants tend to be present in patients with DMP who have an XO in the karyotype. Male pseudohermaphrodites who have no internal müllerian remnants usually have no XO component; more virilization is observed both internally and externally. Included in this latter group are patients with Klinefelter syndrome with an XXY karyotype or patients with the sex-reversal syndrome with an XX karyotype.

• A major feature shared by patients with MGD and DMP is the risk of gonadal malignancy 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 commonly 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 patients with DMP had malignancies, most often a gonadoblastoma. Early gonadectomy appears wise because tumors have been reported to arise in the first decade in both syndromes.

• Gender assignment for patients with DMP and MGD remains under debate. Glassberg, citing 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 virilized sufficiently. The authors tend to agree with Rajfer and Walsh, who 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. In both MGD and DMP, consider male gender assignment only for the most significantly virilized patients with a completely descended testis.

• 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 intersex abnormality, with bilateral streak gonads appearing as ovarian stroma without oocytes, usually is not recognized in newborns because the phenotype typically is 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 XX type of pure gonadal dysgenesis appear to be associated with increased risk of gonadal malignancy. Therapy in these children (from an intersex standpoint) primarily is limited to appropriate estrogen and progesterone support.

• The 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 XX type of pure gonadal dysgenesis appears to have an autosomal recessive transmission, and the XY type apparently is an X-linked recessive trait.

DIFFERENTIALS

Section 4 of 11

3-Beta-Hydroxysteroid Dehydrogenase Deficiency
5-Alpha-Reductase Deficiency
Androgen Insensitivity Syndrome
Congenital Adrenal Hyperplasia
Denys-Drash Syndrome
Genital Anomalies
Gonadoblastoma
Hydrocele and Hernia in Children
Hypogonadism
Hypopituitarism
Hypospadias
Menstruation Disorders
Microphallus
Precocious Puberty
Sexuality: Gender Identity

WORKUP

Section 5 of 11

Lab Studies:

• Logical workup in infants with ambiguous genitalia includes the following:


• • Chromosomal analysis
  
  
  
  • Endocrine screening
  
  
  
  • Serum chemistries/electrolyte tests
  
  
  
  • Androgen-receptor levels
  
  
  
  • 5-alpha reductase type II levels
  
  
  

Imaging Studies:

• Renal/bladder ultrasound: Ultrasound can be performed at the bedside in the neonatal ICU. Ultrasound usually allows visualization of a neonate's adrenal glands, which may be enlarged in infants with CAH; however, normal ultrasound findings in the adrenal glands do not exclude a diagnosis of CAH. When adrenal glands are enlarged in patients with CAH, the glands have a cribriform appearance. Ultrasound also helps identify müllerian structures. In a neonate, findings of ambiguous genitalia, enlarged adrenal glands, and evidence of a uterus are virtually pathognomonic for CAH.



• Genitography: A genitogram helps determine ductal anatomy. In a neonate with ambiguous genitalia, a catheter can be inserted into the distal urogenital sinus (urethra). Contrast is injected to outline the internal ductal anatomy. Findings may indicate normal urethral anatomy, an enlarged utricle, a müllerian remnant in a male, a common urogenital sinus, or an area of vaginal and urethral confluence in female neonates.



• CT scanning and MRI are usually not indicated but may help identify internal anatomy.

Procedures:

• Exploratory laparotomy/gonadal biopsy: Open exploration may help identify internal duct anatomy and allow gonadal tissue to be obtained for histologic characterization; however, many authors advocate laparoscopy for this purpose.



• Diagnostic laparoscopy/gonadal biopsy: A laparoscope may be inserted just inferior to the umbilicus under general anesthesia, allowing rapid identification and delineation of the internal duct anatomy without the morbidity associated with open exploration. Biopsy of gonads may be performed laparoscopically by placing additional trocars.

TREATMENT

Section 6 of 11

Medical Care: Medical therapy for intersex conditions depends on the underlying cause and is indicated for the conditions associated with ambiguous genitalia, including CAH. Supplemental hormone therapy may be implemented if gonadal function is compromised.

Surgical Care:

• In a virilized female, the surgical procedure is termed feminizing genitoplasty and includes vaginoplasty and clitoroplasty.



• Undervirilized males typically have hypospadias requiring surgical reconstruction. Gender reassignment may be considered in patients with male pseudohermaphrodism and genital inadequacy.

Consultations:

• Geneticist/genetic counselor



• Endocrinologist



• Surgeon



• Obstetrician/urologist



• Psychologist

MEDICATION

Section 7 of 11

Medications used in intersex conditions depend on the underlying cause.

Drug Category: Glucocorticoids -- These agents have anti-inflammatory properties and cause profound and varied metabolic effects. They modify the body’s immune response to diverse stimuli. Children with CAH require corticosteroid replacement for survival. Replacement also reduces the production of corticotropin and, therefore, the overproduction of androgens.

Drug Name	Hydrocortisone (Hydrocortone, Cortef) -- Drug of choice because of mineralocorticoid activity and glucocorticoid effects.
Adult Dose	30-150 mg/d IV divided q8-12h
Pediatric Dose	10-20 mg/m2/d IV divided into 2 equal doses
Contraindications	Documented hypersensitivity; viral, fungal, or tubercular skin infections
Interactions	CYP450 2D6 and 3A3/4 substrate; corticosteroid clearance may increase with phenytoin, barbiturates, or rifampin treatment or decrease with estrogens; cholestyramine may decrease AUC; corticosteroids may increase digitalis toxicity secondary to hypokalemia; coadministration with potassium-depleting agents (eg, diuretics) may increase risk of hypokalemia; corticosteroids may decrease growth-promoting effect of GH; decreases effects of salicylates and vaccines used for immunization; monitor for hypokalemia with coadministration of diuretics or amphotericin B; antagonizes effects of anticholinergics; may increase anticoagulant effects of warfarin; decreases hypoglycemic effects of sulfonylureas and insulin; increases toxicity of cyclosporine
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in hyperthyroidism, osteoporosis, peptic ulcer disease, cirrhosis, nonspecific ulcerative colitis, diabetes, and myasthenia gravis

FOLLOW-UP

Section 8 of 11

Further Inpatient Care:

• Prompt diagnosis of intersex conditions secondary to CAH is important.

MISCELLANEOUS

Section 9 of 11

Medical/Legal Pitfalls:

• Treatment for intersex states is controversial. No one debates the need to address and treat underlying physiologic problems such as those associated with CAH. The controversy revolves around issues of gender reassignment. Gender assignment by the physician and family may not correlate with gender preference by the patient in adulthood. Remember that the most important sex organ is the brain, which may undergo hormonal imprinting in utero.



• Moratorium: Intersex activists and some health care professionals have called for a moratorium on gender reassignment and genital surgery until studies have been completed on the long-term effects of such surgery. Several long-term follow-up studies are being conducted, including a study by the North American Task Force on Intersexuality. Many health care professionals oppose the proposed moratorium.



• From a medicolegal standpoint, the best approach to managing these cases is to provide parents with as much information as possible so that they can make informed decisions. Adequate counseling and support for parents is vital. The ideal management method is a team approach including neonatologists, geneticists, endocrinologists, surgeons, counselors, and ethicists.

TEST QUESTIONS

Section 10 of 11

CME Question 1: Which of the following causes of ambiguous genitalia in a newborn is most common?

A: 5-alpha-reductase deficiency
B: Mixed gonadal dysgenesis
C: Pure gonadal dysgenesis
D: Congenital adrenal hyperplasia (CAH)
E: None of the above

The correct answer is D: CAH is the most common cause of ambiguous genitalia in a newborn. Analysis of worldwide infant screening of 6.5 million newborns found an incidence of the severe form of CAH of 1 case per 15,000 live births. Mixed gonadal dysgenesis is the second most common cause of ambiguous genitalia. Often unrecognized until puberty, 5-alpha-reductase deficiency occurs less commonly than CAH.

CME Question 2: Which of the following describes the goal of treatment in patients with congenital adrenal hyperplasia (CAH)?

A: Correct the underlying endocrinopathy
B: Prevent vascular collapse and death
C: Surgically correct ambiguous genitalia immediately
D: A and B
E: A, B, and C

The correct answer is D: Monitor a neonate with CAH for salt-wasting nephropathy. Appropriate medical therapy can begin after the underlying endocrinopathy is diagnosed. If indicated, surgery can be performed on an elective basis.

Pearl Question 1 (T/F): The most common cause of congenital adrenal hyperplasia (CAH) is 11-hydroxylase deficiency.

The correct answer is False: The most common cause of CAH is 21-hydroxylase deficiency.

Pearl Question 2 (T/F): All children with intersex conditions and ambiguous genitalia should undergo immediate gender assignment.

The correct answer is False: Children with intersex states and ambiguous genitalia should undergo thorough evaluation before gender assignment decisions are made. The optimal team to become involved in these decisions includes neonatologists, geneticists, endocrinologists, surgeons, counselors, and ethicists.

Pearl Question 3 (T/F): A hernia uteri inguinale is caused by a deficiency of müllerian-inhibiting substance (MIS).

The correct answer is True: Isolated MIS-deficiency syndrome is rare, but its most common presentation is that of a phenotypic male with an inguinal hernia on one side and an impalpable contralateral gonad.

Pearl Question 4 (T/F): Children with a streak gonad and a Y chromosome have increased risk for gonadal malignancies.

The correct answer is True: In patients with mixed gonadal dysgenesis, 25% of gonads (including streak gonads) can be expected to undergo malignant change, most commonly to gonadoblastoma, unless the patient has a gonadectomy before adulthood. In addition to gonadoblastomas, seminomas and embryonal cell carcinomas may develop.

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Section 11 of 11

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