This is a term infant noted to have atypical genitalia with perineoscrotal hypospadias and a marked ventral chordee. This could be a penis or an enlarged clitoris. Gonads are nonpalpable bilaterally on examination of the labioscrotal folds. The parents aren't sure whether their child is male or female and this constitutes a neonatal (social) emergency. Further evaluation is commenced immediately. An ultrasound reveals a normal uterus and ovaries, as well as normal kidneys and bladder. Chromosomal analysis shows a 46XX karyotype. A genitogram reveals a short distal common urethrovaginal confluence, a vagina with a normal cervical impression, and a normal urethra.
At two weeks of age, this infant is admitted to the ICU with hypovolemic shock, and found to have hyponatremia and hyperkalemia. Plasma 17-hydroxy-progesterone levels are markedly elevated and plasma cortisol levels are low. Hydrocortisone and mineralocorticoid replacement are administered, along with intravenous fluids and electrolyte replacements, with a good response. She is diagnosed with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency.
A feminizing genitoplasty is performed at one year of age. This includes clitoral reduction and a flap vaginoplasty. In her mid-teens, the patient undergoes a vaginoplasty revision for introital stenosis.
Ambiguous genitalia are uncommon in a primary care pediatrician's practice, but their diagnosis and prompt treatment require urgent medical attention. Any delay may result in death in early infancy from an uncorrected metabolic disorder, if present. Quickly establishing a definitive diagnosis and appropriate treatment plan will minimize medical, social and psychological complications.
It is important to understand normal sexual differentiation in order to understand the development of intersex (ambiguous genitalia and sex determination) disorders. Up until six weeks of gestational age, the internal and external genitalia of the male and female fetuses are indistinguishable. The indifferent gonad is located on the urogenital ridge, with the Wolffian and Mullerian ducts nearby, which are destined to form the male and female internal ducts, respectively. The external genitalia in both sexes are represented by the genital tubercle, the urethral folds, and the labioscrotal swellings that surround the cloacal membrane (1). These primordial structures have the potential to produce either male or female genitalia.
The SRY gene, on the short arm of the Y chromosome, initiates male sexual differentiation (2). The SRY influences the undifferentiated gonad to form a testes, which produces the hormonal milieu that results in male sexual differentiation. Testosterone stimulates the Wolffian structures (epididymis, vas deferens, and seminal vesicles), and anti-Mullerian hormone suppresses the development of the Mullerian structures (fallopian tubes, uterus, and upper vagina). Testosterone converts to dihydrotestosterone in the skin of the external genitalia and masculinizes the external genital structures. By 12 weeks most of this male differentiation has occurred, after which the penis grows and the testes descend into the scrotum (3).
In the absence of these genetic (SRY gene) and hormonal influences (testosterone, anti-Mullerian hormone), the fetus will develop as a female. Intersex conditions arise because of an error along the male pathway that interferes with complete masculinization, or, in the case of a genetic female, some virilizing influence that acts on the developing embryo (3).
Infants whose genitalia are obviously indeterminate and ambiguous are investigated so that sex of rearing can be assigned. However, appearance can be deceptive. An apparent male may be a severely virilized female with congenital adrenal hyperplasia (CAH). An apparent female infant with only mild clitoral hypertrophy may be a male with severe androgen insensitivity.
Clinical findings in a newborn infant that raise the possibility of intersexuality (1,3) in an apparent male:
. . . . . Bilateral nonpalpable testes in a full-term infant.
. . . . . Hypospadias associated with clefting of the scrotal sacs.
. . . . . Undescended testes with hypospadias.
Clinical findings in a newborn infant that raise the possibility of intersexuality (1,3) in an apparent female:
. . . . . Clitoral hypertrophy.
. . . . . Foreshortened vagina with single opening (instead of a urethral meatus and vaginal introitus noted separate from one another, there is just a single opening at the introitus and no separate urethral meatus visible).
. . . . . Inguinal hernia containing a gonad.
Also, as noted above, those in whom the external genitalia are clearly ambiguous so that the sex cannot be immediately decided should be investigated.
A small number of children will only come to light in adolescence because of amenorrhea, inappropriate breast development, virilization, or the onset of cyclic "hematuria" (gross hematuria that occurs every 28 days, as a menstrual cycle would).
A careful history should be taken. An obstetric history should include any evidence of endocrine disturbance during pregnancy (mother with a Cushingoid or virilized appearance), and any medications taken during pregnancy (particularly any treatment for recurrent abortion or the use of hormonal contraceptives). As many intersex states are recessively inherited familial disorders, a family history may reveal genital anomalies, unexplained neonatal deaths, abnormal pubertal development, or infertility.
The physical exam starts with a search for evidence of a malformation syndrome. The genitalia are examined with the size of the phallus noted (a normal newborn stretched penile length should be greater than 2 cm and a normal clitoris is less than 7mm), and the position of the urethral meatus noted. Any penile chordee should be noted. The labioscrotal folds are evaluated for fullness, symmetry, rugosity and the presence or absence of a gonad (If a gonad is palpable in a female infant, then congenital adrenal hyperplasia is not present, as the CAH infant would have normal ovaries in the abdominal cavity). The position of the urethral meatus helps to determine the extent to which the urogenital sinus has closed (a separate urethral meatus and vaginal opening shows complete closure of the urogenital sinus while a single orifice suggests the persistence of a common urogenital sinus with the vagina and urethra connected distally). Areolar and labioscrotal hyperpigmentation associated with high levels of ACTH suggest congenital adrenal hyperplasia. The palpation of a uterus or cervix may be noted on rectal exam.
Since the appearances of the external genitalia vary so widely among patients who have the same condition, it is unwise to attempt a definitive diagnosis from the physical findings alone (1,3).
A chromosomal karyotype should be done in all patients. Since congenital adrenal hyperplasia is the most common cause of ambiguous genitalia in the newborn, serum 17-hydroxy-progesterone and deoxycorticosterone levels should be checked along with serum electrolytes and glucose in the infant with symmetrical masculinization and nonpalpable gonads (3,4).
A pelvic ultrasound will delineate the uterine anatomy, if present. It should normally be located posterior to the bladder. The kidneys and ureters should also be imaged. A genitogram will delineate the anatomy of the vagina, the uterine canal, one or two fallopian tubes, and/or the vasa deferentia, as well as the level at which the vagina enters into the urogenital sinus, if present (1,3). It is performed by injecting contrast retrograde through the common urogenital sinus (or the urethra and vagina if the urogenital sinus has closed), under fluoroscopy.
Further biochemical profiles may be necessary to identify a block in testosterone biosynthesis, decreased 5-alpha-reductase activity or androgen insensitivity (3).
Gonadal inspection and biopsy are necessary and can be done laparoscopically in many cases by an experienced pediatric urologist or pediatric surgeon. This will not be necessary in established cases of congenital adrenal hyperplasia and Turner syndrome. Cystovaginoscopy provides valuable information because it augments the genitogram's findings and aids in treatment planning.
The classification of intersex disorders are most conveniently divided into four main groups based on gonadal histology: 1) Female pseudohermaphrodites (two normal ovaries present). 2) Male pseudohermaphrodites (two normal testes present). 3) True hermaphrodites (both ovarian and testicular tissue are is found in the same patient). 4) Gonadal dysgenesis conditions (the gonads are histologically disordered; e.g., streak gonads) (1,3,5).
Female pseudohermaphrodism is a disorder in which a chromosomal female (46XX), with normal ovaries and mullerian derivatives and normal fertility potential, has virilized external genitalia (enlargement of the phallus and labioscrotal fusion are present to varying degrees). This virilization of the female fetus is secondary to androgens from either the maternal circulation or the fetal adrenal gland.
Congenital adrenal hyperplasia (CAH) is the most common cause of female pseudohermaphrodism, as well as the most common intersex disorder. The adrenal glands, in CAH, overproduce testosterone because an enzyme defect in intermediate metabolism results in decreased cortisol synthesis, which leads to an increase in circulating adrenocorticotropic hormone (ACTH), and thus to hyperstimulation of the adrenals (5). Because some forms of CAH are associated with salt-wasting, prompt monitoring and correction of electrolytes and corticosteroid/mineralocorticoid replacement are crucial. CAH is an autosomal recessive disorder that occurs in 1 of 15,000 births in the United States (6).
21-hydroxylase deficiency is the most common (95% of the cases) enzyme defect that causes CAH, with salt-losing a feature of a complete deficiency. 11-beta-hydroxylase deficiency is a rare form of CAH, which results in an accumulation of deoxycorticosterone, a potent mineralocorticoid. This results in salt retention and hypertension.
21-hydroxylase deficiency is suspected in a masculinized infant without palpable gonads and with Mullerian derivatives (female internal pelvic organs) evident on pelvic ultrasound. A 50 to 100 fold increase in serum 17-hydroxyprogesterone and a 46XX karyotype confirms the diagnosis. Salt wasting occurs in 75 percent of patients with classical disease, and is evident within the first two weeks of life, with resultant hyponatremia, hypokalemia, and inappropriate sodium wasting (high urine sodium despite hyponatremia) due to low serum aldosterone and elevated plasma renin activity (7). It is crucial to recognize this potentially life-threatening condition in the newborn period and institute replacement of cortisol and mineralocorticoid as necessary.
Other causes of female pseudohermaphrodism are maternal progesterone ingestion (with androgenic side effects) administered during pregnancy to prevent abortion, a virilizing ovarian or adrenal tumor in the mother, or idiopathic causes.
Male pseudohermaphrodism results from inadequate virilization of the male embryo. Chromosomal males (46XY) possess testes, but the male anatomic genital development is abnormal. Cellular testosterone sensitivity is abnormal in 80 percent of cases, and testosterone production is deficient in the remaining 20 percent. The causes include androgen insensitivity, gonadotropic failure, Leydig cell agenesis, bilateral vanishing testes syndrome, persistent mullerian duct syndrome, testosterone biosynthesis defects and 5-alpha-reductase deficiency (5).
Patients may have abnormal male genitalia, ambiguous genitalia, or female genitalia with palpable or nonpalpable testes, depending on the completeness and nature of the defect and the extent of gonadotropin oversecretion.
Androgen insensitivity is the most common (1 in 20,000 male births) cause of male pseudohermaphrodism and results from dysfunction or reduction of the androgen receptor. For complete testicular feminization, the androgen receptor is absent or completely nonfunctional. The pituitary and hypothalamus are insensitive to testosterone and thus secrete large amounts of gonadotropins, which results in the oversecretion of testosterone and estrogen (5). Breast development, general body habitus, and distribution of body fat are female in character. The clitoris is normal or small, and the vagina is short with a blind ending, but the external genitalia are female in appearance. All internal genitalia are absent (no uterus or ovaries) except for the gonads, which have the histologic appearance of undescended testes (6). Because of increased tumor risk in the undescended testes (5% to 10%), gonadectomy is recommended after puberty.
Patients with complete androgen insensitivity syndromes (testicular feminization) are normal phenotypic females who present during childhood with one or both testes palpable in an inguinal hernia, or with amenorrhea at puberty. A few are diagnosed based on discrepancy between prenatal karyotype and phenotype at birth (i.e., a 46XY karyotype with female external genitalia at birth). The diagnosis is based on clinical and family history, endocrine studies and, if indicated, androgen binding analysis in genital skin fibroblasts (5).
In the 17-beta-hydroxysteroid dehydrogenase deficiency (the most common biochemical defect causing deficient testosterone biosynthesis without CAH, which causes male pseudohermaphrodism), males have feminine external genitalia with mild to moderate degrees of clitoral hypertrophy, but with a separate urethra and blind ending vaginal pouch. Testes are usually inguinal. The diagnosis is often made at puberty, when progressive virilization associated with penile growth, attainment of male secondary sex characteristics, testicular descent, and a change in gender identity may occur (5).
5-alpha-reductase deficiency (pseudovaginal perineoscrotal hypospadias) is an autosomal recessive disorder associated with failure of dihydrotestosterone (DHT) formation, resulting in normal male internal Wolffian duct derivatives, but the external genitalia fail to virilize in utero (DHT is necessary for the external genitalia to masculinize while the internal genitalia masculinize in the presence of testosterone). The internal male genitalia are normal, and the testes are located in the labioscrotal pouch. The external genitalia typically show severe perineoscrotal hypospadias and a blind vaginal pouch opening into the urogenital sinus or urethra. At puberty, normal levels of luteinizing hormone and testosterone result in masculinization of the external genitalia, and breasts do not develop (5,6).
True hermaphrodism is a rare condition in which ovarian and testicular tissue exist in the same individual. 70 percent are 46XX (but they possess the SRY gene), 10% are 46XY, and the remainder show either mosaicism or chimerism (evidence of development from two zygotes). Patients most commonly have ambiguous genitalia, but near-normal female and male genitalia may be present. A unicornuate or bicornuate uterus is usually present, and the differentiation of the genital ducts is determined by the ipsilateral gonad, with the ovary usually located on the left side (5). The most common gonad found is the ovotestes (50%), followed by ovary (30%) and testes (20%). Combinations are ovotestes/ovary (34%), bilateral ovotestes (27%), ovary and testes (27%) and ovotestes/testes (12%). The ovarian tissue is potentially fertile, but the testes are not (5).
A well masculinized patient may rarely present after puberty with gynecomastia, cyclical hematuria, or scrotal pain secondary to ruptured ovarian follicles.
In most patients, the external genitalia are masculinized to some extent, and two thirds of true hermaphrodites are raised as males. Of those raised as males, 80 percent have hypospadias and over 50 percent have labioscrotal fusion. Of those raised as females, two thirds will have clitoromegaly. All patients have a urogenital sinus, and in most cases, a uterus is present. The ovary is found in a normal location, but the testes or ovotestes may be at any point along the path of testicular descent (5). In addition to imaging studies, a gonadal biopsy is necessary to prove the existence of both ovarian and testicular tissue.
Dysgenetic gonads (histologically disordered gonads) are noted primarily in mixed gonadal dysgenesis, pure gonadal dysgenesis, and gonadal dysgenesis (Turner Syndrome). Mixed gonadal dysgenesis is the second most common intersex disorder. Karyotype is usually a mosaic 45XO/46XY. A testis is usually found intraabdominally opposite a streak gonad (resembling ovarian stroma histologically). A unicornuate (only one side of the uterus is present) uterus, fallopian tubes and vagina are present. The genitalia are ambiguous with severe hypospadias, a urogenital sinus, and labioscrotal fusion, with an undescended testicle. One third exhibit Turner stigmata (short stature, shield like chest, webbed neck, multiple pigmented nevi, and cubitus valgus) as well as cardiovascular and renal anomalies (5,6).
The incidence of gonadal tumors is 25 percent in patients with mixed gonadal dysgenesis and may arise in the streak gonad or the undescended testes. A gonadal tumor has not been described in a scrotal testes (8). Early bilateral gonadectomy with female rearing is appropriate in phenotypic females. In phenotypic males with a scrotal testes, male rearing is appropriate, but the streak gonads must be removed.
Pure gonadal dysgenesis is an abnormal differentiation of the gonads without a chromosomal abnormality. A 46XX female has normal immature female external genitalia, intact Mullerian duct structures and bilateral streak gonads. They have no stigmata of Turner syndrome. They usually present as adolescent females who fail to mature and reach menarche (5).
Patients with 46XY "pure gonadal dysgenesis" also have bilateral streak gonads, intact Mullerian structures, a female phenotype, and the absence of Turner stigmata. Some may present in the newborn period with clitoromegaly. These patients with the Y chromosome are at high risk for the development of gonadal tumors, so prophylactic gonadectomy is indicated (6,8).
Gonadal Dysgenesis (Turner Syndrome) is due to the loss of the second X chromosome (45XO), with resultant bilateral streak gonads, normal Mullerian duct development, and phenotypically female external genitalia. Mosaicism (45XO/46XX) lessens the severity of the gonadal abnormality. As neonates do not have ambiguous genitalia, the syndrome is usually diagnosed from investigations for other neonatal anomalies, which include: intrauterine growth retardation, head and facial anomalies, lymphatic anomalies, cardiovascular or urinary tract malformations or skeletal anomalies) (8). All should be raised as females, with gonadectomy indicated only in those with virilization or with clear evidence of a Y cell-line (6,8).
A child born with ambiguous genitalia constitutes a social and medical emergency. In the delivery room, no attempt should be made to suggest a diagnosis or assign a gender. The parents should be told that development is incomplete and further tests will reveal the appropriate gender. The infant should be referred to as "your baby" not "it", "he", or "she". Examination of the child in the presence of the parents to demonstrate the precise abnormalities of genital development is helpful, noting that the genitalia of both sexes develop from the same primordial structures, that both incomplete development or overdevelopment of the external genitalia can occur, and that the abnormal appearance can be corrected and the child raised as a boy or girl, as appropriate (3). A family should never be told that their child is male, but will be made female, or vice versa. Parents should be encouraged not to name the child or register the birth, if possible, until the sex of rearing is established. The parents need to be included in the discussions regarding sex of rearing decisions.
Transfer of the child to a tertiary care facility is usually necessary for optimal assessment and treatment. A multidisciplinary medical team, with representation from neonatology, endocrinology, urology, psychiatry and genetics services is useful. Pediatricians have a key role in coordinating the diagnostic evaluation, helping families understand their child's medical condition, and maintaining open communication between the family and other health care team members. The presence of the nursing staff is also critical at meetings, for it is they who will be spending the most time with the family and neonate.
The decision as to the appropriate sex of rearing of an infant, born with ambiguous genitalia, is based on the fertility potential, capacity for normal sexual function, endocrine function, potential for malignant change in a gonad, and psychosexual factors (testosterone imprinting) (3).
In female infants with CAH, exposure to maternal androgens, and rarely true hermaphrodites, can be expected to be potentially fertile and should be raised as females. The potential for fertility in most other intersex conditions is either reduced or absent.
Phallic size and its potential to develop at puberty into a sexually functional organ, are very important when male sex of rearing is considered. Testosterone injections may need to be given in equivocal cases, and the infant raised as male only when there is a very good response (especially in those with partial androgen insensitivity). The severity of the hypospadias should not be a deciding factor in the sex of rearing, as the results of hypospadias repair, using current techniques, are satisfactory, both functionally and cosmetically.
It is advantageous to retain a gonad appropriate to the assigned sex if it is likely to function adequately. The ovaries of virilized genetic females can be assumed to be normal. The ovaries of true hermaphrodites may also produce estrogen adequately. The testes of true hermaphrodites and those of infants with mixed gonadal dysgenesis may initially show good function, that later declines, so that testosterone supplements may be necessary from puberty onward (3).
There is potential for malignant degeneration in streak gonads, especially those with a Y-chromosome-bearing cell line. Testes that show dysgenetic features on biopsy should also be excised. Histologically, normal undescended testes have an increased incidence of tumor development, but can be preserved in a sex assigned male, with an orchiopexy, and the patient kept under long-term observation. Gonadectomy is considered when the risk of malignancy exists, or when gonadal tissue inappropriate to the assigned gender has been identified.
In the past, it was assumed that sexual identity was largely a result of rearing. However, in the past decade it has become apparent that testosterone imprinting of the fetal brain may play a role in determining male sexual orientation. Some girls with CAH engage in more typically male-like behavior patterns than their unaffected peers. Despite these findings, extreme caution should be exercised when a recommendation is made that the sex of the rearing should be different than the chromosomal sex (3).
Genital reconstruction is necessary in the majority of patients with ambiguous genitalia and intersex disorders once the multidisciplinary team, in conjunction with the family, have decided on the appropriate gender assignment.
Male reconstruction may require hypospadias repair (usually done between 6 months and 1 year of age), orchiopexy, and removal of inappropriate gonads as well as internal Mullerian structures.
Female reconstruction, also known as a feminizing genitoplasty, may involve a clitoral reduction and a vaginoplasty. Clitoral reduction can be done in a nerve sparing fashion, so as to preserve sensation and allow for orgasm, and is carried out as early in life as possible. Minor clitoromegaly can be left alone, as clitoral involution will take place once the source of androgen is shut down.
Vaginoplasty in a low lying vagina (flap-vaginoplasty) can be usually done at the time of clitoral reduction. This primarily widens the introitus. A major vaginal reconstruction for creation of a vagina de novo (substitution vaginoplasty) is best deferred until at least one year of age, or even until puberty.
Psychological and metabolic supports are also essential over time. Most individuals are able to function in the normal range and are well adjusted after treatment of intersex disorders. Certain affected individuals will have conflicts between their psychosexual orientation and their genital appearance and function. Thus, ongoing counseling of the parents and the affected child is advisable. Problems can be minimized when evaluation and treatment is done promptly by an appropriately constituted intersex team.
1. What clinical findings in an apparent newborn male raise the possibility of intersexuality?
2. What clinical findings in an apparent newborn female raise the possibility of intersexuality?
3. What findings in an apparent adolescent suggest the possibility of intersexuality?
4. What are the two most common causes of ambiguous genitalia in the newborn?
5. What laboratory and imaging studies should be done to investigate the infant with ambiguous genitalia?
6. What factors need to be weighed in deciding the appropriate sex of rearing for a newborn with ambiguous genitalia?
7. What genital reconstruction may be necessary in an infant with ambiguous genitalia and an assigned male sex of rearing? An assigned female sex of rearing?
1. Aaronson IA. Chapter 31-Sexual Differential and Intersexuality. In: Belman AB, King LR, Kramer SA (eds). Clinical Pediatric Urology, 4th edition. 2002, London: Martin Dunitz, pp. 995-1059.
2. Blyth B. The Genetic Blueprint for Maleness. Contemp Urol 1995;7 (2):37-44.
3. Kaye C, et al. Evaluation of Newborn with Developmental Anomalies of the External Genitalia. Pediatrics 2000;106 (1):138-142.
4. Therrell BL, et al. Results of Screening 1.9 Million Texas Newborns for 21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia. Pediatrics 1998;101(4):583-590.
5. Rubenstein SC, Mandell J. The Diagnostic Approach to the Newborn with Ambiguous Genitalia. Contemp Urol 1994;6(1):13-26.
6. Chan A, Chang B, Bauer S. Chapter 19- Pediatric Urology-Disorders of Sexual Differentiation. In: Siroky MB, Edelstein RA, Krane RJ (eds). Manual of Urology: Diagnosis and Therapy, 2nd edition. 1999, Philadelphia: Lippincott, Williams and Wilkins, pp. 290-293.
7. Barthold JS, Gonzales R. Chapter 32-Intersex States. In: Gonzales ET, Bauer SB (eds). Pediatric Urology Practice. 1999, Baltimore: Lippincott, Williams and Wilkins, pp. 547-578.
8. Drahms WT, Danish RK. Part 4. Abnormalities of Sexual Differentiation in Chapter 47-Metabolic and Endocrine Disorders. In: Fanaroff A, Martin RJ (eds). Neonatal-Perinatal Medicine, 7th edition. 2002, St. Louis: Mosby, pp. 1416-1457.
Answers to questions
1. Bilateral non-palpable testes in a full term infant. Hypospadias associated with separation of the scrotal sacs. Undescended testes with hypospadias.
2. Clitoral hypertrophy. Foreshortened vagina with single opening. Inguinal hernia containing a gonad.
3. Amenorrhea, inappropriate breast development, virilization, or the onset of "cyclic hematuria".
4. Congenital adrenal hyperplasia and mixed gonadal dysgenesis.
5. Chromosomal karyotype, pelvic ultrasound, genitogram, cystovaginoscopy, gonadal inspection and biopsy, and biochemical studies as necessary (i.e., in an infant with symmetrical masculinization and non-palpable gonads, serum 17-hydroxyprogesterone, deoxycorticosterone, electrolytes, and glucose would be checked because of suspected congenital adrenal hyperplasia).
6. Fertility potential, capacity for normal sexual function, endocrine function, potential for malignant change in a gonad, and psychosexual factors.
7. Male reconstruction may require hypospadias repair, orchiopexy, and removal of inappropriate gonads and internal Mullerian structures. Female reconstruction may require a feminizing genitoplasty (clitoral reduction and vaginoplasty), as well as the removal of inappropriate gonadal tissue.