Ambiguous Genitalia and Pseudohermaphroditism

T Symposium on Pediatric Endocrinolugy

Ambiguous Genitalia and Pseudohe rmaph roditism

Barbara M. Lippe, M.D.*

GENDER ASSIGNMENT: A MEDICAL EMERGENCY The newborn infant who presents with genital ambiguity is a medical emergency. Appropriate and rapid gender assignment during the initial or referral hospitalization will often determine the success of the outcome for child and family regardless ofthe complexity of the problem. The clinician must have a rapid and rational approach to assessment, recognizing that the goal is not determination of "what it is" but assignment of a gender concordant with how he or she will best function anatomically and sexually. This decision is based on delineation of the existing anatomy and an understanding of the pathologic and physiologic reasons for the ambiguity. Prior to the institution of the evaluation, certain guidelines have assisted us in successful management. Parents must be immediately informed of the physicians' concern, and told the birth certificate should not be filled out. Explanations to the parents should initially include descriptions such as "the baby was born with genitalia which have not yet fully developed" or terms such as "overdeveloped," "incompletely developed," or "underdeveloped." They should be informed that rapid initiation of diagnostic studies and consultation will assist the physician in determining the nature of the problem and how the internal organs have developed. They should be allowed to see the baby and to examine the genitalia with the physician. All the anatomic structures should be described, where appropriate, in both male and female terms, i.e., "we're going to find out if this is a penis that has not yet developed or if it's a clitoris that may be a bit overdeveloped." Words such as intersex should be avoided but, where appropriate, concepts may be introduced which foster the recognition that since infants carry the genetic material of both parents, they may indeed have some of the hormonal or gonadal potentials of both parents. Parents should not be encouraged (or allowed?) to give the newborn infant a neuter name. This promotes am• Associate Proressor of Pediatrics, University of California School of Medicine, Los Angeles. California Pediatric Clinics of North America-Vol. 26, No. l. February 1979

91

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bivalence on their part and suggests to them that the physicians themselves may be somewhat arbitrary in their ultimate assignment. Instead, every attempt should be made to withhold naming until gender assignment is determined, and then to use the name the family had originally and anticipatorily associated with that sex. A family who waits nine months for a son to be a David III should not get a "Francis" or "Teri." If the baby is born in a small outlying hospital, transfer to a secondary or tertiary care facility is usually necessary and should be encouraged. Again, gender will almost always be assigned based on the ability to define anatomy and predict future development (especially in complex cases of gonadal intersex) so it is the baby, not its chromosomes, plasma, or urine, who must be investigated thoroughly and quickly. There is often concern over what impact the parents' initial impression of what the child looks like will be on their later acceptance of the assigned gender. One can argue that in the case of some infants with hermaphroditism or mixed gonadal dysgenesis, reconstruction of the genitalia in either a female or male mode is possible and the parents should then be "allowed" to choose what they first "saw" or "wanted" most. Conversely, one certainly does not use this concept in the virilized female with congenital adrenal hyperplasia, for example, no matter how severe the virilization appears to the family. In this case, the physicians explain the nature of the defect, and because of their comfort in understanding the mechanism, transmit this comfort to the family, and assign what will then be accepted as the appropriate gender. It is this second approach that ought to be fostered even in more complicated conditions. Physicians are in the best position to predict the future medical and surgical course that each gender assignment will entail. They should come to the family with an explanation of the anatomic potential for the baby which should result in acceptance ofthe one, proper gender choice. There is no reason that, when done early enough in the neonatal qmrse, the same acceptance and understanding cannot be developed as in the case of the child with adrenal hyperplasia. In our institution the pediatric endocrinologist is the consultant who works most closely with the family and their primary physicians, and is responsible for integrating the opinions of the urologist, surgeon, or geneticist. It has been our policy to be completely honest with the family in the final explanation of anatomy, gonadal histology, hormonal defect, and chromosomal karyotype. Medical-legal considerations notwithstanding, future compliance with the treatment plan, consents for surgery, relief from anxiety, and acceptance all depend on honesty and comprehension. In the future, this will extend to how we talk to and explain the nature of the disorder to the patients themselves, and it must start with the family. There are times when religious tenets may be in question and the family may need support from the clerical sector. For example, for the male infant with congenital absence of the phallus and imperforate anus, in whom all consultants concur that reconstruction in the male gender would be impossible, and for whom gonadectomy and assignment of the female gender is recommended, consent for castration may require religious support. 27

I

II I' 1\

[I I

AMBIGUOUS GENITALIA AND PSEUDOHERMAPHRODITISM

93

NORMAL SEXUAL DIFFERENTIATION AND DEVELOPMENT

II

!

I

I I

The formation of the external genitalia depends upon all the embryologic, physiologic, and hormonal events that affect the genital tubercle, labioscrotal folds, and urogenital sinus. The normal events leading to sexual differentiation begin with gonadal development. During the fourth week of fetal gestation (fertilization age) the gonadal ridges develop as proliferations of coelomic epithelium and mesenchyme, and then begin to undergo differentiation by forming "sex cords." At this time, primordial germ cells, located in the yolk sac, migrate by amoeboid movement (mechanism unknown) along the dorsal mesentery, and by the sixth week have invaded the genital ridges. This process then affects gonadal development by several, as yet undefined, mechanisms. Ordinarily, the fertilized zygote contains 46 chromosomes bearing either an XX or XY genome, and the migrating germ cells bear a similar genome. Gonadal induction and subsequent differentiation into either an ovary or a testis appear to be a function of the presence or absence of a cell surface antigen, H-Y antigen, on the cells of the gonadal ridge and! or the germ cells. 23 Testicular development is believed to occur when Y antigen is present and not to occur in its absence. The presence of a Y chromosome is most commonly associated with the detection of H-Y antigen and testicular development. However, there are reported examples of testicular development and positive H-Yantigen determination where chromosomal evidence of the Y is lacking. Similarly, in cases in which ovaries or ovarian follicles and testes or testicular tubules develop in the same fetus (defining a true hermaphrodite) either on contralateral sides or together as an ovo-testis, H-Y antigen may be detectable in varying concentrations with or without karyotypic demonstration of a Y chromosome. 22 Finally, mosaic cell lines may be present and detected in the tissues one ordinarily assesses for a chromosomal karyotype (leukocytes or fibroblasts from a tissue biopsy) but the actual karyotype of the genital ridges on either side, or the germ cells that migrate to each ridge, may not even be reflected by the demonstrated karyotype. Thus, chromosomal karyotype as the major determinant of gonadal sex may only be applicable when the patient is normal and helpful only when it confirms the clinical and anatomic findings. Under the influence of, or associated with, H-Y antigen, condensation of the cortical portion of the gonadal primordium occurs to form a tunica, and the medullary sex cords develop into seminiferous tubules. This process is rapid in the male and by the ninth week testicular function begins. In the absence ofH-Y antigen, ovarian organogenesis occurs more slowly. This process involves development of cortical cords from the germinal epithelium and ~ontinued invasion by primordial germ cells. The medulla takes on a cord-like appearance with the germ cells grouped around them, and then these undergo their first meiosis. Finally follicles and stroma develop and a recognizable ovarian structure is present at 17 to 20 weeks. 14 Internal genital duct development is also a paired process, occurring as a mechanism to transport the product of the gonad to a position either

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to be excreted or fertilized. The embryo first develops pronephric ducts which degenerate rapidly. The metanephric ducts follow thereafter and differentiate into the functional excretory kidney. By four weeks a third set of ducts, the mesonephric ducts, are present bilaterally and in close proximity to the genital ridges. When a testis develops, its close apposition to the mesonephros results in the "organization" of this duct (then called the wolffian duct) into the duct of the epididymis, the ductus deferens, the seminal vesicle, and the common ejaculatory duct at the level of the bladder trigone. Jost has shown that the developing testis secretes testosterone, and it is this locally secreted testosterone that is the socalled organizing substance. This process occurs independently on each side, and the testosterone does not cross over to influence ductal development on the contralateral side. 10 Additionally, recent studies indicate that the active hormone in this process is testosterone itself, and it does not require reduction to dihydrotestosterone (DHT) to affect ductal development. 8 However, systemically administered or produced testosterone does not bring about a similar local effect. Thus, disorders that result in exposure of the fetus to testosterone of nongonadal origin may masculinize the external genitalia but will not affect ductal differentiation. The process of mesonephric organization into the wolffian structures is obvious by the ninth week and may be complete by the fourteenth week. In the absence of a testis or local testicular organizer, the mesonephric duct degenerates by the tenth week. There is no known factor responsible for this regression. At five weeks, in all fetuses, a fourth set of ducts, the paramesonephric or mullerianducts, develop lateral to the genital ridges. When a testis is developing, it normally secretes not only testosterone, but also a substance known as mullerian regression substance or mullerian inhibitory factor (MIF). This material, a partially characterized glycoprotein of greater than 20,000 molecular weight, is of testicular Sertoli cell origin. 2 It causes the specific regression of mullerian ducts only, and it, like local organizer, acts only on the side on which it is produced. When a testicle is not present, or there is a defect in the ability to produce or respond to the production ofMIF, the paramesonephric duct will develop into a fallopian tube, hemi-uterus, and form part of the upper two-thirds of the vagina. The presence (or absence) of an ovary has no direct influence on this process. Thus mullerian development is a step in embryologic differentiation that proceeds in the absence of a gonad and only regresses when MIF is secreted. 9 These steps have been schematically depicted in Figure 1. The final step in fetal sexual differentiation involves the development ofthe external genitalia. This process involves two complex mechanisms: the embryologic steps responsible for the formation of the excretory systems of the kidney and the alimentary tract (many of the steps of which are under genetic controls that are unknown and unrelated to the "sex" of the fetus); and the development of that part of the external genitalia that is associated with sex assignment and is under the influence of circulating androgens. At three weeks of gestation, cloacal folds develop around the cloacal

95

AMBIGUOUS GENITALIA AND PSEUDOHERMAPHRODITISM ASSENT Y CHROMOSOME

NEGATIVE

PRESENT Y CHROMOSOME

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PAIRED GONADAL RIDGES

OVARY

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>

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~

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substance

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UNFUSED LABIA MINORA

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testosterone

TOT I POTENTIAL UROGENITAL SINUS GENITAL TUBERCLE _ LABIAL SCROTAL SWELLINGS

VAGIN~A

testosterone

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UNVIRIUZED CLITORIS

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LOWER 1/3

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FALLOPIAN lUBE (HEMI) uTERUS

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'~

______ Mullerian regression

~

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TESTIS

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MEMBRANOUS URETHRA PHALLIC GROWTH LABIAL FU 51 ON

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SCROTAl GROWTH DESCENDED SCROTAL GONAD .".,_ _ _ _- - - '

~ APPEARANCE FEMALE

APPEARANCE MALE

Figure 1. Development of the genital tract.

membrane and unite cephalad to form the genital tubercle. Its original position, therefore, is not sex hormone dependent but subject to congenital malformation (i.e., congenital absence of the penis). At the sixth week the cloacal membrane subdivides into the urogenital and anal membranes and the cloacal folds into the urethral folds and anal folds. Concomitantly, a second set of paired structures, the genital swellings, develop on either side of the urethral folds. By the eighth week, the cloaca divides into an anterior urogenital groove (sinus) and posterior anorectal canal. These steps are common to the fetus of either sex and anomalies such as imperforate anus or penoscrotal transposition occur during this early embryologic period and are not hormonally mediated. 17 After eight weeks the development of the external genitalia diverges (Fig. 2A). In the normal male fetus the genital tubercle rapidly elongates, pulls the urethral folds forward to form a deep urogenital or urethral groove, and by 12 weeks forms the penile urethra (Fig. 2B). This process is a result of circulating testosterone. Normally, this testosterone is secreted by the developing fetal testis, which has developed the ability to synthesize and release the hormone by the eighth week. 20 Thus, any defect in the testis which impairs its ability to synthesize or secrete adequate amounts of testosterone will result in inadequate virilization. There are at least five enzymatic steps in testosterone synthesis for which specific deficiencies have been demonstrated. Since these same enzymes are generally present in the adrenal along the pathways of corticosteroid as well as sex steroid metabolism, complex clinical presentations of inadequate virilization coupled with salt loss or hypertension may occur (Table I-A). Similarly, testicular absence of Leydig cells, and thus testosterone synthesis capacity, may result in failure of virilization at this time. Conversely, in the clinical syndrome of anorchia, in which testicular tissue cannot be demonstrated in an otherwise virilized

96

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(~~---Genital tubercle !

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Figure 2. Development of the external genitalia.

c Anus VIRILIZED

NONVIRILIZED (FEMINIZED)

EXTERNAL GENITALIA

male, it must be assumed that testicular function was present at this critical embryologic period and subsequently was lost, hence the term "vanishing testis" syndrome. Further evidence for this concept is the absence of mullerian structures in the anorchic male, indicating Sertoli cell MIF production. Once testosterone is secreted into the general circulation, it must be peripherally converted to DHT by the enzyme 5-alpha reductase, present in the tissues of the genital tubercle at this time 19 •24 to effect genital virilization. Additionally, cytosol receptors for testosterone and DHT must be present, and post-receptor events activated before virilization can occur. 26 Thus, defects in androgen action may also result in clinical syndromes of inadequate virilization of the 46 XY male infant (male pseudohermaphroditism). A number of clinical syndromes previously described in separate families and identified by eponyms (Gilbert-Dreyfus, Lubs, Reifenstein) are being reinvestigated 1 and classified according to the step at which androgen action appears to be impaired (Table I-B). The mechanism responsible for final formation of the glandular urethra (to the tip of the phallus) is not clear and occurs later (fourth month) as an invagination of the penile ectoderm to reach the urethral lumen. Thus the sporadic occurrence of hypospadias may be independent of disorders of testosterone production or action. However, maternal ingestion of progestational agents may be associated with anomalies at this step. Finally, the genital swellings move caudally to make up the

97

AMBIGUOUS GENITALIA AND PSEUDOHERMAPHRODITISM

Table 1. Errors in Testosterone Synthesis or Action DEFECT

EFFECT ON THE MALE

EFFECT ON THE FEMALE

A. Disorders of Deficient Testosterone Synthesis l. 20,22-Desmolase defi-

Inadequate virilization; salt loss (adrenal)

Normal genitalia; salt loss (adrenal)

2. 3 !3-Hydroxysteroid dehydrogenase deficiency

Inadequate virilization; salt loss (adrenal)

± Mild virilization; salt loss (adrenal)

3. 17,20-Desmolase deficiency

Inadequate virilization

Not reported? X-linked

4. 17 ,,-Hydroxy steroid dehydrogenase defiCiency

Inadequate virilization; hypertension (adrenal)

Normal genitalia; 1 amenorrhea; hypertension (adrenal)

5. 17-Ketosteroid reductase

Inadequate virilization

ciency

0

deficiency 6. Leydig cell agenesis

Inadequate virilization

B. Disorders of Defective Androgen Action 7. 5 a-Reductase deficiency

Inadequate virilization at birth; degrees of masculinization at puberty; pseudohermaphroditism Type II

8. Incomplete androgen receptor binding defects

Variable virilization with sexual hair at puberty; pse udo hermaphroditis m Type I

Does not occur X-linked

9. Classical androgen receptor binding defect

Complete testicular feminization syndrome

Does not occur X-linked

10. Post androgen receptor binding defects

Inadequate masculinization

?

C. Disorders of Excessive Androgen Production 11. 21-Hydroxylase deficiency

Excessive postnatal virilization; ± salt loss

Ambiguous genitalia; ± salt loss

12. 11 /3-Hydroxylase deficiency

Excessive postnatal virilization; hypertension

Ambiguous genitalia; ± hypertension

13. Maternal virilizing syndrome; iatrogenic (maternal medication); fetal tumor

? Hypospadias

Ambiguous genitalia

halves of the scrotum (Fig. 2C), enlarging mechanically in the third trimester following testicular descent. In the female fetus, in whom the levels of circulating androgen are normally much lower than in the male, the indifferent primordium develops more slowly into the so-called female genitalia. This development can be considered the unmodified embryologic differentiation of the fetal genitoexcretory system. The genital tubercle elongates slightly to form the clitoris, but the urethral folds are not pulled anteriorly and therefore

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do not fuse. Instead they remain as the labia minora (Fig. 2B). By 14 weeks' gestation, the relative position of the urethral orifice is fixed and exposure to androgen will no longer pull the urethral folds or the labia minora anteriorly. However, the genital tubercle or clitoris always has the potential to elongate and later exposure to androgen may enlarge the clitoris without being able to affect labial fusion or the position of the urethra. This time limit in embryologic differentiation can date prenatal exposure to androgenic steroids; the female fetus exposed after 14 weeks will exhibit clitoromegaly without labial fusion, whereas earlier exposure can result in fusion as well. Finally, the genital swellings do not migrate, but enlarge to form the labia majora, and the urogenital groove remains open to form the vaginal vestibule (Fig. 2C). Normal ovarian or adrenal androgen secretion is not necessary or sufficient to affect this unmodified embryologic pathway. Ovarian agenesis or dysgenesis, therefore, is associated with normal female external genitalia. Similarly, defects in testosterone synthesis or action do not affect the female genitalia unless they result in the increased production of other androgenic steroids. Enzyme defects that primarily result in increased testosterone or androgen production are associated with virilization of the external genitalia, and represent the major cause of female sexual ambiguity. Of these (Table I-C), adrenal 21-hydroxylase deficiency is the most common (and is discussed in the article on Congenital Adrenal Hyperplasia).

CLINICAL EVALUATION AND DIFFERENTIAL DIAGNOSIS OF AMBIGUOUS GENITALIA Since ambiguity of the external genitalia at birth may be the consequence of a sporadic developmental embryologic event or occur secondary to a derangement in the hormonal environment of the fetus or its ability to respond to hormonal stimuli, diagnoses may encompass otherwise "normal" female infants who appear virilized, otherwise "normal" males who have anomalies or are incompletely masculinized, or infants with combined gonadal and/or chromosomal H-Y antigen defects. Since the ambiguity is the obvious clinical feature, we have developed an approach to evaluate and differential diagnosis based on what the clinician first sees (Fig. 3). The diagnostic categories in this figure will be referred to subsequently by their roman numerals. The presence or absence of palpable lower inguinal or scrotal gonad(s) is a most important clinical feature and serves as the basis for a division into groups of predictably different disorders. Gonads in this position are virtually always testicular or partly testicular, and their presence rules out the simple virilization of an otherwise unambiguous female. A normal ovary may rarely herniate, but if so, appears just outside the inguinal ring and does not usually migrate down into a labioscrotal fold. Additionally, were an ovary to be ectopically positioned in the labial fold, it would not ordinarily be associated with other ambiguous features such as clitoromegaly or labial fusion. Conversely, the

PHYSICALDCAMINATION

I No

ASym~elrical

exterr') gonads

Sym~etriCill

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900IMIS)

Genilcgrarn: ultrasoundl----_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _- '

I

I

~nnill~agina.

Mullerlanslructures

Urine&),llasma steroids

Microphililus

I ND salt IDss

alone

Genitogram:

I

ultrasound

Hormonaistimulilioniests

;r;

~u~~rian~

Surgical exploration Goniilllilibiopsy

{valuilleforpituilary dysfunction &

structures

No

:~ .~-

~

MullipleamrloflHc malformations

Sattloss

I

Additionalevilluillion:

I

I

I

Abllormalor ilbsenl

CIIrvix,uterus

hypoglycemia

I

I

IV' VCUG

,--L-, Abnormal

Normal

I

I

Kilryotype

CA.

A'

"""

errors in

descended

lestesor

If

III

IV

VI

ilnorchiaor VII

agenesis

testosteron action

KJinelelter's

Vllt

IX

XIV XI

XII

XIII

Figure 3. Evaluation of a newborn infant with ambiguous genitalia.

XV

XVI

XVII

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BARBARA

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infant born with ambiguous genitalia but without palpable gonads most often represents a virilizing syndrome in a female, since nongonadal androgen can induce marked changes in the genitalia but cannot "create" a testis in an otherwise normal female. Thus, the apparently similar appearances of the infants shown in Figure 4 are clinically distinguished by the presence of gonads in the "folds" of the child to the right. One could argue that the exception to the logical predictability of this initial division is the "nonambiguous" infant without gonads, that is, the so-called "male" born with undescended testes. However, we regard the failure to identify testes at birth in a full term infant with a normal appearing phallus and phallic urethra as a form of ambiguity and as worthy of evaluation as any other infant to be discussed. While it is true a majority of these will be normal males with cryptorchidism (and a minority true anorchia or chromosomal abnormalities such as 47 XXY) , virilization of an otherwise normal female infant can be marked enough that clinical distinction is impossible. Since true bilateral cryptorchidism is rare in the carefully examined neonate, this condition warrants inclusion in the assessment of the newborn infant with ambiguous genitalia. The initial anatomic evaluation of the child without scrotal gonads is thus designed to distinguish the infant with external virilization and internal mullerian structures from the infant without mullerian internal genitalia. We have found that the genitogram and ultrasound are the most useful tests to assist in these distinctions. Demonstration, by genitography, that the introitus communicates with a vagina and cervix, and by genitography or ultrasound that a cervix and uterus are present, rapidly categorizes many infants. Infants in categories 1 through VII (Fig. 3) will almost always be assigned the female gender, regardless of phallic size, since they are either normal females with reproductive potential (I to V) or patients with intersex in whom anatomic reconstruction in the female mode is almost always chosen if a uterus and vagina are present. Thus the female gender assignment can often be made even before the next steps in the medical evaluation are complete.

Figure 4. Left, labial fusion, clitoromegaly, and empty scrotal folds of virilized female. Right, Similar appearance but symmetric, scrotal gonads (testes) of incompletely masculinized male.

AMBIGUOUS GENITALIA AND PSEUDOHERMAPHRODITISM

101

This initial medical evaluation of the infant with ambiguous genitalia without palpable gonads is designed to distinguish the female infant with congenital adrenal hyperplasia (I, II) from other nonprogressive forms of virilization (III, IV, V), or gonadal intersex (VI, VII). This part of the medical evaluation including measurement of plasma and urinary steroids, close assessment for the possibility of salt loss, karyotype analysis, and possibly exploratory laparotomy with gonadal biopsy, are outlined in Figure 3 and expanded in Table 2.

Table 2. Laboratory Tests Employed in the Differential Diagnosis of Patients with Ambiguous Genitalia SPECIFIC TEST DESCRIPTIONS AND INTERPRETATION DIAGNOSTIC CATEGORIES IN FIGURE

3

OF RESULTS

I Female-Congenital adrenal hyperplasia-Salt loser

Increased plasma 17 a hydroxyprogesterone; 13 increased 24 hour urine 17-ketosteroids; neonatal 24'hour urine pregnanetriol may (or may not) be increased but increases if patient remains untreated; hyponatremia and acidosis (with low CO,) followed by hyperkalemia. Affected siblings have salt 10ss.18

II Female-Congenital adrenal Hyperplasia-Non-salt loser

21-0H deficiency with steroids as above; 11-0H deficiency with increased plasma 11 deoxycortisol (specific compound S) and increased urine 17 ketosteroids, THS, and THDOC. Plasma 17 a hydroxyprogesterone and urine pregnanetriol may be mildly elevated. 18

III Female-Virilized-iatrogenic

No diagnostic test; history of ingestion by mother of virilizing agent (Le., progestins such as Norlutin'") must concur with anatomic virilization-fusion ± clitoromegaly prior to 14 weeks' gestation, onlY,clitoromegaly thereafter .

IV Female-Virilized maternal condition

Specific demonstration of increased androgens in mother.

V Female-Virilized-idiopathic

Plasma and urine steroids are normal; karyotype is 46XX. This category requires "clinical judgment," as gonadal (Leydig) tissue may be present but demonstrable only by gonadal biopsy. hCG stimulation test may be helpful if plasma androgens rise significantly,

VI Mixed or asymmetric gonadal dysgenesis

No specific laboratory test; anatomic diagnosis based on surgical exploration with gonadal histology (usually a streak gonad on one side and testicular tissue on the other). Documentation of internal genital development radiographically or surgically. Karyotype may be "typical" 45XO/46XY or may be multiple mosaic (Le., 44XO/46XXI 47XXY) or nondiagnostic (Le., 46XX or 46Xy).

VII True hermaphrodite

No specific laboratory test; gonadal histology must include ovarian follicles and testicular tubules. Karyotype may be 46XX, 46XY, or any mosaic including those listed under VI. H-Y antigen will be present. 22,2:<

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Table 2. Laboratory Tests Employed in the Differential Diagnosis of Patients with Ambiguous Genitalia (Continued) SPECIFIC TEST DESCRIPTIONS AND INTERPRETATION DIAGNOSTIC CATEGORIES IN FIGURE

3

OF RESULTS

VIII Male with absent MIF

46XY karyotype; normal steroids; testes + uterii inguinali; clinical test for MIF not available (this testicular substance is probably not present in the postnatal or mature testis). 9

IX Male with undescended testes or anorchia

In undescended testes normal neonatal hormone concentrations and gonadotrophins; the infant with anorchia may have castrate (very high) plasma FSH, LH, and low plasma testosterone," and subsequently negative hCG stimulation test. 7.12

X Male with Leydig----<:ell agenesis on hypoplasia

Very low plasma testosterone, no rise of testosterone follOWing hCG stimulation; LH high, FSH normal; diagnostic testicular biopsy. 3

XI Male with unknown error in androgen action

No diagnostic test to explain "peripheral unresponsiveness" to normal testosterone and DHT in 46XY male.

XII Male errors in androgen action

Type I---46XY male with sex-linked defect; diagnosed by in vitro tissue binding studies; LH concentrations may be high. Testosterone and DHT concentrations are normal. 26 Type II-46XY male with autosomal recessive defect; testosterone concentrations are normal but DHT is low; FSH and LH are normal. 24

XIII Male with errors in testosterone synthesis

No salt loss-{Table I-A 3,4,5) decreased urine 17ketosteroids in defects 3,4; increased urine 17-ketosteroids but low plasma testosterone. in defect 5.

XIV Male with errors in testosterone synthesis

Salt loss-{Table I-A, 1,2) decreased urine 17-ketosteroids in defect 1; increased pregnenolone and derivatives in blood and urine in defect 2.

XV Male with microphallus

No specific diagnostic test.

XVI Male with hypopituitarism

Demonstration of GH deficiency ± other pituitary trophic hormone deficiencies; usually associated with neonatal hypoglycemia. I.

XVII Male with congenital malformations

No specific diagnostic test.

Conversely, in the infant without scrotal gonads in whom no vagina, cervix, or uterus can be demonstrated radiographically, the male gender assignment will often depend on the adequacy of the phallic structure. In the infant with cryptorchidism or anorchia (IX), the phallus is usually adequate, and the male assignment is made initially. Later hormonal studies and/or surgical exploration are planned to distinguish between the two. Karyotype and H-Y antigen assessment will usually be confirmatory. Some male infants with errors in testosterone synthesis or action may have associated undescended testes and present with both

AMBIGUOUS GENITALIA AND PSEUDOHERMAPHRODITISM

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cryptorchidism and inadequate virilization. The decision as to gender assignment in these infants is difficult. Those with errors in testosterone synthesis will respond to exogenous testosterone and may then potentially virilize. Potential for phallic reconstruction is the deciding factor. Errors in testosterone action tend to preclude virilization and these infants are best assigned the female gender. The presence or absence of salt loss, and the plasma and urine steroids may distinguish these (Table 2).

Infants with a scrotal gonad or gonads are similarly assessed anatomically first, then functionally. A distinction can often be made on the physical examination between infants with anatomic anomalies, those with gonadal asymmetry, and those with symmetrically descended testes but inadequate virilization. This distinction not only assists in determining the type of evaluation with which to proceed, but also suggests acute medical problems for which the infant in this group may be at risk. In the group of infants with symmetrical scrotal gonads and inadequate virilization, it is essential to distinguish the male with 3-f3 hydroxysteroid dehydrogenase deficiency, since he is at risk for early salt loss, dehydration, and death. Thus rapid medical assessment and continuous monitoring of these babies is essential. On the other hand, when obvious anatomic defects are present and responsible for the ambiguity, such as in the infant with penoscrotal transposition (Fig. 5), then an enzymatic disorder does not enter the differential diagnosis and the risk of immediate salt loss need not be of concern. Other anatomic malformations such as imperforate anus or tracheoesophageal fistula must be looked for in these infants. Finally, conditions such as hypopituitarism with neonatal hypoglycemia are associated with microphallus, and should be considered when this defect is the presenting clinical feature. 16 The infant with obviously asymmetric external genitalia most often represents the form of ambiguity that will involve chromosomal and gonadal intersex. Again, since medical concerns of salt loss or shock are minimal (barring the rare combination of an enzymatic error and gonadal asymmetry), the evaluation should proceed in the direction of de-

Figure 5. Penoscrotal transposition, hypospadias, and imperforate anus. Note mid position of phallus between separate scrotal sacs (containing testes); colostomy in upper right.

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fining the existing anatomy. Chromosomal karyotype per se is usually not helpful in the decision making process. For example, a majority of true hermaphrodites are 46XX by karyotype regardless of their degree of phallic development and of whether there is a uterus or vagina present. Similarly the 45XO/46XX mosaic karyotype may be associated with an anatomic and clinical spectrum ranging from that seen in classic Turner's syndrome, without any genital ambiguity and normal uterus and vagina, to the very asymmetric findings of streak gonad, hemiuterus, and vagina coupled with a well developed phallus and scrotal gonad. 4 The anatomy of the infant is a strong influence in gender assignment. In those infants whose genitalia are very ambiguous and asymmetric, and in whom reconstruction may potentially be possible in both the male and female mode, the radiographic demonstration of a vagina and uterus will often be the deciding factor in favor of feminine reconstruction even when a potentially adequate phallic structure is present (Fig. 6). Following gender assignment, plans for reconstruction of the external genitalia are outlined to the family. In the female, when clitoroplasty or clitoral reduction is indicated, we plan the procedure for age 18 to 24 months. This affords time for some tissue growth to facilitate reconstruction, but is early enough to prevent self recognition of ambiguity. We

Figure 6. Le.ft. Appearance of genitalia in neonate with asymmetric gonadal dysgenesis. Right, Contrast genitography fills a vagina CV) and a uterine cavity CUt). Below , Grey scale ultrasonography may demonstrate a vagina CV) and uterus CUt) even if no communication with urethra is present. Transverse scan. U = umbilicus, P = pubis, B = bladder.

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Figure 7. Left, Clitoromegaly and posterior labial fusion in an untreated female with non salt-losing congenital adrenal hyperplasia. Center, Surgical clitoral recession. Right, Postoperative results one month later.

have developed a method of clitoral reduction that leaves the organ intact and functionally and cosmetically acceptable.:; An example of this procedure in an older child is shown in Figure 7. Clitorectomy is no longer performed in our institution. Partial fusion of the posterior labia can also be corrected at this time. Extensive vaginoplasty, however, must be postponed until adolescence or young adulthood, since postoperatively the patient may be required to use dilators or mechanical forms, and her cooperation and motivation are essential. When a testis is present and must be removed, we advocate early surgery (often at the time of the diagnostic laparotomy). This not only removes the psycho~ogically discordant gonad, but also eliminates a source of testosterone secretion which continues to stimulate the clitoris to some degree. In the male, phallic reconstruction is also a staged procedure, depending on the degree of associated hypospadias or chordee. When testes are absent, the placement of acceptable Silastic prostheses will result in normal appearing scrotal contents. Some physicians advocate placement of prepubertal prostheses initially, with replacement by larger prostheses during adolescence. Others, including ourselves, feel that if phallic reconstruction is adequate, masculine self-image is not usually affected by the prepubertal anorchia, and we therefore suggest the placement of only one set of adult prostheses following the initiation of androgen therapy early in adolescence. Finally, the management of the child with ambiguous genitalia should include genetic counseling and appropriate family education. Many of the conditions discussed are autosomal recessive or X-linked errors with predictable risks for recurrence. Similarly, there is heterogeneous expression within families of some of these disorders, and examination or testing of potentially affected members may be indicated. Thus the physician caring for the child with genital ambiguity must be prepared to deal with a problem that ranges from the acute medical emergency of gender assignment to the long-term management of the patient and his or her family.

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REFERENCES 1. Amrhein, J. A., Klingensmith, G. J., Walsh, P. C., et aL: Partial androgen insensitivity: The Reifenstein syndrome revisited. New EngL J. Med., 297:350, 1977. 2. Blanchard, M. G., and Josso, N.: Source of the anti-mullerian hormone synthesized by the fetal testis: Mullerian-inhibiting activity of fetal bovine sertoli cells in tissue culture. Pediat. Res., 8:968, 1974. 3. Brown, D. M., Markland, C., and Dehner, L. P.: Leydig cell hypoplasia: A cause of male pseudohermaphroditism. J. Clin. Endocrino!. Metab., 46:1, 1978. 4. Davidoff, F., and Federman, D. D.: Mixed gonadal dysgenesis. Pediatrics, 52:725, 1973. 5. Fonkalsrud, E. W., Kaplan, S., and Lippe, B. M.: Experience with reduction clitoroplasty for clitoral hypertrophy. Ann. Surg., 186:221, 1977. 6. Givens, J. R, Wiser, W. L., Summitt, R L., et al.: Familial male pseudohermaphroditism without gynecomastia due to deficient testicular 17-ketosteroid reductase activity. New EngL J. Med., 291 :938, 1974. 7. Grant, D. B., Laurance, B. M., Atherden, S. M., et aL: HCG stimulation test in children with abnormal sexual development. Arch. Dis. Child., 51 :596, 1976. 8. Imperato-McGinley, J., and Peterson, R. E.: Male pseudohermaphroditism: The complexity of male phenotypic development. Am. J. Med., 61 :251, 1976. 9. Josso, N.: Fetal sexual differentiation in mammals. Pediat. Ann., 3:67, 1974. 10. J ost, A.: A new look at the mechanisms controlling sex differentiation in mammals. Johns Hopkins Med. J., 130:38, 1972. 11. Keenan, B. S., Meyer, W. J., Hadjian, A. J., et al.: Syndrome of androgen insensitivity in man: Absence of 5 alpha-dihydrotestosterone binding protein in skin fibroblasts. J. Clin. EndocrinoL Metab., 38: 1143, 1974. 12. Levitt, S. B., Kogan, S. J., Schneider, K. M., et al.: Endocrine tests in phenotypic children with bilateral impalpable testes can reliably predict "congenital" anorchism. Urology, 11 :11, 1978. 13. Lippe, B. M., LaFranchi, S. H., Lavin, N., et al.: Serum 17-hYdroxyprogesterone, progesterone, estradiol, and testosterone in the diagnosis and management of congenital adrenal hyperplasia. J. Pediat. 85 :782, 1974. 14. Lippe, B. M.: Sexual differentiation and development. In Hershman, J. M., (ed): Endocrine Pathophysiology: A Patient Oriented Approach. Philadelphia, Lea and Febiger, 1977. 15. Lippe, B. M., and Sample, W. F.: Pelvic ultrasonography in pediatric and adolescent endocrine disorders. J. Pediat., 92:897, 1978. 16. Lovinger, R D., Kaplan, S. L., and Grumbach, M. M.: Congenital hypopituitarism associated with neonatal hypoglycemia and microphallus: Four cases secondary to hy: pothalamic hormone deficiencies. J. Pediat., 87: 11 71, 1975. 17. Miller, S. F.: Transposition of the external genitalia associated with the syndrome of caudal regression. J. UroL, 108:818, 1972. 18. New, M. I., and Levine, L. S.: Congenital adrenal hyperplasia. Pediat. Ann., 3 :27, 1974. 19. Peterson, R E., Imperato-McGinley, J., Gautier, T., et al.: Male pseudohermaphroditism due to steroid 5a-reductase deficiency. Am. J. Med., 62:170,1977. 20. Reyes, F. I., Winter, J. S. D., and Faiman, C.: Gonadotropin-gonadal interrelationships in the fetus. In Diabetes and other Endocrine Disorders During Pregnancy and in the Newborn. New York, Alan R Liss, Inc., 1976. 21. Scott, M. D., Hendren, W. H., and Crawford, J. D.: The dynamics of hypothalamic-pituitary-gonadal interplay in early infancy. EndOCrinology, 94 (Supp!.): A-56, 1974. 22. Silvers, W. K., and Wachtel, S. S.: H-Y antigen: Behavior and function. SCience, 195:956, 1977. 23. Wachtel, S. S., Koo, G. C., and Ohno, S.: H-Y antigen and male development. The testis in normal and infertile men. New York, Raven Press, 1977. 24. Walsh, P. C., Madden, J. D., Harrod, M. J., et al.: Familial incomplete male pseudohermaphroditism, type II. New EngL J. Med., 291:944,1974. 25. Wilkins, L.: Masculinization of the female fetus due to the use of orally given progestins. J.A.M.A., 172:1028, 1960. 26. Wilson, J. D., Harrod, M. J., Goldstein, J. L., et al.: Familial incomplete male pseudohermaphroditism, type I. New Engl. J. Med., 290:1097, 1974. 27. Young, H. H., Cockett, A. T. K., Stoller, R, et al.: The management of agenesis of the phallus. Pediatrics, 47:81, 1971. Department of Pediatrics University of California School of Medicine Los Angeles, California 90024.