Disorders of Sex Development
Jonathan M. Swartz
Yee-Ming Chan
KEY POINTS
Disorders of sex development (DSD) are a heterogeneous group of disorders broadly defined by atypical development of genetic, gonadal, and/or anatomic sex. DSD frequently present in the newborn period with ambiguous genitalia and/or other issues.
The rapid evaluation of infants with genital ambiguity is critical to identify and, if necessary, treat salt-wasting congenital adrenal hyperplasia, which is potentially life-threatening.
The main goal of sex assignment in children with DSD is to attempt to match the child’s future gender identity. This is a challenging, imperfect, and humbling endeavor.
I. DEFINITION AND NOMENCLATURE. The term disorders of sex development (DSD) was introduced to replace older terms such as ambiguous genitalia, pseudohermaphroditism, and intersex to denote atypical development of genetic, gonadal, and/or anatomic sex (Table 63.1). Examples of DSD presenting in the newborn period include infants with the following findings:
A. Ambiguous genitalia
B. A penis and bilaterally nonpalpable testes (cryptorchidism)
C. Unilateral cryptorchidism with hypospadias
D. Severe penoscrotal, scrotal, or perineal hypospadias, with or without microphallus, even if the testes are descended.
E. Apparently female appearance with enlarged clitoris (clitoromegaly) and/or inguinal hernia(s) or palpable gonad(s)
F. Asymmetry of in size, pigmentation, or rugation of labioscrotal folds
G. Discordance of external genitalia with prenatal karyotype
Because internal genital anatomy, karyotype, and sex assignment cannot be determined from a baby’s external appearance, a thorough evaluation is required. The evaluation must be expedited because of the possibility of saltwasting congenital adrenal hyperplasia (CAH), which can be life-threatening within the first week of life as well as the urgency felt by most parents in assigning a sex of rearing.
Table 63.1. Revised Nomenclature | ||||||||||||||||||||||||
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II. IMMEDIATE POSTNATAL CONSIDERATIONS PRIOR TO SEX ASSIGNMENT. Although a rapid decision about sex assignment is essential for the parents’ peace of mind, care must be taken to avoid drawing premature conclusions. Until a sex assignment is made, gender-specific names, pronouns, or other references should be avoided. Prompt consultation with a pediatric endocrinologist will facilitate the evaluation, and most causes of DSD can be identified in 2 to 4 days, although some cases may take 1 to 2 weeks or longer. The physician should examine the infant’s genitalia in the presence of the parents and then discuss with them the process of genital development, that their child’s genitalia are incompletely or variably formed, and that further tests will be required before a decision can be made regarding the infant’s sex. Circumcision is contraindicated until a determination is made concerning the need for surgical reconstruction.
III. NORMAL SEX DEVELOPMENT. The process of gonadal differentiation and genital development is depicted in Figure 63.1. In general, early structures will develop down the female pathway unless specific factors are present that direct development down the male pathway.
A. Genetic sex refers to the sex chromosome complement.
B. Gonadal sex. Undifferentiated gonads develop in the bilateral genital ridges around 6 weeks of gestation and begin to differentiate by 7 weeks. SRY, which encodes the primary testis-determining transcription factor on the
short arm of the Y chromosome, promotes the gonads to develop into testes. Several other genes can also promote testicular and/or ovarian development, including NR5A1 (SF1), NR0B1 (DAX1), SOX3, SOX9, WNT4, and RSPO1.
short arm of the Y chromosome, promotes the gonads to develop into testes. Several other genes can also promote testicular and/or ovarian development, including NR5A1 (SF1), NR0B1 (DAX1), SOX3, SOX9, WNT4, and RSPO1.
 Figure 63.1. The process of gonadal, internal genital, and external genital differentiation. (From Holm IA. Ambiguous genitalia in the newborn. In: Emans SJ, Laufer M, Goldstein D, eds. Pediatric and Adolescent Gynecology. Philadelphia, PA: Lippincott Williams & Wilkins; 1998:53.) |
C. Anatomic sex refers to the external and internal genitalia. The testis secretes two hormones critical for male genital formation: Anti-müllerian hormone (AMH, also called müllerian inhibiting substance or factor, MIS or MIF) is produced by Sertoli cells, and testosterone is produced by Leydig cells.
1. Internal genitalia. AMH causes regression of the müllerian ducts that would otherwise become the uterus, fallopian tubes, cervix, and upper vagina. Testosterone prevents the regression of the wolffian ducts and promotes their development into the vas deferens, seminal vesicles, and epididymis. Müllerian duct regression and wolffian duct development require high local concentrations of AMH and testosterone, respectively. Failure of a testis to develop on one side may result in ipsilateral retention of müllerian structures and regression of wolffian structures.
2. External genitalia. The enzyme 5α-reductase, present in high concentration in genital skin, converts testosterone to dihydrotestosterone (DHT). DHT is the primary hormone responsible for masculinizing the external genitalia, including the genital tubercle and labioscrotal folds, which form the penis and scrotum, respectively. In the absence of DHT, these undifferentiated structures develop into the clitoris and labia. Testicular descent from the abdomen to the inguinal ring requires insulin-like peptide 3 (INSL3), and descent from the inguinal ring into the scrotum requires testosterone. This generally occurs in the last 6 weeks of gestation.
Formation of normal male internal and external genitalia under the influence of testosterone and DHT requires functional androgen receptors in the target tissues.
D. Time course. The timeline of fetal sexual differentiation is depicted in Figure 63.2 and Table 63.2.
1. First trimester. Testicular synthesis of testosterone is stimulated by activation of the luteinizing hormone (LH) receptor by human chorionic gonadotropin (hCG) produced by the placenta. The first trimester is the only period during which the labioscrotal folds are susceptible to fusion. If a 46,XX fetus is exposed to excess androgens during the first trimester, the clitoris and labioscrotal folds will virilize and may appear indistinguishable from a normal male penis and scrotum, although the latter will be empty.
2. Second and third trimesters. Testicular androgen production is stimulated by LH from the fetal pituitary and is responsible for penile growth, scrotal maturation (rugation, pigmentation, and thinning), and final testicular descent. High intrauterine concentrations of testosterone may influence brain development, possibly affecting later behavior, sexual orientation, and gender identity.
 Figure 63.2. Timelines for six aspects of sex differentiation. (Adapted from White PC, Speiser PW. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Endocr Rev 2000;21[3]:245-291. Adapted from Barthold JS, Gonzalez R. Intersex states. In: Gonzalez ET, Bauer SB, eds. Pediatric Urology Practice. Philadelphia, PA: Lippincott Williams & Wilkins; 1999:547-578.) |
Table 63.2. Timetable of Sex Development | ||||||||||||||||||||||
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IV. NURSERY EVALUATION OF A NEWBORN WITH SUSPECTED DISORDERS OF SEX DEVELOPMENT
A. History
1. Maternal drug exposure during pregnancy, such as to androgens (e.g., testosterone, danazol), drugs that interfere with androgen synthesis or action (e.g., finasteride, spironolactone), or antiseizure medications (e.g., phenytoin, trimethadione)
2. Maternal virilization during pregnancy due to poorly controlled maternal CAH, a virilizing adrenal or ovarian tumor, or placental aromatase deficiency
3. Placental insufficiency. First-trimester synthesis of testosterone in the fetal testis is dependent on placental hCG due to its activation of the LH receptor.
4. Prenatal findings of genital ambiguity; sex chromosome mosaicism; a karyotype discordant with phenotypic sex; or potential DSD-associated conditions, such as oligohydramnios, renal anomalies (genitourinary malformations), or skeletal abnormalities (campomelic dysplasia)
5. Family history of CAH, hypospadias, cryptorchidism, infertility, pubertal delay, corrective genital surgery, genetic syndromes, or consanguinity. Death of a male family member from vomiting or dehydration in early infancy may suggest undiagnosed CAH.
B. Physical examination
1. External genitalia. The examiner should note the stretched penile length, width of the corpora, engorgement, presence of chordee (abnormal downward curvature of the penis), position of the urethral orifice,
presence of a vaginal opening, and pigmentation and symmetry of the scrotum or labioscrotal folds. The normal full-term male infant has a penile length of at least 2.5 cm, measured stretched from the pubic ramus to the tip of the glans (Fig. 63.3), and usually 1 cm or more in width. The normal full-term female infant has a clitoris <1 cm in length and <0.5 cm in width. Posterior fusion of the labioscrotal folds is assessed by determining the anogenital ratio, which is the distance between the anus and the posterior fourchette divided by the distance between the anus and the base of the phallus. An anogenital ratio >0.5 indicates first-trimester androgen exposure.
presence of a vaginal opening, and pigmentation and symmetry of the scrotum or labioscrotal folds. The normal full-term male infant has a penile length of at least 2.5 cm, measured stretched from the pubic ramus to the tip of the glans (Fig. 63.3), and usually 1 cm or more in width. The normal full-term female infant has a clitoris <1 cm in length and <0.5 cm in width. Posterior fusion of the labioscrotal folds is assessed by determining the anogenital ratio, which is the distance between the anus and the posterior fourchette divided by the distance between the anus and the base of the phallus. An anogenital ratio >0.5 indicates first-trimester androgen exposure.
 Figure 63.3. Stretched penile length of normal premature and full-term babies (closed circles), showing lines of mean ±2 standard deviations. Superimposed are data for two small-for-gestational-age infants (open triangles), seven large for gestational age infants (closed triangles), and four twins (closed boxes), all of whom are in the normal range. (From Feldman KW, Smith DW. Fetal phallic growth and penile standards for newborn male infants. J Pediatr 1975;86:395.) |
2. Gonadal size, position, and descent should be carefully noted. A gonad below the inguinal ligament is usually a testis (normal or dysgenetic) but may be an ovotestis or even a uterus herniating into the inguinal canal. Abnormal genital development with bilateral nonpalpable gonads should raise immediate concern for salt-wasting CAH.
3. Associated anomalies should be noted. Additional features may indicate a more generalized disorder, although such features may not be present at birth. Denys-Drash syndrome (Wilms tumor and/or diffuse glomerulosclerosis) or WAGR (Wilms tumor, Aniridia, Genitourinary anomalies, and mental Retardation) syndrome, both due to mutations
of WT1 (11p13), can cause DSD in 46,XY infants. A few examples of other conditions associated with DSD include Smith-Lemli-Opitz, Robinow, Antley-Bixler, and Goldenhar syndromes; campomelic dysplasia (SOX9 mutations); and trisomy 13.
of WT1 (11p13), can cause DSD in 46,XY infants. A few examples of other conditions associated with DSD include Smith-Lemli-Opitz, Robinow, Antley-Bixler, and Goldenhar syndromes; campomelic dysplasia (SOX9 mutations); and trisomy 13.
C. Diagnostic tests
1. Laboratory tests are tailored to the differential diagnosis.
a. Chromosome analysis on peripheral blood can be performed by karyotype within 48 hours in many centers and sometimes more rapidly by fluorescent in situ hybridization (FISH). Although a standard karyotype may show 46,XX, FISH for SRY may reveal that it has been translocated to an X chromosome or an autosome. Any abnormal karyotype detected prenatally should be confirmed immediately after birth.
b. First-line testing in addition to a karyotype should include a 17-hydroxyprogesterone (part of newborn screens in all U.S. states), LH, and testosterone to be drawn after 48 hours of life. Baseline labs can also include serum electrolytes, blood urea nitrogen (BUN), and creatinine, with electrolytes followed frequently to look for evidence of salt wasting.