Cloacal exstrophy is a rare anomaly in which there is external exposure of the bladder and the terminal aspect of the gut. Genital anomalies are common in patients with cloacal exstrophy. In male patients, there is separation of the penis into 2 hemiphalluses in conjunction with pubic diastasis. Cryptorchidism is usually present. About two-thirds of females with cloacal exstrophy have fusion anomalies of the Müllerian duct structures (e.g., uterus didelphys) and one-third have vaginal agenesis. There is additional discussion of cloacal exstrophy in Chapter 44.^1–6

The features that determine the gender of an individual include the chromosomal complement, the composition of the gonads, the morphology of other internal genital structures, and the external genital anatomy. Intersexuality is defined as a lack of accord among these basic determinants of gender. Classically, 4 major categories of intersexuality are recognized: female pseudohermaphroditism, male pseudohermaphroditism, true hermaphroditism, and disorders of gonadal differentiation (Table 55-1). There is controversy regarding the terminology for these conditions, however. The Lawson Wilkins Pediatric Endocrine Society and the European Society for Paediatric Endocrinology recommend use of the term disorders of sex development in lieu of intersex and intersexuality. They also recommend usage of terminology that emphasizes the genetic etiology, and avoidance of the terms pseudohermaphrodite and hermaphrodite.^7,8

The term ambiguous genitalia refers to incomplete differentiation of the external genitalia. Ambiguous genitalia are present in most intersex states. However, the presence of ambiguous genitalia does not always indicate intersexuality. For instance, hypospadias in a karyotypic male with normal testes represents incomplete masculinization of the external genitalia, but is not a true intersex state. In addition, intersex states are not always accompanied by ambiguous genitalia. Normal-appearing female external genitalia are sometimes present in genetic males (complete testicular feminization). Patients with true hermaphroditism and mixed gonadal dysgenesis sometimes have normal-appearing male or female external genitalia. Other disorders that usually include normal or near-normal external genital development include Turner syndrome, pure gonadal dysgenesis, Klinefelter syndrome, persistent Müllerian duct syndrome, and sex reversal syndrome.

The identification of ambiguous external genitalia in the neonate generally triggers an immediate medical and radiological evaluation to allow appropriate gender assignment, to characterize internal genital anatomy, and to detect associated anomalies. Subtle anomalies of genital differentiation may not be detected until later during childhood or at the time of puberty.

Female Pseudohermaphroditism; 46,XX DSD

Female pseudohermaphrodites have virilized external genitalia, but a normal female karyotype (46,XX) and normal female internal genitalia with 2 ovaries. The alternate nomenclature for this condition is 46,XX disorder of sex development (46,XX DSD). This is the most common type of intersex anomaly, and accounts for approximately 60% of neonatally evident intersex cases. The pathogenesis of this anomaly involves fetal exposure to androgens early during gestation. The most frequent cause of excessive androgen exposure is congenital adrenal hyperplasia (caused be an enzymatic defect in the cortisol synthesis pathway, most often 21-hydroxylase deficiency). Rare causes include transplacental exposure due to maternal drug ingestion or an androgen-secreting tumor in the mother. The gestational age at which the exposure occurs determines the severity of the anomaly. The duration and magnitude of exposure also presumably are important. Prior to the 12th week of gestation, exposure to androgens causes persistence of the urogenital sinus, fusion of the labioscrotal folds, and, in some cases, male phallus formation. If exposure does not occur until after the 12th week, clitoromegaly may be the only manifestation.⁹ An additional, but quite rare, potential cause of female fetus virilization is a recessively inherited deficiency of aromatase.¹⁰

Male Pseudohermaphroditism; 46,XY DSD

Male pseudohermaphroditism (46,XY disorder of sex development) refers to a variety of disorders that are characterized by a normal male karyotype (46,XY), a male pattern of internal genital development, and incomplete masculinization of the external genitalia. Occasionally, these patients are phenotypically female, and the diagnosis is made at puberty due to primary amenorrhea and lack of pubertal secondary sexual development. Male pseudohermaphroditism can be caused by defective synthesis of testosterone or end-organ insensitivity to androgens. Diminished synthesis of testosterone can result from hypoplasia or agenesis of the testicular Leydig cells or an enzymatic deficiency in the biosynthetic pathway for testosterone formation.¹¹

Androgen insensitivity is the most common cause of male pseudohermaphroditism; this group of disorders is termed testicular feminization or androgen insensitivity syndrome. The cause is absent or defective androgen receptors; circulating testosterone levels may be normal in these patients. The male internal genitalia are not present. The testes are cryptorchid; orchiectomies are indicated due to the risk for testicular neoplasms. With complete testicular feminization, the external genitalia are those of a normal female. The vagina is blind ending. Incomplete testicular feminization refers to instances of androgen insensitivity with ambiguous external genitalia. There is enlargement of the clitoris, sometimes forming a microphallus with hypospadias. A large prostatic utricle or blind-ending vagina with a long urogenital sinus is often present. The testes are often small and cryptorchidism is frequently present.

In the Dominican Republic, there is a relatively high frequency of male pseudohermaphroditism due to a deficiency in 5α-reductase. The resultant disorder is termed familial pseudovaginal penoscrotal hypospadias. 5α-reductase converts testosterone to dihydrotesterone. Dihydrotesterone is required for appropriate fetal masculinization of the phallus and urogenital sinus. Therefore, affected infants typically have a microphallus, perineal hypospadias, a bifid scrotum, and a persistent urogenital sinus. The testes are cryptorchid or located within the labial–scrotal folds. Although the external genital appearance is predominantly female during infancy, increased secretion of testosterone at the time of puberty causes dramatic virilization, including phallic enlargement and development of a male body habitus.

True Hermaphroditism; Ovotesticular DSD

True hermaphroditism (ovotesticular disorder of sex development) refers to the presence of both testicular and ovarian tissues, within either the same or separate gonads. This rare anomaly may be due to a chromosomal aberration or mutation of a gene that participates in the determination of testicular differentiation. A uterus is usually present. The morphology of the internal and external genitalia otherwise varies greatly between affected patients; frequently, the external genitalia are ambiguous. The most common (60% to 70%) karyotype is 46,XX. Chimeric and mosaic forms can also be present in these patients; 46,XY is rare.

Mixed Gonadal Dysgenesis

Mixed gonadal dysgenesis refers to a variety of sex differentiation abnormalities in which both a testis (either normal or dysgenetic) and a contralateral streak gonad (composed of fibrous tissue) are present. There often is a vas deferens ipsilateral to the testis and a fallopian tube on the side of the streak gonad. A uterus, sometimes small or rudimentary, is typically present. The testis is often intra-abdominal. The most common karyotype in patients with mixed gonadal dysgenesis is a mosaic of 45,XO/46,XX. Other mosaicisms can occur. Some patients have a 46,XY karyotype. The term partial gonadal dysgenesis refers to any combination of a dysgenetic testis contralateral to a normal, dysgenetic, or streak gonad. Patients with mixed or partial gonadal dysgenesis usually have ambiguous external genitalia. The most common pattern is unfused labioscrotal folds, a urogenital sinus that opens at the base of a variably sized phallus, and a vagina (Figure 55-1). These individuals have an elevated risk for gonadal malignancies (up to 20% before the age of 20 years).