Chapter 582 Disorders of Sex Development
Sexual Differentiation (Chapter 576)
In normal differentiation, the final form of all sexual structures is consistent with normal sex chromosomes (either XX or XY). A 46,XX complement of chromosomes as well as genetic factors such as DAX1 and the signaling molecule WNT-4 are necessary for the development of normal ovaries. Development of the male phenotype is even more complex. It requires a Y chromosome and, specifically, an intact SRY gene, which, in association with other genes such as SOX9, SF1, and WT1 and others (Chapter 576), directs the undifferentiated gonad to become a testis. Aberrant recombinations may result in X chromosomes carrying SRY, resulting in XX males, or Y chromosomes that have lost SRY, resulting in XY females.
In the XX fetus with normal long and short arms of the X chromosome, the bipotential gonad develops into an ovary by about the 10th-11th wk. This occurs only in the absence of SRY, testosterone, and AMH and requires a normal gene in the DSS locus DAX1, and the WNT-4 molecule. A female phenotype develops in the absence of fetal gonads. However, the male phenotype development requires androgen production and action. Estrogen is unnecessary for normal prenatal sexual differentiation, as demonstrated by 46,XX patients with aromatase deficiency and by mice without estradiol receptors.
Chromosomal aberrations may result in ambiguity of the external genitalia. Conditions of aberrant sex differentiation may also occur with the XX or XY genotype. The appropriate term for what was previously called intersex is disorders of sex development (DSD). This term defines a condition “in which development of chromosomal, gonadal or anatomical sex is atypical.” It is becoming more preferable to use the term “atypical genitalia” rather than “ambiguous genitalia.” Comparison with the previous terms and a new etiologic classification are seen in Tables 582-1 and 582-2. Some of the genes involved in disorders of sex development are listed in Table 576-1.
Table 582-1 REVISED NOMENCLATURE
| PREVIOUS | CURRENTLY ACCEPTED |
|---|---|
| Intersex | Disorders of sex development (DSD) |
| Male pseudohermaphrodite | 46,XY DSD |
| Undervirilization of an XY male | 46,XY DSD |
| Undermasculinization of an XY male | 46,XY DSD |
| 46,XY intersex | 46,XY DSD |
| Female pseudohermaphrodite | 46,XX DSD |
| Overvirilization of an XX female | 46,XX DSD |
| Masculinization of an XX female | 46,XX DSD |
| 46,XX intersex | 46,XX DSD |
| True hermaphrodite | Ovotesticular DSD |
| Gonadal intersex | Ovotesticular DSD |
| XX male or XX sex reversal | 46,XX testicular DSD |
| XY sex reversal | 46,XY complete gonadal dysgenesis |
From Lee PA, Houk CP, Ahmed SF, et al: Consensus statement on management of intersex disorders, Pediatrics 118:e488–e500, 2006.
Table 582-2 ETIOLOGIC CLASSIFICATION OF DISORDERS OF SEX DEVELOPMENT (DSD)
46,XX-DSD
Androgen Exposure
Disorder of Ovarian Development
Undetermined Origin
Associated with genitourinary and gastrointestinal tract defects
46,XY DSD
Defects in Testicular Development
Deficiency of Testicular Hormones
Defect in Androgen Action
Ovotesticular DSD
Sex Chromosome DSD
From Lee PA, Houk CP, Ahmed SF, et al: Consensus statement on management of intersex disorders, Pediatrics 118:e488–e500, 2006.
The definition of atypical or ambiguous genitalia, in a broad sense, is any case in which the external genitalia do not appear completely male or completely female. Although there are standards for genital size dimensions, variations in size of these structures do not always constitute ambiguity.
Development of the external genitalia begins with the potential to be either male or female (Fig. 582-1). Virilization of a female, the most common form of DSD, results in varying phenotypes (Fig. 582-2), which start from the basic genital appearances of the embryo (see Fig. 582-1).
Figure 582-1 Schematic demonstration of differentiation of normal male and female genitalia during embryogenesis.
(From Zitelli BJ, Davis HW: Atlas of pediatric physical diagnosis, ed 4, St Louis, 2002, Mosby, p 328.)
Figure 582-2 Examples of atypical genitalia. These cases include ovotesticular disorder of sexual development (A) and congenital virilizing adrenal hyperplasia (B-E). (B-D, Courtesy of D. Becker, MD, Pittsburgh.)
(From Zitelli BJ, Davis HW: Atlas of pediatric physical diagnosis, ed 4, St Louis, 2002, Mosby, p 329.)
Diagnostic Approach to the Patient with Atypical or Ambiguous Genitalia
The appearance of the external genitalia is rarely diagnostic of a particular disorder, and thus does not often allow distinction among the various forms of DSD. The most common forms of 46,XX DSD are virilizing forms of congenital adrenal hyperplasia (CAH). It is important to note that in 46,XY DSD, the specific diagnosis is not found in up to 50% of cases. At 1 center with a large experience, the etiologies of DSD in 250 patients over 25 yr were compiled. The 6 most common diagnoses accounted for 50% of the cases. These included virilizing CAH (14%), androgen insensitivity syndrome (10%), mixed gonadal dysgenesis (8%), clitoral/labial anomalies (7%), hypogonadotropic hypogonadism (6%), and 46,XY small-for-gestational age males with hypospadias (6%).
This potential source of error in diagnosis and management emphasizes the need for careful diagnostic evaluation including biochemical characterization of possible steroidogenic enzymatic defects in each patient with genital ambiguity. The parents need counseling about the complex nature of the baby’s condition, and guidance as to how to deal with their well-meaning but curious friends and family members. The evaluation and management should be carried out by a multidisciplinary team of experts that include pediatric endocrinology, pediatric surgery/urology, pediatric radiology, newborn medicine, genetics, and psychology. Once the sex of rearing has been agreed on by the family and team, treatment can be organized. Genetic counseling should be offered when the specific diagnosis is established.
After a complete history and physical exam, the common diagnostic approach includes multiple steps, described in the following outline. These steps are usually performed simultaneously rather than waiting for results of 1 test prior to performing another, due to the sensitive and sometimes urgent nature of the condition. Careful attention to the presence of physical features other than the genitalia is crucial, to determine if a diagnosis of a particular multisystem syndrome is possible. These are described in more detail in Chapters 582.1, 582.2, and 582.3. A summary of many features of commonly encountered causes of DSD is provided in Table 582-3.
Diagnostic tests include the following:
582.1 46,XX DSD
In this condition, the genotype is XX and the gonads are ovaries, but the external genitalia are virilized. Because there is no significant AMH production—the gonads are ovaries—the uterus, fallopian tubes, and cervix develop. The varieties and causes of this condition are relatively few. Most instances result from exposure of the female fetus to excessive exogenous or endogenous androgens during intrauterine life. The changes consist principally of virilization of the external genitalia (clitoral hypertrophy and labioscrotal fusion).
Congenital Adrenal Hyperplasia (Chapter 570.1)
This is the most common cause of genital ambiguity and of 46,XX DSD. Females with the 21-hydroxylase and 11-hydroxylase defects are the most highly virilized, although minimal virilization also occurs with the type II 3β-hydroxysteroid dehydrogenase defect (see Fig. 582-1). Salt losers tend to have greater degrees of virilization than do non–salt-losing patients. Masculinization may be so intense that a complete penile urethra results, and the condition may mimic a male with bilateral cryptorchidism.
Aromatase Deficiency
In genotypic females, the rare condition of aromatase deficiency during fetal life leads to 46,XX DSD and results in hypergonadotropic hypogonadism at puberty because of ovarian failure to synthesize estrogen (see Fig. 568-1).
Glucocorticoid Receptor Gene Mutation
A 9 yr old girl with 46,XX disorder of sexual development, thought to be due to 21-hydroxylase deficiency (congenital adrenal hyperplasia) since the age of 5 yr, had elevated cortisol levels both at baseline and after dexamethasone, hypertension, and hypokalemia, suggestive of the diagnosis of generalized glucocorticoid resistance. A novel homozygous mutation in exon 5 of the glucocorticoid receptor was demonstrated. In this Brazilian family, the condition was autosomal recessive.
POR, cytochrome P450 oxidoreductase, encoded by a gene on 7q11.2, is a cofactor implicated in combined P450C17 and P450C21 steroidogenic defects. Girls are born with ambiguous genitalia, but the virilization does not progress postnatally and androgen levels are normal or low. Boys may be born undervirilized. Both may exhibit bony abnormalities seen in Antley-Bixler syndrome (ABS). Conversely, in a series of ABS patients, those with ambiguous genitalia and disordered steroidogenesis had POR deficiency. Those without genital ambiguity with normal steroidogenesis had fibroblast growth factor receptor 2 (FGFR2) mutations. The cardinal features of ABS include craniosynostosis, severe midface hypoplasia, proptosis, choanal atresia/stenosis, frontal bossing, dysplastic ears, depressed nasal bridge, radiohumeral synostosis, long bone fractures and femoral bowing, and urogenital abnormalities.
Virilizing Maternal Tumors
Rarely, the female fetus has been virilized during fetal life by a maternal androgen-producing tumor. In a few cases, the lesion was a benign adrenal adenoma, but all others were ovarian tumors, particularly androblastomas, luteomas, and Krukenberg tumors. Maternal virilization may be manifested by enlargement of the clitoris, acne, deepening of the voice, decreased lactation, hirsutism, and elevated levels of androgens. In the infant, there is enlargement of the clitoris of varying degrees, often with labial fusion. Mothers of children with unexplained 46,XX DSD should undergo physical examination and measurements of their own levels of plasma testosterone, dehydroepiandrosterone sulfate, and androstenedione.
Administration of Androgenic Drugs to Women during Pregnancy
Testosterone and 17-methyltestosterone have been reported to cause 46,XX DSD in some instances. The greatest number of cases has resulted from the use of certain progestational compounds for the treatment of threatened abortion. These progestins have been replaced by nonvirilizing ones.
Infants with virilization and 46,XX chromosomes and caudal anomalies have been reported for whom no virilizing agent could be identified. In such instances, the disorder is usually associated with other congenital defects, particularly of the urinary and gastrointestinal tracts. Y-specific DNA sequences, including SRY, are absent. In 1 case, a scrotal raphe and elevated testosterone levels were found, but the cause remains unknown.
Bose HS, Pescovitz OH, Miller WL. Spontaneous feminization in a 46,XX female patient with congenital lipoid adrenal hyperplasia due to a homozygous frameshift mutation in the steroidogenic acute regulatory protein. J Clin Endocrinol Metab. 1997;82:1511-1515.
Diamond M, Sigmundson K. Sex reassignment at birth. Arch Pediatr Adolesc Med. 1997;151:298-304.
Diamond DA, Mitchell C, Lamb K, et al. Sex assignment for newborns with ambiguous genitalia and exposure to fetal testosterone: attitudes and practices of pediatric urologists. J Pediatr. 2006;148:445-449.
Frade Costa EM, Bilharinho Mendonca B, Inacio M, et al. Management of ambiguous genitalia in pseudohermaphrodites: new perspectives on vaginal dilation. Fertil Steril. 1997;67:229-232.
Mendonca BB, Leite MV, DeCastro M, et al. Female pseudohermaphroditism caused by a novel homozygous mutation of the GR gene. J Clin Endocrinol Metab. 2002;87:1805-1809.
Moisan AM, Ricketts ML, Tardy V, et al. New insight into the molecular basis of 3β-hydroxysteroid dehydrogenase deficiency: identification of eight mutations in the HSD3 gene in eleven patients from seven new families and comparison of the functional properties of twenty-five mutant enzymes. J Clin Endocrinol Metab. 1999;84:4410-4425.
Morishima A, Grumbach MM, Simpson ER, et al. Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens. J Clin Endocrinol Metab. 1995;80:3689-3698.
Mullis PE, Yoshimura N, Kuhlmann B, et al. Aromatase deficiency in a female who is compound heterozygote for two new point mutations in the P450arom gene: impact of estrogens on hypergonadotropic hypogonadism, multicystic ovaries, and bone densitometry in childhood. J Clin Endocrinol Metab. 1997;82:1739-1745.
Parisi MA, Ramsdell LA, Burns MW, et al. A gender assessment team: experience with 250 patients over a period of 25 years. Genet Med. 2007;9:348-357.
Saenger P. New developments in congenital lipoid adrenal hyperplasia and steroidogenic acute regulatory protein. Pediatr Clin North Am. 1997;44:397-421.
Wallien MS, Cohen-Kettenis PT. Psychosexual outcome of gender-dysphoric children. J Am Acad Child Adolesc Psychiatry. 2008;47:1413-1423.
582.2 46,XY DSD
In this condition, the genotype is XY, but the external genitalia are either not completely virilized, ambiguous (atypical), or completely female. When gonads can be found, they invariably contain testicular elements; their development ranges from rudimentary to normal. Because the process of normal virilization in the fetus is so complex, it is not surprising that there are many varieties and causes of 46,XY DSD.
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