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SCOPE

DISEASE/CONDITION(S)

The neonate with atypical genitalia at birth.

GUIDELINE OBJECTIVE(S)

Define the terminology and language used to describe neonates with atypical genitalia, the causes and mechanisms of this condition, and the management of infants with atypical genitalia.

BRIEF BACKGROUND

The preferred term for neonates with atypical genitalia is “disorders of sex development” (DSD), defined as any congenital condition in which the development of chromosomal, gonadal, and/or anatomic sex is atypical. Terms such as “intersex,” “sex reversal,” “hermaphroditism,” and “pseudo-hermaphroditism” should be avoided.

NORMAL SEXUAL DEVELOPMENT

Major Genes Involved in Sexual Development

Multiple genes are involved in normal gonadal development, the most important being the SRY gene. Others include the SOX9 gene, the steroidogenic factor 1 gene (SF1 or NR5A1), the desert hedgehog gene (DHH), the DAX1 (NR0B1) gene, the Wilms tumor gene, the WT-1, WnT-4, and Wnt-7a genes, the fibroblast factor receptor 2 gene, and the ATRX gene. Defects of any of these can lead to DSD.

Early Fetal Life

In early fetal development, both 46,XX and 46,XY fetuses have similar reproductive tissue. The Wolffian (mesonephric) and Müllerian (paramesonephric) ducts start developing in both sexes. The bipotential internal genital structures can further differentiate into male or female depending on gene expression. Around the fourth or fifth week of gestation, germ cells migrate from the yolk sac, and paired gonadal ridges develop from the urogenital ridge. The germs cells intermingle with pre-Sertoli and pre-granulosa cells. A summary of the process of sex development is depicted in Figure 50.1.

FIGURE 50.1

The process of sex development. In the early fetal stage, both 46,XX and 46,XY fetuses have similar reproductive tissue with Wolffian (mesonephric) and Müllerian (paramesonephric) ducts. These bipotential internal genital structures further differentiate or regress into male or female depending on the gene expression and hormonal milieu.

Normal Female Development

In XX fetuses, in the absence of SRY expression, the bipotential gonad develops into an ovary. In the absence of anti-Müllerian hormone (AMH), the Wolffian ducts regress and the Müllerian structures develop into the upper vagina, uterus, and fallopian tubes. In the absence of testosterone, dihydrotestosterone (DHT), or normal androgen receptors, the genital tubercle becomes a clitoris, the urogenital folds become the labia minora, and the labioscrotal swelling develops to the labia majora. The separation of the vagina and the urethra is complete by 12 weeks of gestation.

Normal Male Development

In XY fetuses, around the 6th week of gestation, the pre-Sertoli cells and germ cells develop into primitive sex cords ...

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