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Normal and abnormal sexual differentiation 

Normal and abnormal sexual differentiation
Normal and abnormal sexual differentiation

I.A. Hughes

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date: 21 November 2018

Human sex development follows an orderly sequence of embryological events coordinated by a cascade of gene expression and hormone production in a time- and concentration-dependent manner. Underpinning the entire process of fetal sex development is the simple mantra: sex chromosomes (XX or XY) dictate the gonadotype (ovary or testis), which then dictates the somatotype (female or male phenotype).

The constitutive sex in fetal development is female. Male development to form a testis from the indifferent gonad (sex determination) and the internal and external phenotype (sex differentiation) is due to (1) testis-determining genes, in particular SRY (sex chromosome related gene on the Y chromosome), which is first expressed in the XY gonad at 6 to 7 weeks of gestation; and (2) production by the testis of (a) antimullerian hormone—to repress mullerian ducts forming the uterus and fallopian tubes, (b) androgens (testosterone and dihydrotestosterone)—to stabilize the Wolffian ducts; and (c) insulin-like factor 3 (INSL3)—required for the migration of the testis from the urogenital ridge to its site at birth within the scrotum. An understanding of these basic principles is essential to formulate a logical approach to the diagnosis of disorders of sex development.

Disorders of sex development (DSD)—these can be classified into three broad categories based on the knowledge of the karyotype: (1) sex chromosome abnormality—e.g. XO/XY, mixed gonadal dysgenesis; (2) XX DSD—e.g. congenital adrenal hyperplasia (see Chapter 13.7.2); (3) XY DSD—e.g. partial androgen insensitivity syndrome.

Clinical features—the commonest presentations of DSD are (1) ambiguous genitalia of the newborn; and (2) development of secondary sexual characteristics at puberty discordant with the sex of rearing—generally signs of virilization occurring in a child hitherto assumed to be female.

Investigation and management—an extensive repertoire is available, but the choice of genetic, endocrine, and imaging tests should be based on the DSD classification (determined by sex chromosome analysis by fluorescent in situ hybridization (FISH) using X centromeric and SRY probes, followed by full karyotyping) and aimed at reaching a consensus about the choice of sex assignment. Any surgical procedure required to alter the external phenotype consonant with sex assignment need not be undertaken urgently. It is essential that families of children with DSD have the benefit of support and counselling by a multidisciplinary team that comprises at a minimum an endocrinologist, urologist/gynaecologist, geneticist, and psychologist.

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