Abnormalities of Sex Differentiation
Jason M. Wilson
Typical sex differentiation is an intricately choreographed processes involving chromosomally directed gene expression, protein and hormone production, gonadal development, and development of reproductive anatomy. An abnormality of sex differentiation is manifested when there is a misstep in the process, which may occur at any point in development, resulting in atypia of chromosomes, genes, gonads, hormones, and/or anatomy. As critical members of a multidisciplinary team, we may be called upon to evaluate the newborn with genital atypia or, more rarely, when phenotype is not consistent with antenatal karyotype. Abnormalities of sex differentiation may also be diagnosed with newborn screening or during a workup for illness or for either early or delayed secondary sex characteristics.
I. TYPICAL SEX DIFFERENTIATION
Sex determination has long been attributed to X and Y “sex chromosomes,” but observations in patients with Turner syndrome led to the hypothesis that the genetic material responsible for testis development was located on the Y chromosome. Further investigations suggested that the specific region was located on the short arm of the Y chromosome, and in the 1990s, the sex-determining region (SRY) of the Y chromosome was mapped. Female sex determination is dependent on two functional X chromosomes and is a much more complex process than previously believed. Sex differentiation is the process wherein bipotential embryonic tissue becomes sex-dichotomous: gonadal tissue, internal genitalia, and external genitalia. The presence of either 46,XX or 46,XY karyotype determines sex-specific development in bipotential cells.
II. EMBRYONIC DEVELOPMENT
By the third week of embryonic development, gonadal development proceeds from the indeterminate mesoderm (gonadal ridge) and then continues medial to the mesonephros (mesonephric ridge). The gonadal ridge is further differentiated into a nourishing and sustaining environment for gonadal development by the arrival of primordial germ cells (PGCs) by the fifth week of embryonic development. Under the direction of gene expression and transcription factors, the arriving PGCs differentiate into four types of bipotential cells that compose the bipotential gonad: germ cells, steroidogenic cells, supportive cells, and connective tissue. By the fifth to sixth week of bipotential development, the gonadal ridge, mesonephric duct (wolffian), and paramesonephric duct (müllerian) have developed. The coelomic epithelium has invaginated craniocaudally to form the müllerian duct. The invagination actually extends down to the uterovaginal sinus, where the two ducts meet and fuse to form the uterovaginal duct in both sexes. Figure 4-1 represents sex-specific differentiation from bipotential gonadal and ductal tissue.
 FIG. 4-1 Embryologic development of both the male and female reproductive tracts from a common origin. |
III. 46,XY GONADAL AND DUCTAL DEVELOPMENT
The earliest discernible change in the development of the testes is formation of the testicular cords at six to seven weeks of development. This early differentiation is responsible for the development of the seminiferous tubules and Sertoli cells. Other cells among the testicular cords differentiate into Leydig cells between eight and nine weeks of development. Still other PGCs differentiate into male sex-specific germ cells (spermatogonia). By eleven weeks of development, recognizable testes are present with Sertoli, Leydig, and male sex-specific germ cells.
A. Endocrine Function
1. Endocrine function of the fetal testes is responsible for sex-specific ductal development and regression. Between seven and eight weeks of
development, the Sertoli cells secrete müllerian-inhibiting substance (MIS), a paracrine hormone that acts to stimulate regression of the ipsilateral müllerian (paramesonephric) ducts. In typical male sex-specific differentiation, the remnants of the müllerian ducts can be seen as the appendix testis and the prostatic utricle.
development, the Sertoli cells secrete müllerian-inhibiting substance (MIS), a paracrine hormone that acts to stimulate regression of the ipsilateral müllerian (paramesonephric) ducts. In typical male sex-specific differentiation, the remnants of the müllerian ducts can be seen as the appendix testis and the prostatic utricle.
B. Testosterone Production
1. Testosterone production from Leydig cells is detectable as early as nine weeks of development and peaks in the local environment by 13 weeks. During this period, it is produced autonomously, independent of placental human chorionic gonadotropin (hCG) and luteinizing hormone (LH) and is responsible for further development of the wolffian (mesonephric) ductal system into the internal male reproductive tract: epididymis, vas deferens, seminal vesicle, and ejaculatory duct. The conversion of testosterone to dihydrotestosterone by 5α-reductase is necessary for further male sex-specific anatomy, including the prostate, urethra, and external genitalia. The rate-limiting enzyme for production of testosterone within the fetal testes is 3β-hydroxysteroid dehydrogenase (3B-HSD).
IV. 46,XX GONADAL AND DUCTAL DEVELOPMENT
A. Ovarian Development
1. Ovarian development is thought to begin later than testis development at approximately eight weeks of embryonic development. Primordial germ cells arrive at the gonadal ridge by the fifth week of development with primitive sex chords that develop into the testicular cords in the presence of SRY expression. Likewise in the presence of SRY, the medullary cords differentiate into Sertoli cells and invest PGCs. In the absence of SRY, cortical cords develop and invest PGCs. In the absence of SRY, there is development of the cortical cells that invest PGCs (follicle cells), forming ovarian follicles. Differentiation of the bipotential cells in the gonadal ridge into the fetal ovary is complete by as early as fourteen weeks of development. Estrogen is detectable by eight to nine weeks of development. The rate-limiting enzyme for estrogen production in the fetal ovary is aromatase. The absence of MIS and testosterone in the presence of active female gene expression leads to the dissolution of the mesonephric (wolffian) ducts and elongation of the paramesonephric (müllerian) ducts by about the ninth week of development. The müllerian ducts give rise to the fallopian tubes, the uterus, and the upper two-thirds of the vagina. Embryologic remnants of the wolffian ducts can be found in the mesentery of the ovary as the epoophoron and the paroophoron and at the anterolateral vaginal wall as Gartner duct cysts (Table 4-1).
V. DISORDERS OF SEX DEVELOPMENT (DSDS)
A. Proposed Nomenclature
Nomenclature from the 2006 consensus statement provides a flexible framework within which different abnormalities of sex differentiation can be categorized. Instead of the term “disorder,” which is not preferred by some groups, more general or specific terms can be considered. For example, “abnormality or variation of reproductive development” may be used instead of “disorders of sex development” or “congenital adrenal hyperplasia” (CAH) in place of “46,XX DSDs.”
TABLE 4-1 Timeline for Typical Male and Female Sex Differentiation | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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B. Evaluation
Evaluation of the child with a suspected abnormality of sex differentiation should be undertaken by a multidisciplinary team consisting of endocrinologists, genetics/dysmorphology specialists, urologists psychiatric specialists, and social workers. It is useful to have a point person to communicate regularly with the family and possibly to have care conferences with family and providers throughout the process of evaluation, diagnosis, and recommendations. Figure 4-2 illustrates the ways in which a suspected DSD is encountered.
VI. HISTORY
A thorough history should be obtained, including maternal medical history, family history, and whether any similar conditions have been seen in
other family members. In addition, any medications taken during the gestational period or any signs of maternal virilization should be specified. Specific aspects of family history that should be recorded include infant death, amenorrhea, hirsutism, infertility, and known occurrences of specific disorders.
other family members. In addition, any medications taken during the gestational period or any signs of maternal virilization should be specified. Specific aspects of family history that should be recorded include infant death, amenorrhea, hirsutism, infertility, and known occurrences of specific disorders.
 FIG. 4-2 Different presentations of DSDs. |
A. Physical Examination
A physical examination should include inspection for general appearance and any signs of external abnormalities of development such as hemihyperplasia or other morphologic features known to be associated with specific diagnoses. The abdominal and perineal examination should include palpation for abdominal or pelvic masses and careful assessment of external genitalia, including phallic size (stretch length), and whether or not there are one or two palpable gonads in the inguinal area, scrotum, labia, or perineum. An abnormal penile stretch length for a full-term male infant is less than 2.5 cm (Table 4-2). It is important to remember that gestational age at birth affects phallic size. The palpation of a gonad during the physical examination effectively rules out any disorder of androgen excess under the broad category of 46,XX DSDs.
B. Laboratory Evaluation
Metabolic derangements that may be present in CAH may cause hyponatremia, hyperkalemia, and metabolic acidosis, all of which can be assessed with a basic metabolic profile. Signs and symptoms of CAH in the newborn may not be present until the second week of life. Serum measurement of 17-hydroxyprogesterone (17-OHP) after the first 48 hours of life can confirm the diagnosis of 21α-hydroxylase deficiency. Specific serum immunoassays can be ordered if another enzymatic
defect is suspected in the patient with adrenal hyperplasia. Serum immunoassays are widely available and easy to attain. The workup of any patient suspected to have an abnormality of sex differentiation should include serum levels of testosterone, estradiol, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and MIS. An hCG stimulation test may be useful if used for a specific purpose. Undetectable levels of MIS suggest the absence of testicular tissue.
defect is suspected in the patient with adrenal hyperplasia. Serum immunoassays are widely available and easy to attain. The workup of any patient suspected to have an abnormality of sex differentiation should include serum levels of testosterone, estradiol, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and MIS. An hCG stimulation test may be useful if used for a specific purpose. Undetectable levels of MIS suggest the absence of testicular tissue.
TABLE 4-2 Stretched Penile Length | ||||||||||||||||
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C. Genetic Testing
A karyotype from a peripheral blood sample should be obtained in any patient with a suspected abnormality of sex differentiation. Fluorescent in situ hybridization to assess for the presence of the Y chromosome or SRY can be completed within 48 hours. If chromosomal occult mosaicism is suspected, it may be necessary to send biopsies from gonadal tissue for cytogenetic evaluation. Advances in clinical genetic testing have made tests such as chromosomal microarray (CMA) widely available. CMA determines sex chromosome complement, evaluates for the presence of SRY, and screens for known duplication or deletion anomalies associated with DSDs; it is especially useful when a syndromic diagnosis is suspected.
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