A 16-Year-Old With Amenorrhea and Delayed Breast Development

Varshini Chakravarthy, MD; Sehar Ejaz, MD


January 14, 2020

The differential diagnoses based on an XY karyotype in a phenotypic female, such as in our patient, include complete androgen insensitivity, 5-alpha reductase deficiency, and Swyer syndrome.

Individuals with complete androgen insensitivity present with external female genitalia but lack Müllerian structures, such as the uterus and fallopian tubes. These patients are genetically male and usually have undescended abdominal testes.[4] They can also present with elevated levels of testosterone and anti-Müllerian hormone. Patients with 5-alpha reductase deficiency most often present with ambiguous genitalia at birth. If the degree of ambiguity is mild, it can often go unnoticed. These individuals often present with excessive virilization during puberty owing to an increase in androgen production.[5]

Pelvic ultrasonography performed on this patient showed the presence of a small uterus and ovaries, with low levels of anti-Müllerian hormone and normal levels of testosterone, ruling out complete androgen insensitivity. She also did not have signs of virilization (eg, deepening of her voice, excessive hair) on her physical examination, which would have been suggestive of 5-alpha reductase deficiency. Considering these radiologic and physical examination findings and laboratory markers suggestive of premature ovarian insufficiency in the setting of 46,XY karyotype with a MAP3K1 gene mutation on genetic analysis, the diagnosis of Swyer syndrome was established.

Swyer syndrome is a disorder of pure gonadal dysgenesis. It has an incidence of 1 in 80,000 individuals, making it one of the rarer disorders of sex development.[6] Patients with Swyer syndrome typically present with primary amenorrhea. They are phenotypically female, with an underdeveloped uterus, decreased breast development due to lack of estrogen, and nonfunctional ovaries, with a chromosomal makeup of 46,XY. Sex-determining region Y gene mutation accounts for 10%-15% of cases, whereas MAP3K1 gene mutation, such as in the case presented here, is noted in 18% of patients.[7,8] Other gene mutations implicated in this syndrome include DHH and NR5A1.

The sex-determining region Y gene, found on the Y chromosome, is responsible for making the sex-determining region Y protein. This protein ultimately plays a significant role in the process of differentiating the undifferentiated gonads into the male testes during the developmental period. MAP3K1, DHH, and NR5A1 genes produce proteins that work in a similar manner to promote the development of testes.[8] Defects in any of these genes result in a default differentiation of gonads into uterus and ovaries.


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