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Case 1: Ms. Kolthoff is a 27-year-old G0 P0, who was evaluated for accelerated growth and advanced bone age in high school. She is currently married without children. She does not use birth control and despite sexual intercourse approximately a few times a week for the past 2 years, she has not conceived. She complains of having to shave her upper lip as well as hair on her back and abdomen. Her menstrual cycles are irregular and she sometimes will not have one for several months. She has experienced acne for which she took over-the-counter lotions for treatment with partial success, and was also given a short course of antibiotics by her physician. She has been told she has polycystic ovarian syndrome, and presents with concerns about her fertility. Her family history is unremarkable. She has three sisters who do not have hirsutism, and all three have children. The physical exam was significant for short stature, shaved upper lip, acne-related facial scarring, and significant abdominal and back hirsutism. Her external genitalia appeared normal and the pelvic exam was unremarkable. A basal 17-hydroxyprogesterone measure was 1850 ng/dL, while an ACTH stimulation test showed a 17-hydroxyprogesterone rise to 5300 ng/dL. What additional tests and evaluation would you consider for Ms. Kolthoff?

Gynecologic disorders can be heritable, such as polycystic ovarian syndrome, or can be due to sporadic somatic mutations that arise in individual organs, such as uterine leiomyomas. To date gene mutations have been associated with common gynecologic disorders, such as leiomyomas, polycystic ovarian syndrome, endometriosis, and menstrual dysfunction. We also know that specific genomic regions regulate important reproductive landmarks, such as menarche and menopause. In the future, genomic medicine will play a significant role in understanding the causation of gynecologic disorders and guiding individual therapies.


Leiomyomas, or fibroids, are common tumors arising from the myometrial layer of the uterus. They are clinically diagnosed in 25% of women, and are often associated with dysmenorrhea, menorrhagia, infertility, and abdominal discomfort. Subclinical leiomyomas are extremely common, and by age 50 more than 80% of black and 70% of white women have leiomyomas. Family history, black race, age, nulliparity, and obesity are known risk factors for the development of clinically significant leiomyomas. Family aggregation and twin studies show that genes contribute significantly to the genesis of leiomyomas.1 Common leiomyomas are monoclonal in origin, and 40% have associated chromosome abnormalities. Cytogenetic aberrations commonly include deletions in 7q, trisomy of chromosome 12, and various translocations between chromosomes 12 and 14 involving the high-mobility group AT-hook 2 (HMGA2) gene at 12q15, which encodes a transcriptional regulator. Cytogenetic abnormalities are likely a reflection of general genomic instability, as is true for other tumors. Individuals may have leiomyomas either due to germline mutations (rare) or due to somatic mutations that arise only in the uterus (common).

Heterozygous (present on one allele) germline mutations ...

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