Associate professor University of Texas Southwestern Medical School Endocrine Fellowship Program Dallas, Texas, United States
Disclosure(s):
David M. Lee, MD: Ionis: Grant Recipient ()
Background: Developmental sexual disorders (DSDs) are defined as congenital conditions in which there is discordance between chromosomal, gonadal, or anatomic sex. The incidence varies from 1:4500 to 1:5000. We present two cases of 46 XX male and 46 XY female that highlight the intricacies of DSDs.
Case 1 A 52-year-old patient male evaluated for the symptoms of fatigue, erectile dysfunction, and gynecomastia. Exam showed sparse facial and axillary hair, smaller testes and bilateral gynecomastia. Diagnostic evaluation showed low testosterone values with high LH and FSH confirming the diagnosis of primary hypogonadism. Karyotype showed mosaicism: 45XO (2 cells), 45XX (93%), with the presence of an SRY gene on the X chromosome in 96.5% of cells. Semen analysis also showed azoospermia. He and his wife were able to have a son with in vitro fertilization with sperm donor. He has been on testosterone replacement.
Case 2 A 25-year-old female presented for management of known Swyer syndrome. Her Swyer syndrome was diagnosed at birth after prenatal Karyotype showed 46, XY, leading her parents to expect a male baby but was born with female anatomy. Repeat Karyotype revealed 46, XY, inv(9)(p11q13). Work up showed primary hypogonadism and presence of a uterus with streak/absent ovaries. She subsequently underwent a gonadectomy. She was noted to have a masculine body type with a height of 6’2’’, breast development at Tanner stage IIIB and genitalia hair at Tanner stage IV. The repeat genetic testing was completed that confirmed 46,XY inv(9)(p11q13) karyotype with presence of normal SRY gene. Multi-gene difference of sex development panel was positive for a heterozygous, pathogenic variant, c.566T>C (p.Leu189Pro), in MAP3K1, which is associated with 46, XY gonadal dysgenesis. The patient has been on estrogen and progesterone replacement therapy.
Clinical Lessons/
Conclusion: Our two cases illustrate that DSDs can easily be missed until adulthood and the presentation can vary depending upon genetic etiologies. Case 1 involves the presence of an SRY gene on an X chromosome which led to a male phenotype in a XO/XX individual. Case 2 is a female with Swyer syndrome that was found to have a normal SRY gene but a pathogenic variant in MAP3K1, which is associated with gonadal dysgenesis. Both cases emphasize the importance of geneticists’ involvement and in-depth genetic analysis including chromosomal analysis and fluorescence in situ hybridization (FISH) in evaluation of patients with DSDs.
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