Endocrine Abstracts

Background: 46, XX testicular disorder of sex development (DSD) and 11β-hydroxylase deficiency (11β-OHD) are two extremely rare types of disorder of sex development. No coexistence has been reported yet.

Case Description: Here we reported the first patient diagnosed as the coexistence of 11β-OHD and 46, XX testicular DSD basing on clinical, biochemical, molecular, cytogenetic, and functional experiment findings. A 22-year-old male showed small testes and gynecomastia for 2 years. At the age of 3, he was diagnosed as congenital adrenal hyperplasia (CAH). Adrenal ultrasound suggested the bilateral adrenal hyperplasia (both length*width=2.4*0.9 cm) and X ray showed accelerated bone age (12.5 years old). Irregular cortisone acetate 6.25 mg per day was administrated since then. At the age of 18, he was sent to emergency for aortic aneurysm rupture and heart failure, and diagnosed as 11β-OHD. Sanger sequencing revealed that he carried compound heterozygous variants in CYP11B1 gene: NM_000497.4: c.905_907delinsTT and NM_000497.4: c.954+7C>T, which were respectively inherited from his father and mother. According to American College of Medical Genetics and Genomics (ACMG) guideline, c.905_907delinsTT was identified as pathogenic variant, and c.954+7C>T, the novel one, was defined as variant of unknown significance. Pathogenicity of c.954+7C>T were further verified in COS7, CHO, and 273T cell lines by minigene methods, which turned out to cause the gain of a cryptic one at the 5bp downstream of the original one. The patient was treated by neoplasty of thoracic aortic aneurysm and added anti-hypertension drugs in addition to glucocorticoid after surgery. Unexpectedly, small testes and gynecomastia came into notice recently. Laboratory tests revealed hypergonadotropic hypogonadism and azoospermia. Scrotum ultrasound showed bilateral testicular dysplasia. To figure out these unexplainable results, whole exome sequencing was performed and revealed two copy number variants: duplication of Xp22.33-q28 spanning 151.32 Mb and deletion of Yp11.2-q11.23 spanning 23.34 Mb. Karyotype test by culturing blood lymphocytes showed 46, XX (100/100). Another disease, 46, XX testicular DSD, was diagnosed. Fluorescence in situ hybridization (FISH) revealed the presence of SRYgene translocating into the short arm of X chromosome. Under the coaction of two diseases, testosterone level was in male normal range, and replacement was unnecessary. Assisted reproduction was advised to start early.

Conclusion: To our knowledge, this is the first report of the coexistence of 46, XX testicular DSD and 11β-OHD in the same individual. The case illustrates the complexity that might be encountered in the diagnosis of DSD when different genetic defects affecting sex development exist.