PMON270 Coexistence of 46, XX Testicular Disorder of Sex Development and 11β-Hydroxylase Deficiency: In Vivo and In Vitro Studies

BACKGROUND: 46, XX testicular disorder of sex development and 11β-hydroxylase deficiency (11β-OHD) are two extremely rare types of disorder of sex development (DSD). No coexistence has been reported yet. CLINICAL CASE: A 22-year-old male showed small testes (volume=4ml) and gynecomastia for 2 years. At the age of 3.5, he was diagnosed as simple virilizing type of 21-hydroxylase deficiency (21-OHD) for the manifestations of the enlarged penis (length=7.5cm), hyperpigmentation, and normal blood pressure. Adrenal ultrasound suggested bilateral adrenal hyperplasia (both length * width = 2.4*0.9cm) and X-ray showed accelerated bone age (12.5 years old). Irregular cortisone acetate 6.25mg per day was administrated since then. At the age of 18, he was sent to emergency for aortic aneurysm rupture and heart failure, and hypertension urgency was diagnosed. Sanger sequencing revealed that he carried compound heterozygous variants in CYP11B1 gene: NM_000497.3: c.905_907delinsTT and NM_000497.3: c.954+7C>T, which were respectively inherited from his father and mother. Pathogenesis of the novel intron variant (c.954+7C>T) was further verified in COS7, CHO, and 273T cell lines by transfecting wild-type and mutant-type minigene, extracting RNA of cells, reversing RNA into cDNA, PCR, and Sanger sequencing. The result showed that the c.954+7C>T variant introduced a cryptic donor splice site at a site 5 bp downstream of the 3' natural splice donor site of exon 5. The level of adrenal steroids detected by liquid chromatography-tandem mass spectrometry (LC-MS/MS) was consistent with the characteristics of 11β-OHD. The patient was treated by neoplasty of thoracic aortic aneurysm and added anti-hypertension drugs in addition to glucocorticoid after surgery. Unexpectedly, the abnormalities of male characteristics including small testes and gynecomastia appeared since adolescence. Laboratory tests showed an elevated level of FSH and LH and azoospermia. Scrotum Ultrasound showed bilateral testicular dysplasia (right: 1.9*1.4*0.8cm, left: 1.9*1.3*0.8cm). To figure out the unexplainable results, whole-exome sequencing was performed and revealed two copy number variants: the duplication of Xp22.33-q28 which spans 151.32Mb, and the deletion of Yp11.2-q11.23 which spans 23.34Mb. Meanwhile, the karyotype test by culturing blood lymphocytes showed 46, XX (100/100), which confirmed the diagnosis of 46, XX testicular DSD. Fluorescence in situ hybridization (FISH) revealed the presence of the SRY gene, which is translocated into the short arm of the X chromosome. Testosterone replacement is unnecessary for the normal level of testosterone (T) (4.44ng/ml, N: 1.75-7.81ng/ml), which is the result of the combined action of 11β-OHD with adrenal T accumulation and 46, XX testicular DSD with testicular T deficiency. Assisted reproduction consulting should start early. CONCLUSION: This is the first case demonstrating the possibility of coexistence of 46, XX testicular DSD and 11β-OHD and hinting at the significance of a combination of clinical and molecular diagnostic methods. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.