Diagnostic odyssey of a male with 45,X/46,XY mosaicism: case report and review of the literature.

Objective: To conduct longitudinal precision clinical phenotyping and management planning of 45,X/46,XY mosaicism case, including in-depth documentation of notable deviations at the male accessory glands level, monitoring and timely handling of potential comorbidities. Design: Case report. Subject: A 29-year-old phenotypically male patient of European origin presenting for andrological evaluation due to sudden enlargement of the right hemiscrotum. Results: We report a 29-year-old phenotypically male patient with 45,X/46,XY mosaicism and syndromic features, short stature (152 cm), inguinal hernia, azoospermia, moderate testicular hypotrophy (10 mL and 8 mL by orchidometer), distal hypospadias, and autoimmune thyroiditis. The patient presented normal intelligence quotient and cognition. As a novel clinical finding, notable deviations at the male accessory glands' level were documented in follow-up investigations, reduced prostate volume, unilateral hypoplasia of the seminal vesicle, absence of a distal deferential duct and a dilatation of the contralateral counterpart, dilatation of the ejaculatory duct and an extensive prostatic microcalcification. Intriguingly, an initial cytogenetic analysis from the peripheral blood leucocytes showed a normal male karyotype. Incidentally, 45,X/46,XY mosaicism was uncovered using whole exome sequencing (WES) of peripheral blood deoxyribonucleic acid for molecular diagnostic purposes. This genetic diagnosis was confirmed subsequently by interphase fluorescence in situ hybridization (buccal smear), chromosomal microarray analysis, and repeated cytogenetic testing of peripheral blood cells, emphasizing the sensitivity and precision of WES in detecting chromosomal mosaicism. The estimated proportion of 45,X cells ranged from 55% in buccal smear to 60%-67% in peripheral blood. Conclusion: Wolffian anomalies may be present in 45,X/46,XY phenotypic male mosaics and warrant systematic evaluation, particularly in the context of infertility management. This case also demonstrates that using WES instead of conventional karyotyping may enhance the speed in reaching 45,X/46,XY diagnosis, and consequently, longitudinal management of the broad spectrum of comorbidities in this condition.