Molecular cytogenetic analysis and genetic counseling: a case report of eight 46,XX males and a literature review

Abstract Background 46,XX male syndrome is a rare disorder that usually causes infertility. This study was established to identify the genetic causes of this condition in a series of 46,XX males through the combined application of cytogenetic and molecular genetic techniques. Case presentation We identified eight azoospermic 46,XX males who underwent infertility-related consultations at our center. They all presented normal male phenotypes. In seven of the eight 46,XX males (87.5%), translocation of the SRY gene to the terminal short arm of the X chromosome was clearly involved in their condition, which illustrated that this translocation is the main mechanism of 46,XX sex reversal, in line with previous reports. However, one patient presented a homozygous DAX1 mutation (c.498G > A, p.R166R), which was not previously reported in SRY-negative XX males. Conclusions We proposed that this synonymous DAX1 mutation in case 8 might not be associated with the activation of the male sex-determining pathway, and the male phenotype in this case might be regulated by some unidentified genetic or environmental factors. Hence, the detection of genetic variations associated with sex reversal in critical sex-determining genes should be recommended for SRY-negative XX males. Only after comprehensive cytogenetic and molecular genetic analyses can genetic counseling be offered to 46,XX males.