DISCUSSION
46, XX male syndrome is a rare sex reversal syndrome with a frequency of 1 in 20,000-25,000 newborn males(3, 4). Phenotypically, three clinical categories of 46, XX male syndrome individuals have been identified(7). The classic form of 46, XX male syndrome is testicular DSD, which has a female karyotype and phenotypically male. We herein report a classical form of the SRY-negative 46, XX male syndrome co-existing with bone marrow failure.
Broadly, these conditions are caused by gain-of-function variants in crucial testis differentiation genes or loss-of-function variants in ovarian differentiation genes(8). 10% of testicular DSD is SRY-negative. In the absence of SRY, there was overexpression of other pro-testis genes, e.g. SRY-box (SOX) family genes, or failure of pro-ovarian/anti-testis genes, e.g. WNT4, and RSPO1(9). WES reveals the SRY gene was negative in this patient. At the same time, the patient harbored variants gene associated with SRY-negative 46, XX male syndrome. Testicles development is a large and complex network. This patient had multiple genetic mutations associated with testicles development.
Few genes have been implicated in ovarian development compared with testicular development relatively. In humans, patients carrying a heterozygous mutation of the WNT4 gene present Müllerian duct abnormalities and hyperandrogenism(10). Homozygous missense mutation WNT4 gene is a disease-causing in SERKAL syndrome(11). Mutations in the RSPO1 gene have been associated with the SRY gene-negative 46, XX testicular DSD, as well as with ovo-testicular DSD(12). WNT4 and RSPO1 activate canonical WNT signaling, and CTNNB1 is a crucial regulatory molecule of the Wnt signaling pathway. Indeed, several feedback loops help maintain WNT4/RSPO1 signaling, including the insulin signaling pathway (consists of INSR and INSRR). Albeit SRY gene and SOX9 gene are absent in this patient, SV of WNT4, RSPO1, and STNNB1 could result in loss-of-function of the central female pathway, which leads to female-to-male sex reversal of the gonads. Besides, there was a large fragment inserted in INSRR affecting positive feedback loop.
DMRT1 activates testis-promoting genes including Sox9, Sox8 and PTGDS, and represses ovary-promoting genes such as Wnt4 and Rspo1(13). DMRT1 mutations in the case may activate testis-promoting genes and represses ovary-promoting genes. Independent missense mutations of FOG2 gene associated with 46, XY DSD in human. Further studies indicated impaired the ability of FOG2 proteins interact with GATA4, an early testicular development regulator(14). Large fragment deletion in FOG2 had not reported in 46, XX DSD, we should force further theorization to the mechanism.