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.