By Syed Akbar
It is a common knowledge that a person with XX chromosomes is a
woman and the one with XY chromosomes is a man. The sex
chromosomes XX determine the female sex of a foetus while XY
determine the male sex of the unborn in the womb.
There are men with XX chromosomes but they do not have fully
developed male genital organs. However, a team of scientists in
Hyderabad recently came across with a XX man with normal genitals
and complete masculinity. This is a very rare medical phenomenon.
The scientists' team at the Centre for Cellular and Molecular Biology
conducted a research on this XX man with gene SRY-negative and 46
According to CCMB senior scientist Kumarasamy Thangaraj, XX
maleness is a rare syndrome with a frequency of one in 20,000-25,000
males. XX males exist in different clinical categories with ambiguous
genitalia or partially to fully mature male genitalia, in combination with
complete or incomplete masculinisation. But in the present study the
team reported a case of SRY-negative XX male with complete
masculinisation. The "man", however, was infertility and unable to
The patient had fully mature male genitalia with descended but small
testes and no signs of undervirilisation. Polymerase chain reaction
analysis for SRY (sex determining region Y gene) and other sex
determination genes ZFY, amelogenin, AZFa, AZFb and AZFc as also
other tests showed the absence of any Y-chromosome-derived material.
Genotyping with X-STR (short tandem repeat) of the chromosome
ruled out the possibility of any deletion on X chromosome.
"Development of the male phenotype in the absence of SRY probably
resulted from the loss of function mutation in some unknown sex-
determining gene, which normally inhibits the male pathway, or from a
gain of function mutation in a gene downstream to SRY in male
pathway," Dr Thangaraj points out.
We all know that the presence or absence of Y chromosome, SRY gene
in particular, determines the sex in human beings and other mammals.
SRY is thought to direct the sex-determination pathway towards male
development. The fortuitous finding of chromosomal rearrangements in
association with a sex-reversed phenotype has led to the isolation of
SRY gene. Careful genetic analysis of cases with abnormal sexual
development, presented with chromosomal translocations or deletions/
duplications, has resulted in the identification of many genes playing
role in sex determination, Dr Thangaraj says.
"Despite the identification of SRY almost 15 years ago, the pathway
downstream to SRY remains largely unknown, although SOX9 and
DAX1 have recently been proposed to function downstream to SRY
gene in male sex-determination pathway," he adds.
According to the CCMB study, an increasing number of reports suggest
that the male phenotype can develop even in the absence of SRY gene.
Till date, many cases of XX males with or without SRY and apparently
with no other Y-chromosome sequences have been reported.
Such persons exist in three clinical categories: XX males with normal
genitalia; XX males with ambiguous genitalia; and XX true
hermaphrodites with ovarian and testicular tissues.
"Based on the presence or absence of the Y-chromosome sequences,
XX males can be divided into two categories. Approximately 90 per
cent of the cases carry varying amount of the Y sequences due to an
illegitimate recombination between X and Y chromosomes, whereas 10
per cent do not have any Y-chromosome sequences. Most of the XX
males with SRY have normal genitalia, whereas most SRY-negative
cases have ambiguous genitalia," says Dr Thangaraj.
The cause (aetiology) of development of male phenotype in most of the
SRY-negative 46,XX males (like the present case study) remains
He points out that development of the testis and normal male genitals in
a significant number of SRY-negative 46,XX males gives clue to the
existence of other autosomal or X-linked genes in the sex-determining
pathway. Comprehensive genetic analysis of these cases may help to
decipher new gene(s) involved in the sex-determining pathway.
A 34-year-old man attended the genetic clinic of the Institute of
Reproductive Medicine, Kolkata, with complaints of infertility. His
height was 156 cm and weight 64 kg. The patient had fully mature
normal male genitalia with no symptom of undervirilisation.
The testicles were descended in the scrotum but small in size with
volumes 4.8 ml and 5.1 ml (normal range 18-30 ml). Axillary (under
arm) and pubic hairs were of normal pattern and density. Serum
concentrations of reproductive hormones (LH and FSH) were elevated
at 15.8 mIU/ml (normal range 2.0-14.0 mIU/ml) and 25.8 mIU/ml
(normal range 1.5-12.0 mIU/ml), respectively. Testosterone hormones
level was normal at 580 ng/dl (normal adult male range, 437-707
DNA was extracted from peripheral blood leukocytes of the patient, a
normal fertile male and a female for analysis. Absence of PCR
amplification of Y-STR markers further confirmed the lack of Y-
chromosome sequences in the patient DNA. X-STR analysis showed
heterozygous alleles for 42 of 53 markers, suggesting the presence of
two X chromosomes.
According to him, majority of the XX males carry SRY gene
translocated to the X chromosome due to an illegitimate recombination
between X and Y chromosomes. These patients are sterile males and
usually have normal male genitalia.
Dr Thangaraj says XX males without SRY gene have ambiguous to
normal genitalia, show incomplete to complete masculinisation and are
infertile. The existence of SRY-negative males ruled out the prevailing
notion that the mere presence of SRY determines maleness. The most
common observation that the individuals with SRY are male shows that
it is the presence or absence of a normal SRY gene which determines
maleness, provided all downstream genes are functionally intact.
In majority of the cases, XX maleness should result either from the loss
of function mutations in a gene normally inhibiting testes formation in
genotypic females or from the gain of function mutations in a gene
downstream to SRY in testis determining pathway. The hypothetical
gene may be X-linked or autosomal. If the gene is autosomal, the
degree of the male phenotype will be dependent on the extent of the
loss or gain of function in the mutant gene, he says.
"Because the present case had normal male phenotype, it should
either be homozygous mutant for this hypothetical autosomal gene or
a result of preferential inactivation of the normal copy of the X-linked
heterozygous mutant gene," Dr Thangaraj concludes.
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