Wonders of genetics: A rare syndrome called XX maleness

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 
chromosomes.
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 
conceive.
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 
unexplained. 
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 
ng/dl).
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.