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.
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