Maleness is normally inherited as a dominant trait because of a single copy of the Y chromosome. Later, it appeared that a factor in the short arm of Y chromosome determines the differentiation of the indifferent gonads into testes and it was designated as a testis-determining factor (Simpson et al., 1987). In the next step, the sex-determining region on the human Y chromosome was defined to a 35-kb region of Y-specific DNA adjacent to the pseudoautosomal boundary, and in this 35-kb region, a gene was identified and named SRY (sex-determining region Y) gene (Sinclair et al., 1990). SRY encodes a member of the high-mobility group-box family of DNA-binding proteins and thus possibly for putative transcription factor (Behlke et al., 1993). It initiates a cascade of gene interactions orchestrated by SOX9, leading to the formation of testes from bipotential gonads (Sekido, Lovell-Badge, 2009).
Sex reversal syndromes represent a special group of human genetic diseases with sex dysplasia, which is characterized by inconsistency between gonadal sexuality and chromosomal sexuality. The group of sexual reversal syndromes comprises 46,XY females and 46,XX males. The XX males syndrome (OMIM ID 4000045) was first described by De la Chapelle et al. (1964), recently termed testicular disorders of sexual differentiation. The XX male syndrome is very rare; the incidence rate was estimated to be about 1 : 20 000–25 000 (Rajender et al., 2006).
Here, we report on a patient with the XX male syndrome as the first Hungarian case in our population of 10 million individuals.
Patients and methods
The patient, that is, proband (Gy.O.), was born on 18 October 1969. His father was born in 1939, and he died of a brain tumor in 2001. The mother of the proband was born in 1950; she has no major diseases. This couple had three sons; the first was the proband. Their second son was born in 1970; he married and his wife delivered a boy in 1999. The third son was born in 1974; he also married and his wife delivered a girl in 2010. Both healthy brothers of the proband had good spermatograms.
The proband visited our Genetic Counseling Clinic on 6 April 2009 because he had been living with a woman since October 2007; they had been attempting to conceive, without success, despite frequent sexual intercourse (in general two or three times a week). This infertility problem was the reason for their visit. The healthy female partner of the proband was born in 1973; she had two previous pregnancies from two different males. Her first pregnancy was terminated for social reasons, but she delivered a healthy daughter in 2005. Her gynecological and hormonal examination did not indicate any disease and/or malfunction.
The height of the proband was 170 cm; his body weight was 70 kg. His secondary sexual phenotype was a typical male, with strong hirsutism (Fig. 1). His skeletal development, general health, and intelligence were normal. The first night ejaculation (pollution) as the onset of his puberty occurred in his age of 13 years; later, he had no problem with erection and ejaculation. He had a few female sexual partners, with whom he sometimes had sex without contraception, but did not lead to conception.
His sperm analysis indicated azoospermia in the normal sperm volume. The manual examination of his genital organs indicated a normal-size penis, but both his testes showed severe hypoplasia. The testicular volume measured was 2.2 cm3 in the right and 1.1 cm3 in the left testis (the Hungarian standard of testis is 18.0–19.6 cm3 in the right and 16.9–17.1 cm3 in the left side in adult men). The histological examination of testis tissue after biopsy showed the presence of Leydig and Sertoli cells, and severely decreased and atrophied seminiferous tubules without spermatogenesis. The ultrasound and MRI examinations of his pelvic region did not indicate any pathological condition. The diameter of the right and left testis was 23 and 11 mm, respectively, whereas the diameter of the prostate was 2 cm.
The total testosterone level measured was 22 ng/dl (the normal value is about 40 ng/dl).
Repeat chromosomal examination with G-banding yielded the 46, XX karyotype (Fig. 2). In the next step, fluorescence in-situ hybridization analysis (Yp11.3/Xp11.1-q11.1 translocation analysis) was carried out with probe LSI, SRY/CEPX (Vysis, 32-191007, 9041).ish (SRY+), and this examination indicated the presence of the SRY gene on one the X chromosomes (Fig. 3). Thus, the final genetic diagnosis was a 46, XX, SRY+ male.
We informed the patient that we aimed to publish his data and photos in a case report, and he provided written, signed consent.
The SRY (sex-determining region of Y) gene and the AZF (azoospermia factor) gene, genes from a gene family with multiple members, are both localized on the Y chromosome, and are crucial for testis determination and spermatogenesis, respectively. Sex reversal XX males may result from translocation of sequences from Yp onto Xp owing to meiotic recombination. Thus the part of the Y chromosome containing the SRY gene was translocated to the X chromosome and in general this type of chromosomal mutations explains the existence of major part of XX males. (Andersson et al., 1986). Eighty-ninety percent of XX males are SRY+ (Wang et al., 2009; Kim et al., 2010) and, in one-third of these, interchanges take place between the two PRK homologs, PRKX and PRKY, producing a typical fusion fragment. Usually, genes from Yq including the AZF locus are not present in these cases and therefore there is no spermatogenesis. However, molecular studies have shown that TSPY genes and also DYZ3 sequences were absent; in addition, there is a lack of deletions or duplications of SOX9, NR5A1, WNT4, and NROB1 regions (Alves et al., 2010).
As we mentioned previously, female-to-male sex reversal in humans is rare (Rajender et al., 2006; Alves et al., 2010), and when it is familial, it is extremely rare (De la Chapelle et al., 1978, 1979).
There is probably pathogenetic heterogeneity in the origin of XX males (McElreavey et al., 1993; Cox et al., 2011). The presence of factors controlling spermatogenesis on the nonfluorescent part of the long arm of Y (distal part of Yq11) was suggested by the study of six men with deletion of this segment and azoospermia (Tiepolo and Zuffardi, 1976).
Our proband with the 46,XX karyotype was SRY+. However, rarely XX males with a lack of SRY gene occur and this phenomenon needs special explanation. McElreavey et al. (1993) generated a hypothesis that these individuals carry a recessive mutation in a gene termed Z that allows expression of male characteristics. They proposed that the wild-type Z product is a negative regulator of male sex determination and is functional in wild-type females. In males, SRY product represses or otherwise negatively regulates Z and thereby allows male sex determination. This hypothesis can also explain others types of sex reversal in mammals, in particular, XY females with SRY.
However, we had one theoretical problem during the evaluation of the karyotype of our proband: he had two X chromosomes with the translocation of the Y chromosome comprising the SRY gene; thus, we expected a phenotypic manifestation of Klinefelter syndrome. Sometimes, an X–Y chromosomal interchange has been found in the etiology of XX Klinefelter syndrome (Ferguson Smith, 1966), but other cases with heteromorphic X chromosomes in 46,XX males had a male phenotype (Evans et al., 1979; Vorona et al., 2007).
The genetic counseling was quite easy: we had to inform the couple that the proband was incapable of conception; thus, they had to accept this condition or find an alternative method (artificial insemination from donors) to achieve conception. At present, they do not prefer this alternative; they hope that the cloning technique can be used in the future, but we explained that at present this method does not exist, in general ethically refused and legally prohibited in European countries. Partly, counseling was very difficult from the psychological aspect because both the proband and his female partner were convinced of the maleness, the ‘good maleness’, of the proband. In fact the proband phenotypically and sexually was male, thus it would be very disturbing from psychological aspect to inform directly them on the genetic diagnosis of 46,XX maleness. We faced a similar problem after the first diagnosis of testicular feminization (androgen insensitivity syndrome with 46,XY karyotype) in a beauty wife of a man with complete female phenotype. We informed them on the male genetic sex of this woman, but her husband was upset to say: “I am not homosexual!!!”. These experiences helped us with counseling of other couples with androgen insensitivity syndrome, and in this couple, to provide ‘intermediate’ information, that is, to inform them of infertility, but not the ‘genetic femaleness’ of the male patient.
Conflicts of interest
There are no conflicts of interest.
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