9.4.4 XX male

This disorder is characterized by the combination of male external genitalia, testicular differentiation of the gonads, and an apparent 46,XX karyotype. Designation of the karyotype as 46,XX is based on conventional cytogenetic analysis, where the X chromosomes have an inconspicuous appearance. If molecular methods are applied, most XX males can be shown to have translocated Y-chromosomal material on the tip of one X chromosome. Strictly speaking, the karyotype of these patients should be written as 46,X,der(X)t(Xp;Yp).

It has been suggested that this disorder be renamed ‘46,XX testicular disorder of sex development’ (1). The authors prefer to stay with the the less clumsy ‘XX male (syndrome)’.

The prevalence is estimated to range somewhere between one in 9000 and one in 20 000 male newborns. Eighty per cent of XX men carry a tiny unbalanced translocation of Y chromosomal material (‘SRY positive’ patients). This genomic rearrangement almost universally arises de novo in the meiosis of their fathers’ gametes. In most cases, the ectopic Y sequences are found on one of the X chromosomes, but rare translocations to an autosome have been described. For the remaining 20% ‘SRY negative’ patients the mechanism underlying their sex reversal is unclear. A few of them may be due to cryptic 47,XXY/46,XX or 46,XY/46,XX mosaicism, where a minor Y-carrying cell line has evaded detection.

For their major parts, the human sex chromosomes are made up of sequences unique to either the X or Y, respectively. Their terminal short and long arms, however, consist of DNA highly homologous between the X and Y chromosomes. These two pseudoautosomal regions (PAR) are the sites of X/Y pairing and recombination during meiosis. For the aetiology of the XX male syndrome, only the short arm PAR is of relevance. It occupies the terminal 2.6 megabases of Xp and Yp. The sex determining SRY gene resides a mere 5 kilobases away from the pseudoautosomal boundary on Yp, a minimal distance in genetic terms. Even though it is Y-specific and thus has no X chromosomal homologue, SRY may be accidentally included into an X/Y recombination event. Such ectopic X/Y interchanges occur in specific recombination hotspots that are located centromeric to the pseudoautosomal boundary and SRY (2) (Fig. 9.4.4.1).

The 20% of XX males who do not feature Y-specific sequences in their genome are termed SRY-negative. It is unclear whether all these patients share a common pathophysiology. In some sibling cases, SRY-negative XX maleness and XX true hermaphroditism have been observed to occur in close relatives (3). These pedigrees suggest the existence of an autosomal dominant mutation that interferes in a variable fashion with the normal pathways of sexual differentiation. Curiously, this as yet hypothetical mutation can be transmitted through normal men and women. In formal genetic terms, it would therefore feature both variable expressivity and incomplete penetrance.

The testicular histopathology of postpubertal SRY positive XX males is characterized by atrophy and hyalinization of the seminiferous tubules with loss of the germ cell lineage. A testicular biopsy from a prepubertal individual was reported to display normal histology. Many SRY negative XX males have undescended testes, scrotum bifidum, or hypospadias. Because of the ambiguity of their external genitalia, they commonly undergo a diagnostic work-up during childhood. Reports on postpubertal testicular histology in SRY-negative XX males are therefore scant, and no reliable information concerning this issue can be presented. All prepubertal SRY-negative XX males have a testicular pattern of gonadal histology. This simply reflects the fact that 46,XX individuals with ovotestes or an ovary on one and a testis on the other side would be called XX true hermaphrodites.

Before karyotyping reveals the correct diagnosis, most SRY-positive XX males are suspected to have Klinefelter’s syndrome (4). In fact, on clinical grounds alone the two conditions are indistinguishable. SRY-negative XX males often display some degree of genital ambiguity (4), a feature requiring distinction less from Klinefelter’s syndrome than from the numerous rare disorders of sexual differentiation.

SRY-positive XX males commonly remain undiagnosed until adolescence or young adulthood (5, 6). Pubertal development may be delayed or incomplete, but this is not an obligate feature. Where testosterone production was sufficient to support normal pubertal development, it fails at a later age. The signs and symptoms of male endocrine hypogonadism are described in Chapter 9.3.1, to which the reader is referred for detailed discussion. Cryptorchidism and hypospadias are observed in 15 and 10%, respectively, of SRY-positive patients. The testes may be soft or firm and are hypotrophic, with an average volume of 2–3 ml. Ejaculate analysis reveals azoospermia, and the elevated serum follicle-stimulating hormone (FSH) level testifies to its nonobstructive nature. Infertility is one of two symptoms through which most XX males come to medical attention. The other is gynecomastia, a feature present in about half of SRY-positive patients. In contrast to Klinefelter’s syndrome, the mean height of XX men falls slightly below the population mean (6). Clinical impressions suggest that intelligence is generally normal, but exact quantitative data are lacking.

In addition to the signs and symptoms observed in SRY-positive cases, most, but not all SRY-negative XX males have some degree of genital ambiguity. Small penis size, chordee, penile, scrotal, or even perineal hypospadias, bifid scrotum, cryptorchidism, and vas deferens abnormalities are encountered in various combinations. There may be a reporting bias in favour of cases with clinically impressive genital anomalies.

Subnormal serum testosterone levels necessitate the initiation of hormonal replacement therapy. The principles of treatment with various testosterone preparations are outlined in Chapter 9.5.1. If cosmetically embarrassing, surgical treatment may be considered for gynaecomastia. The authors are not aware that an attempt has been made yet to approach infertility in XX males through testicular sperm extraction and intracytoplasmic sperm injection. The rationale for such a trial would be as in Klinefelter’s syndrome where small foci of spermatogenesis may be present in the otherwise atrophic testes.