46, XX male sex reversal syndrome

In humans, the sex of an individual is determined by the Y chromosome-related SRY gene, however, testicular differentiation may occur in the apparent absence of this gene, as in XX male sex reversal syndrome, which was first reported in 1964 by de la Chapelle et al [2]; it is also called the de la Chapelle syndrome and is one of the rarest sex chromosomal aberrations seen clinically [3]. Sex reversal syndrome can be divided into 46, XX male sex reversal syndrome and 46, XY female sex reversal syndrome. In humans, XX maleness occurs with an incidence of about one in 20 000 to 30 000 newborn boys [4]. Familial occurrences are very exceptional [5].

Individuals with a classical 46, XX male sex reversal syndrome have an apparently normal male phenotype, while non-classical XX male individuals have various degrees of sexual ambiguity such as hypospadias and XX true hermaphrodites. Generally, most of the patients fit the first subset with normal male psychosexual identification and intelligence evaluation. Urogenital malformations are infrequent. Cryptorchidism occurred in 15 % and hypospadias in 10 % - 15 % [6] of the patients. The testes are always underdeveloped with no spermato-genesis. Most of the patients may not be apparent until adulthood with the chief complaint of infertility and less than 20 % have been reported before adolescence [7]. However, the present series were all detected in the childhood due to the presence of hypospadias; another peculiar finding is hirsutism in a 7-year-old boy. In 46, XX male syndrome, the usual finding is a female pattern with scarce hair distribution.

Endocrine determination usually revealed hypergonadotrophic hypogonadism. The most distinct feature in our patients was hypoandrogenism. Deficient testosterone production by the fetal testes may account for the genital ambiguity. Several hypotheses have been put forward to explain the development of 46, XX chromosome abnormality. First, the majority of cases were due to an interchange of a fragment of the short arm of Y chromosome containing the region that encoded the testis-determining factor with the X chromosome [8-10]. Koopman et al [11]indicated that the initiation of male development in mammals requires one or more genes on the Y chromosome and SRY in humans and SRY in mouse have many of the genetic and biological properties expected of a Y-located testis-determining gene. About 10 % - 20 % of XX males had no detectable Y sequence, McElreavey et al [12] described a regulatory cascade hypothesis for mammalian sex determination and concluded that the great variability of the phenotypes in XX males might be easily explained by different Z mutations with various residual activity or leakage to different extents. Hines et al [13] identified patients with SRY mutations that caused XY sex reversal female individuals. More recently, SOX9, like SRY, was reported to be adequate to induce testis differentiation in transgenic XX mice [14]. The third proposed mechanism was a possible mosaicism. SRY sequencing was useful to search for mutation of the gene and several human Y-specific single copy probes have definitively demonstrated the presence of Y-chromosomal material in the genome of some 46, XX males. Therefore, in addition to the clinical and endocrine criteria, cytogenetic analysis and SRY sequencing were also necessary for an accurate diagnosis and differential diagnosis from Klinefelter syndrome, since these two syndromes often had similar phenotype and pathological findings. SRY sequencing could help the clinicians to classify the XX males into 3 subgroups: 46, XX males with SRY gene, 46, XX males without SRY gene and possible XX/XY mosaics. In this series, 3 boys were SRY positive, belonging to the first subgroup; for the other two, the classification is not clear.

In the adults, microrchidia and infertility were found in almost all the patients with 46, XX male syndrome, while the penis had a normal size. They could experience intercourse with normal erection and ejaculation. Bilateral gynecomastia and short stature were often present in this syndrome, but absent in this series as they are too young to have these manifestations apparent.

In patients diagnosed during the childhood, associated malformations such as hypospadias and cryptorchidism were frequently the chief complaints and treatment should first be directed to the correction of the urogenital malformations. Testosterone replacement should be initiated after puberty to maintain the secondary sexual characteristics.

Sincere thanks for the support by the National Natural Science Fundation of China (No.30170481) and the Science and Technology Program of Guangdong Province (No.010438).