Jan. 5, 2011 -- Two adult brothers and a paternal uncle in the U.K. all appear to be normal males -- but genetically are women with two X chromosomes.
Both brothers are married to women, and they and their uncle have the sexual anatomy, behavior, growth, and skeletal development of males. All have normal health and intelligence.
However, all three are infertile and unable to produce sperm. When the brothers responded to testosterone replacement with pain, their testes were removed and replaced with cosmetic prostheses.
Genetic tests showed that both they and their uncle lacked a Y chromosome. Instead they had the two X chromosomes characteristic of women (normal men have one X and one Y chromosome).
What happened? During normal male development, the Y chromosome triggers a flood of gene interactions that is managed by the SOX9 gene. Once triggered, male development continues even in the absence of the Y chromosome.
In the three U.K. men, an inherited duplication in a DNA sequence triggered the SOX9 gene and reversed their sexual destiny.
This unusual case report, from University of Cambridge geneticist James J. Cox and colleagues, appears in the Jan. 6 issue of the New England Journal of Medicine.
While it's extremely rare for sex reversal to run in a family, it's not unheard of for genetic females to develop as men or for genetic males to develop as women. Sex determination is a complex process that can go awry at various stages of early development.
XY female and XX male sex reversals occur in about one in 20,000 live births.
Less complete sex reversals, known as disorders of sexual development (DSDs), are partial mismatches between genetic sex and the "secondary" sexual characteristics that give a person the appearance of being male or female.
DSDs occur in at least one in 100 births. These often result in "relatively mild forms" such as hypospadias, where the male urethra emerges from the underside of the penis, note Edwina Sutton and colleagues of the University of Adelaide, Australia, in the January issue of the Journal of Clinical Investigation.