The patient was a 14-year-old male who was referred for evaluation of mild exogenous obesity. Upon physical examination, the patient's testes were noted to be smaller than normal. Penile size was appropriate for his age and he had pubic hair. Secondary causes of obesity were excluded by history/physical examination or laboratory testing. Excluded were: hypothyroidism, growth hormone deficiency, Cushing syndrome, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, and syndromic forms of obesity such as Prader-Willi syndrome and Bardet-Biedl syndrome.
Because of the possibility of Klinefelter syndrome (based on his small, firm testes), a karyotype was sent. When the karyotype was reported as 46,XX, the clinician called the director of the cytogenetics laboratory to confirm that this was correct. Indeed, the karyotype was correct (46,XX). The director of the cytogenetics laboratory said that the lab was going to perform one more test before the results were formally reported.
Can you explain why this boy could have a 46,XX karyotype and what additional test was going to be performed?
Answer: This teenage boy can be described as a "sex reversed 46,XX male." “Sex-reversed” is a descriptive term for individuals whose external genitalia are the “reverse” predicted by their sex chromosome constitution, i.e., males are usually 46,XY and females are usually 46,XX. This is not a case of Klinefelter syndrome.
In 46,XX sex-reversed males, during gametogenesis in the father, a chromosomal crossover occurs between non-pseudoautosomal areas of the X and Y chromosomes. Normally crossing-over only occurs between pseudoautosomal areas of the X and Y chromosomes. The non-pseudoautosomal crossover transfers the SRY gene and/or other male-determining genes from the Y chromosome to the X chromosome. The SRY-gene positive X chromosome then provides the genetic information needed to form testes. However, the testes are not normal because there are essentially two copies of the X chromosome and not all of the Y-chromosome male-determining genes may be present. This situation is similar to a male with Klinefelter syndrome (47,XXY). However in contrast to Klinefelter syndrome, because sex-reversed 46,XX males lack a complete Y chromosome, height may be decreased. The abnormal testes are small in size at puberty. Mild primary hypogonadism is manifested in low or low normal testosterone and elevated LH and FSH levels.
The diagnosis of 46,XX male sex reversal is based upon karyotypic analysis and a search for the presence of an SRY gene. Indeed, the FISH study that the director of the cytogenetics laboratory planned to perform was for the SRY gene (which was positive in this patient). 80% of 46,XX sex-reversed males are SRY positive.
Now, what is a 45,XY sex-reversed female?