NACB - Scientific Shorts
NACB - Scientific Shorts (formerly NACB Blog)
By William Winter, MD
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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?

 

 

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Posted by
On 8/8/2011

The LH was high normal and the FSH was mildly elevated. The testosterone was ~200 ng/mL (low normal for age). In any form of testicular failure in adolescent males or adult males with a normal hypothalamic-pituitary axis, LH and FSH can be elevated. These endocrine findings, however, don't tell us the cause of the testicular failure. - Bill

Posted by
On 8/6/2011

I agree with the above comments . It could still be a case of Klinefilter's of the mosaic type, a repeat of the karyotype on another cell type could be performed to rule out this possibility. Also the presence of a hidden Y chromosome using FISH technique might help confirm the diagnosis. Other simpler tests should be done first such as serum LH, FSH, total testosterone and estradiol to distinguish hypothalamic- pituitary hypogonadism from other types of hypogonadism. Usually a high LH and estradiol level with a low normal total testosterone level can be expected in Klinefilter's Syndrome.

Posted by
On 8/4/2011

Very unusual, but I think maybe they are going to perform a karyotype on another cell to rule out mosaicism. Also- what about performing an FSH and LH?

Posted by
On 8/4/2011

In Klinefelter syndrome there is an over production of gonadotrophins (LH and FSH) from the pituitary gland. (known as a hypergonadotrophic condition) In Kallmann syndrome there is an absence of gonadotrophins (LH and FSH) from the pituitary gland. (known as hypogonadotrophic condition) so perform LH and FSH?

Posted by
On 8/4/2011

I agree with the explanation above, i would do a FISH to find out if there is hidden Y chromosome somewhere. If not found we should rule out all other masculinizing enzyme deficiencies in the adrenal gland.

About the Author
William Winter, MD
William Winter, MD