The Principles of Clinical Cytogenetics - Extra Materials - Springer

Sex Chromosomes and Sex Chromosome Abnormalities 235
hyperplastic Leydig cells, and usually no spermatogonia (277). There are also 46,XX sex-reversed
patients with true hermaphroditism having both testicular and ovarian tissue in gonads, either separately
or, more commonly, as an ovotestis. They usually have ambiguous external and internal genitalia,
depending on the amount of functional testicular tissue present (see below).
There are at least three different mechanisms to explain the male phenotype in XX males: (1) translocation
of Y sequences, including the SRY gene, to an X chromosome or autosome; (2) a mutation in an
as yet unknown X-linked or autosomal gene in the testis-determining pathway; or (3) cryptic Y chromosome
mosaicism (278,279). The majority of patients (90%) fall into category 1, most often with Y
sequences including SRY translocated to the X chromosome. The pseudoautosomal regions of Xp and
Yp pair during male meiosis, and there, sometimes, might be unequal interchange of material extending
beyond the pseudoautosomal boundaries. This theory has been used to explain the origin of XX
males with SRY and other portions of Yp translocated to Xp (280). Ten percent of XX males have no
detectable SRY or other Y sequences (279).
Most SRY-positive XX males have normal male external genitalia, whereas those lacking Y-derived
sequences are more likely to have ambiguous genitalia (281,282). However, 46,XX sex-reversed
patients with SRY present could have ambiguous genitalia and evidence of true hermaphroditism.
This variability could be the result of differential inactivation of the X chromosome carrying SRY
(283). The amount of Yp present on Xp could be an additional factor (284).
There have been familial cases of 46,XX males, suggesting autosomal recessive inheritance (285).
There have also been families reported with both XX males and XX true hermaphrodites, so that there
might be a common origin for both (281). Others have also found evidence that full virilization requires
the expression of a second Y-linked gene, near SRY, which could be expressed outside the testis (286,287).
46,XY Females
The etiology of 46,XY sex reversal is unclear in most cases. In approximately 15% of cases of
46,XY complete gonadal dysgenesis, there is a mutation in the SRY gene (288). Some 46,XY females
have been described with loss of SRY (289), whereas others have complete androgen insensitivity (“testicular
feminization”), an X-linked condition. Malformation syndromes such as Smith–Lemli–Opitz
and campomelic dysplasia also produce female or ambiguous genitalia with a 46,XY karyotype. These
are the result of mutations or deletions in the autosomal genes DHCR7 (7-dehydrocholesterol reductase)
and SOX-9, respectively. There is also a dosage sensitive region on Xp (DSS) that, when duplicated,
leads to female external genitalia in a 46,XY individual. DAX1 (dosage-sensitive sex reversal/
adrenal hypoplasia congenita/critical region on the X chromosome, gene 1) appears to be the gene
responsible for this (191,290,291). Mutations in this gene are associated with congenital adrenal
hypoplasia and hypogonadotropic hypogonadism (292,293). WT1 on 11p, DMRT1 on 9p, and SF1 on
9q are other important genes in sex determination (reviewed in refs. 269 and 279). Familial cases
suggesting X-linked sex-limited, autosomal recessive, or autosomal dominant inheritance have been
reported (reviewed in ref. 288).
True Hermaphroditism
This is a rare condition where both testicular and ovarian tissue is present either as separate structures
or as an ovotestis. Most patients have ambiguous external genitalia with a phallus of variable
length and urogenital sinus and are reared as males. Secondary sex characteristics in each patient will
be the result of the predominant steroid hormone produced. Ovulation and pregnancy have been
reported in a few cases (279). A few patients who were chimeras with 46,XX and 46,XY cell lines
arising from the fusion of two zygotes have been described (277), although not all 46,XX/46,XY
individuals have true hermaphroditism (294). At least 50% of true hermaphrodites are 46,XX with no
Y DNA (277). Cryptic gonadal mosaicism for SRY has been found in some patients, whereas others
could have alterations in unknown X-linked or autosomal sex-determining genes (279).
Gonadal neoplasia and breast cancer have been reported in these patients (56,294).