The chromosomal etiology of congenital gonadal defects

Abstract

1. 1. A unified theory is presented to explain the origin of certain congenital gonadal defects on the basis of genetic imbalance involving the sex chromosomes (X,Y) and the autosomes. Non-disjunction of the sex chromosomes, chromosomal aberrations of the sex chromosomes (such as deletion, crossing over or translocation of sex genes between the X and Y chromosomes) and gene mutation have been implicated. (Chart 1.) The clinical characteristics of gonadal defects are reviewed and representative cases are included from the literature to support the theory. 1 Genetic Process Leading to Abnormal Sexual Development Chromatin-Positive Individual Chromatin-Negative Individual Non-disjunction in the germ cell Non-disjunction in the zygote /O/X (Gonadal dysgenesis) XXX (“Superfemale”) XXY (Klinefelter syndrome) Mosaic individuals XX-XXY (Klinefelter syndrome) XX-XO (Gonadal dysgenesis) XX-XO (Gonadal dysgenesis) XXX-XO (Gonadal dysgenesis) /X/O (Gonadal dysgenesis) Deletion or mutation of sex genes on the X or Y chromosome XX individual Gonadal dysgenesis Ovarian hypoplasia “Precocious menopause” XY individual 1. 1. “Pure gonadal dysgenesis” 2. 2. “Incomplete gonadal dysgenesis” 3. o 4. a. Seminiferous tubule dysgenesis Klinefelter syndrome Germinal aplasia “Turner's syndrome in males” “Low fertility men” Male pseudohermaphrodite 5. b. Congenital anorchia Crossing-over or translocation involving the X and Y chromosome (bilateral or unilateral side-specific sex genes) X XY 46 chromosome individual True hermaphrodite Some patients with gonadal dysgenesis who have “poorly differentiated Ovotestes” X XY 46 chromosome individual True hermaphrodite Translocation of X sex genes to an autosome Translocation of Y sex genes to an autosome XO (with bilateral ovaries) XO (male pseudohermaphrodite) Autosomal mutation XX individual Possibly present in those patients with various non-sex-linked congenital somatic defects associated with hypogonadism XY individual 1. 2. Non-disjunction of the sex chromosomes, during the development of the mature sperm or ovum, produces the more commonly recognized forms of gonadal dysgenesis (Turner's syndrome-XO) and seminiferous tubule dysgenesis (Klinefelter's syndrome-XXY) as well as the “superfemale” syndrome-XXX. Non-disjunction or loss of a sex chromosome in the zygote may give rise to mosaic patterns of XO-XX, XO-XXX, XX-XXY and XY-XO in a few individuals. 2. 3. A chromosomal aberration (e.g., deletion of sex genes) is postulated as the basis for congenital defective ovarian development in chromatin-positive females with an XX sex chromosome complement. 3. 4. Mutation or deletion of X or Y chromosome sex genes is postulated as the cause of certain congenital testicular defects in chromatin-negative individuals (XY) with Klinefelter's syndrome, germinal aplasia, Turner's syndrome in boys and men, low fertility, congenital anorchia or “pure gonadal dysgenesis.” Male pseudohermaphroditism may be due to a hereditary mutation of the maternal X chromosome or a maternal autosome which is capable of modifying the action of the Y chromosome sex genes. 4. 5. The linkage of sex determining genes located on the Y chromosome to an X chromosome by means of crossing over or by a translocation during spermatogenesis is postulated to be the cause of chromatin-positive true hermaphrodites. Similarly, the linkage of sex determining genes located on the X chromosome to a Y chromosome is postulated to cause chromatin-negative true hermaphrodites. A theory for the unilateral action of separate sex genes in the X and Y chromosome is presented to explain the different gonad on each side of the body in these individuals. A broadened concept of true hermaphroditism to include some instances of gonadal dysgenesis with vestigial ovarian and testicular elements is suggested. 5. 6. Translocation of female-determining genes from a broken X chromosome to an autosome may influence the production of ovaries in an XO individual. Translocation of male-determining genes from a broken Y chromosome to an autosome may influence the production of testes in an XO male pseudohermaphrodite. 6. 7. Autosomal mutations may result in hypogonadism in certain individuals with non-sex-linked congenital somatic defects (evidence of the autosomal aberration). 7. 8. Congenital anomalies associated with gonadal aplasia and dwarfism are known to occur in an XO individual. It is postulated that the varying somatic defects in Turner's syndrome may be related to the presence of recessive genes with deleterious effects on the X chromosome or the influence of genetic imbalance.