Approximately 43% of patients with Turner syndrome either are mosaics (one of the cell lines being 45,X) or have structural abnormalities of the X chromosome. The most common is deletion of the short arm, resulting in the formation of an isochromosome of the long arm, 46,X,i(X) (q10). The net effect of the associated structural abnormalities is to produce partial monosomy of the X chromosome. Combinations of deletions and mosaicism also occur. It is important to appreciate the karyotypic heterogeneity associated with Turner syndrome because it is responsible for significant variations in the phenotype. In contrast with the patients with monosomy X, those who are mosaics or have deletion variants may have an almost normal appearance and may present only with primary amenorrhea.
The molecular pathogenesis of Turner syndrome is not completely understood, but studies have begun to shed some light. As mentioned earlier, both X chromosomes are active during oogenesis and are essential for normal development of the ovaries. During normal fetal development, ovaries contain as many as 7 million oocytes. The oocytes gradually disappear so that by menarche their numbers have dwindled to a mere 400,000, and when menopause occurs fewer than 10,000 remain. In Turner syndrome, fetal ovaries develop normally early in embryogenesis, but the absence of the second X chromosome leads to an accelerated loss of oocytes, which is complete by age 2 years. In a sense, therefore, “menopause occurs before menarche,” and the ovaries are reduced to atrophic fibrous strands, devoid of ova and follicles (streak ovaries). Because patients with Turner syndrome also have other (nongonadal) abnormalities, it follows that genes required for normal growth and development of somatic tissues also must reside on the X chromosome. Among the genes involved in the Turner phenotype is the short stature homeobox (SHOX) gene at Xp22.33. This is one of the genes that remain active in both X chromosomes and is unique in having an active homologue on the short arm of the Y chromosome. Thus, both normal males and females have two active copies of this gene. Loss of one copy of SHOX gives rise to short stature. Indeed, deletions of the SHOX gene are noted in 2% to 5% of otherwise normal children with short stature. Whereas loss of one copy of SHOX can explain the growth deficit in Turner syndrome, it cannot explain other important clinical features such as cardiac malformations and endocrine abnormalities. Clearly, several other genes located on the X chromosome also are involved.
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Infemales,oneXchromosome,maternalorpaternal,israndomlyinactivatedduringdevelopment(Lyonhypothesis).
InKlinefeltersyndrome,therearetwoormoreXchromosomeswithoneYchromosomeasaresultofnondisjunctionofsexchromosomes.Patientshavetesticularatrophy,sterility,reducedbodyhair,gynecomastia,andeunuchoidbodyhabitus.Itisthemostcommoncauseofmalesterility.
InTurnersyndrome,thereispartialorcompletemonosomyofgenesontheshortarmoftheXchromosome,mostcommonlycausedbytheabsenceofoneXchromosome(45,X)andlesscommonlybymosaicism,orbydeletionsinvolvingtheshortarmoftheXchromosome.Shortstature,webbingoftheneck,cubitusvalgus,cardiovascularmalformations,amenorrhea,lackofsecondarysexcharacteristics,andfibroticovariesaretypicalclinicalfeatures.
Three groups of diseases resulting from mutations affecting single genes do not follow the mendelian rules of inheritance:
Diseases associated with alteration of imprinted regions of the genome