Turner Syndrome (Monosomy X)

Definition

The phenotypic pattern of Turner syndrome was described in 1938 and defined cytogenetically in 1959 as an absent or abnormal second sex chromosome. Individuals with Turner syndrome always have short stature, typically have a webbed neck, and often have lymphedema, cardiac malformations, renal malformations, gonadal dysgenesis, and/or endocrinopathies. Many of these findings can be identified prenatally with ultrasound (US).

Prevalence and Epidemiology

Turner syndrome is the most common sex chromosome abnormality, and the second most common chromosomal abnormality associated with spontaneous abortion. Its true prevalence is difficult to ascertain because mild phenotypes may go undiagnosed. Best estimates are that it occurs in 4–5 : 10,000 live-born females. Turner syndrome is not associated with advanced maternal or paternal age, and has no known ethnic or racial influences.

More than 90% of conceptions with Turner syndrome spontaneously abort. Karyotypic analysis of products of conception from spontaneous pregnancy losses demonstrates an approximate 10% prevalence of 45,X. Prenatal prevalence, estimated through evaluation of cytogenetic registries, is about 40 : 10,000 in the late first trimester by chorionic villus sampling, and 17.5 : 10,000 in the second trimester by amniocentesis.

Etiology and Pathophysiology

Distinct etiologies are responsible for the various Turner syndrome karyotypes. Complete monosomy (45,X), the most common etiology of Turner syndrome, is due to absence of one sex chromosome, usually the paternal (80%).

More than 50% of individuals with Turner syndrome have a mosaic chromosomal complement, such as 45,X/46,XX. In the case of cell line mosaicism, the loss of genetic material occurs after fertilization. Mosaicism can also result from a cell division error, resulting in one cell line that exhibits a 45,X karyotype and a second line containing a 46,XX, 46,XY, or 47,XXX karyotype. Less commonly, there may be a structurally altered second X chromosome, or some cells carry a Y chromosome, resulting in a virilized adolescent. Individuals who are mosaics for sex chromosomes and/or have structurally abnormal karyotypes appear female and usually have fewer anomalies than the 45,X phenotype.

Postnatal karyotype of 200 patients with phenotypic Turner syndrome demonstrated 46% were 45,X, 41% had a second structurally abnormal X chromosome, 7% were 45,X/46,XX or 45,X/46,XX/47,XXX mosaics, and 6% had a structurally abnormal Y chromosome. In contrast, in 90% of prenatally diagnosed Turner syndrome, the karyotype is 45,X ( Table 152.1 ).

Clinical manifestations appear to result from a reduced complement of genes normally expressed on the randomly inactivated X chromosome and therefore karyotype alone cannot predict phenotype. Short stature is the only clinical finding invariably associated with 45,X individuals although, while this has been associated with a pseudoautosomal deletion encompassing a homeobox gene (short stature homeobox-containing gene on the X chromosome, SHOX ), this deletion is also present in 2% to 15% of cases of idiopathic short stature.

Common clinical manifestations, such as webbing of the neck, shield chest, renal anomalies, and cardiac defects may be a consequence of lymphedema interfering with organ development. For instance, it has been proposed that lymphatic obstruction at the level of the ascending aorta may directly cause flow-related cardiac defects such as bicuspid aortic valve and/or aortic coarctation as well as neck webbing.