Turner Syndrome

Introduction
Turner syndrome is one of classical syndromes caused by numerical chromosomal aberrations, among which we include the Down, the Edwards, the Patau, the Klinefelter, the triple X and the XYY syndromes as well (the last two mentioned being formerly called the "Superfemale" and the "Supermale" syndrome respectively). Unlike these syndromes, which are (in most cases) caused by a trisomy of either a somatic or a sex chromosome, Turner syndrome represents likely the only complete monosomia whose bearers are capable of long-term survival.

Approximately a third of patients with Turner syndrome are diagnosed in the neonatal period based on a congenital heart defect (the coarctation of the aorta, bicuspidal aortal valve) and a characteristic appearance (pterygium colli, swollen hands and feet). Another third is diagnosed in childhood within the differential diagnosis of stunted growth. The remaining third is discovered during the maturation based on primary amenorrhea and the insufficient development of secondary sexual characteristics.

Overview
This syndrome is typically characterized by a 45,X karyotype in females (in about 50% of cases), with the absence of one X chromosome (and therefore absence of a Barr body). The single X chromosome is of maternal origin in about 70% of cases; therefore there is loss of a sex chromosome due to paternal error. Other possible variations include: Its incidence is about 1:2000 (less common than Klinefelter's) and it is present in about 1.5% of all conceptions.
 * 46,X,i (Xq) in 15% of cases (isochromosome of X);
 * 45,X or 46,XX mosaics in 15% of cases;
 * 45,X or 46,X,i (Xq) mosaics in about 5%;
 * other.

Patients present with the following features:
 * 1) short stature (without hormonal treatment, average height is 145cm);
 * 2) ovarian dysgenesis (streak ovary); this is the most common cause of primary amenorrhea;
 * 3) infertility;
 * 4) shield chest with widely-spaced nipples;
 * 5) webbing of the neck postnatally (cystic hygroma in fetal life; seen in ultrasound);
 * 6) low posterior hairline;
 * 7) average intelligence;
 * 8) renal and cardiovascular abnormalities (e.g. coarctation of the aorta).

There is no actual cure for this syndrome but treatments can be done to alleviate some of its symptoms, e.g. growth hormone, estrogen replacement therapy, and reproductive technologies (to get pregnant as they are infertile, donor egg cell is needed).

History
The history of Turner syndrome as a singular pathological unit has more or less started in the 20th century, nowadays the syndrome is being linked to the American endocrinologist Henry Turner and his article – A syndrome of infantilism, congenital webbed neck and cubitus valgus – published in 1938. In the name of the article itself the most significant symptoms of the syndrome are already described. During the following years the diagnostics of the syndrome, including prenatal diagnostics, have improved along with cytogenetic and molecular genetic methods. Promising development was noted in treatment as well, most importantly the therapy by substitution of missing hormones. Today, it is no exception that women with Turner syndrome can give birth to a healthy child thanks to a donated oocyte and hormonal substitution therapy.

Cytogenetic appearance
Turner syndrome is most often caused by the X chromosome monosomy, also called the 45,X karyotype (the older description as 45,X0 is unacceptable since the ISCN 2009 norm). The lack of the Y chromosome directs the maturation towards female sex – thus the syndrome is typical for women. However, about 50 % of Turner syndrome cases are caused by a different karyotype – most often by chromosomal mosaics: 45,X/46,XX; 45,X/47,XXX; eventually even 45,X/46,XX/47,XXX, as well as structural aberrations – isochromosome X: 46,X,i(Xq); rarely 46,X,i(Xp), deletions of short or long arms of the X chromosome: 46,X,del(Xp); respectively 46,X,del(Xq); circular chromosome X: 46,X,r(X) or idiocentric chromosome X: 46,X,idic(X).

These structural aberrations and appear even in chromosomal mosaics – e.g. 45,X/46,X,r(X). Examples of rare chromosomal findings are the presence of the marker chromosome: 46,X + mar. or various reciprocal translations of the X chromosome.

Special attention should be given to cases connected to the presence of the Y chromosome in the karyotype. Not all of these cases can be considered a case of Turner syndrome in its proper sense. Moreover, they don't even have to be connected exclusively to the female phenotype. It is most notably the 45,X/46XY mosaic (linked to mixed gonadal dysgenesis) or the 46,XY karyotype linked to pure gonadal dysgenesis. The Y chromosome doesn't have to be present fully, it can even be a small translocated sequence, an idiocentric chromosome or a marker chromosome.

Pathogenesis
From the cytogenetic point of view there is a certain link between Turner syndrome cases, it is the absence of the entire X chromosome or the deletion of some of its parts. Pathological is therefore the absence of certain genes which would otherwise be present. However, it is necessary to approach this problem more closely, because males (46,XY karyotype) also have only a single X chromosome and even in women with the complete karyotype (46,XX) is one of the two X chromosomes inactivated.

It is nonetheless important that some genes on the inactivated X chromosome continue being transcribed regardless (therefore they are exceptionally interesting in regards to the pathogenesis of Turner syndrome). These genes can be classified into three groups:


 * 1) genes localized in the so-called pseudoautosomal segments of the X chromosome. These are two segments – the PAR 1 (larger segment, circa 2,7Mb = millions of bases, 24 genes) at the end of short arms, and the PAR 2 (shorter segment, circa 330kb = thousands of bases, 5 genes) at the end of the long arms. Thanks to these areas (especially PAR1) the X and Y chromosomes can create a "homologous" pair during the meiosis; crossing-over is possible between genes in this area. The SHOX gene (Short Stature Homeobox; Xp22.32; OMIM: *312865) is one example of a gene in the PAR1 area, as is his homologous gene SHOXY (Yp11.2; OMIM: *400020).
 * 2) Genes located outside the pseudoautosomal segments of the X chromosome that nonetheless have their homologous copies on the Y chromosome as well.
 * 3) Genes located only on the X chromosome (without a homologous copy on the Y chromosome), but which don't undergo lyonization – for example the SSDD gene (Steroid Sulfatase Deficiency Disease; Xp22.32; OMIM: +308100; the gene is a code for the steroid sulphatase and its mutation causes the X-linked form of congenital ichthyosis).

Since the X chromosome doesn't have to be missing entirely – only some genes – the phenotype of the affected individuals can be different depending on which genes are missing. The most severe is exactly the simple 45,X monosomy (it is recorded that up to 99% of the fetuses with this karyotype are miscarried), forms with only specific structural aberrations of the second X chromosome or mosaic forms are clinically less severe (an opinion exists which states that simple 45,X monosomy is incompatible with survival and the living bearers of this karyotype are actually unrecognized mosaics).

Related articles

 * Disorders of the Sex Chromosomes