Síndromes

TURNER

INTRODUCTION — Turner syndrome is an important cause of short stature in girls and primary amenorrhea in young women that is usually caused by loss of part or all of an X chromosome. The clinical manifestations and diagnosis of Turner syndrome will be reviewed here. Treatment of this disorder is discussed separately.

INCIDENCE — Turner syndrome, first described in 1938, is the most common sex chromosome abnormality in females and occurs in approximately 1/2,500 live births, based on data from Europe, Japan, and the United States. The true prevalence of Turner syndrome is difficult to ascertain, since those with mild phenotypic features may remain undiagnosed.

PATHOGENESIS — Molecular studies have shown that the maternal X is retained in two-thirds of patients with Turner syndrome and the paternal X in the remaining one-third. More than one-half of all patients with Turner syndrome have a mosaic chromosomal complement (eg, 45,X/46,XX) detectable in peripheral blood leukocytes. Mosaicism with a normal cell line in the fetal membranes may be necessary in all affected cases for adequate placental function and fetal survival.

The identification of mosaicism depends directly upon the method of ascertainment. It varies from 34 percent with conventional cytogenetic techniques to 60 percent with fluorescence in situ hybridization (FISH) techniques to 74 percent in a study in which reverse transcriptase polymerase-chain-reaction (PCR) assays were used.

Some patients with Turner syndrome lack only part of one sex chromosome, and the Turner syndrome phenotype can be seen with a variety of structural abnormalities, such as isochromosomes, rings, or terminal deletions. A rare but very informative class of Turner syndrome includes patients who have deletions of the Y chromosome that remove the testes-determining gene, SRY; these individuals develop as females. Based upon this finding and the fact that males require only one X chromosome for normal development, Ferguson-Smith hypothesized that copies of Turner syndrome genes are also present on the Y chromosome.

Specific localization of Turner syndrome candidate genes proved elusive until one group successfully identified a pseudo-autosomal deletion encompassing a novel homeobox gene, SHOX (short stature homeobox-containing gene on the X chromosome), which is associated with short stature not only in Turner syndrome, but also in Leri-Weill dyschondrosteosis and in an estimated 2 to 15 percent of cases of idiopathic short stature.

The tips of the short arms of chromosomes X and Y are logical sites for Turner syndrome genes, as sex chromosomes undergo meiotic recombination within the pseudo-autosomal region and all genes in this region that have been examined escape X-inactivation. Characterization of XYp females provides additional support for the hypothesis of a distinct Turner syndrome stature locus: most of these patients have unbalanced X,Y translocations and, in the most fully documented patients with this karyotype, two intact copies of the pseudo-autosomal region are present. It is not surprising that these patients attain normal stature, despite the presence of features consistent with Turner syndrome. As noted above, an absence of SHOX was identified as the genetic cause of the short stature phenotype in patients with Turner syndrome .

Studies that have examined the relationship between the chromosomal and karyotypic abnormalities and clinical findings in patients with Turner syndrome have been disappointing. Short stature is the only clinical finding invariably associated with the 45,X karyotype; it also is the only phenotypic abnormality present in virtually 100 percent of patients. Specific karyotypic abnormalities may also correlate with the presence of hypothyroidism. The webbing of the neck, shield chest, and probably the ear malformations, renal anomalies, and cardiac defects may be a consequence of fetal lymphedema, which interferes with organ development.

Deletions of the long arm of the X chromosome have been reported in otherwise normal women (ie, normal stature) with secondary amenorrhea. A 45,X/46,XY karyotype has been associated with a variety of phenotypes, ranging from the typical phenotype of Turner syndrome, to ovotesticular disorder of sex development with genital ambiguity, to a normal male phenotype with infertility.

CLINICAL MANIFESTATIONS

Typical features — The most characteristic feature of girls and women with Turner syndrome is their short stature. Other common features are a “shield” chest with widely spaced nipples, webbed neck, cubitus valgus, and Madelung deformity of the forearm. Neonates may have congenital lymphedema of the hands and feet and two or more of the following dysmorphic features: webbed neck, nail dysplasia, high-arched palate, and short fourth metacarpal. The height of patients with Turner syndrome should be plotted on growth curves specific for this disorder.

Hearing loss, hypothyroidism, and liver function abnormalities can occur as these women get older. Liver enzymes are mildly elevated in approximately 35 to 45 percent of adult patients, and improve with postmenopausal hormone therapy. Intelligence is usually within the normal range, but patients may have specific neurocognitive deficits, eg, problems with visuo-spatial organization.

Other manifestations include autoimmune diseases (including chronic autoimmune thyroiditis) and specific morphologic defects of facial development and cardiovascular, urologic, and bone structure.

Ovarian failure — Although most affected women have no pubertal development and primary amenorrhea, some develop normally and then have secondary amenorrhea, while occasionally others have no morphologic defects and achieve normal stature.

The ovaries in Turner syndrome characteristically consist of small amounts of connective tissue and no follicles or only a few atretic follicles ("streak gonads"). However, the degree of ovarian dysfunction and the extent of the defects are variable.

Thus, the consequences of X chromosome deletions are highly variable, ranging (at the extremes) from intrauterine death to normal health with normal menarche and normal reproductive function for a few years thereafter. The incidence of 45,X and 45,X/46,XX mosaic karyotypes in women with normal fertility is unknown.

Only one X chromosome is active in somatic cells after the third week of gestation. As a result, a deletion of any part of one X chromosome will affect fertility only if the normal copies of the missing gene or genes do one of the following:

●Imprint somatic cells before three weeks of gestation

●Escape inactivation so that two copies are normally required

●Are critical for oocyte development (since oocytes have two active X chromosomes)

Short stature — Short stature combined with a square appearance is the most common clinical feature of Turner syndrome. The adult height of untreated patients correlates significantly with mid-parental height (ie, the height corresponds to the average of the height percentiles of the mother and the father). Recombinant human growth hormone therapy is recommended to maximize final height.

Renal anomalies — Renal anomalies are common in patients with Turner syndrome. Congenital malformations of the urinary system are present in approximately 30 to 40 percent. The most common abnormalities are collecting system malformations (20 percent) and horseshoe kidneys (10 percent), followed by malrotation and other positional abnormalities (5 percent). Patients should undergo renal ultrasonography at the time of diagnosis and, if structural abnormalities are identified, they should be monitored yearly for urinary tract infection.

Anomalies associated with obstruction of the ureteropelvic junction can produce clinically significant hydronephrosis or pyelonephritis. Idiopathic hypertension is common in Turner syndrome, even in the absence of recognizable renal or cardiac malformations. Blood pressure should therefore be monitored carefully, and hypertension treated vigorously.

Cardiovascular disease — There is an increased risk of cardiovascular morbidity in women with Turner syndrome, presumably due to their risk of cardiovascular malformations, renal abnormalities, and hypertension. The malformations are associated with increased risks for aortic dissection and increased mortality rates. Neck webbing and increased thoracic anterior-to-posterior diameters are predictors for cardiovascular abnormalities.

The following rates of cardiac malformations were reported:

●Any malformation – 44.5 percent

●Aortic valve abnormalities (primarily bicuspid aortic valve) – 34.1 percent

●Aortic arch abnormalities (primarily coarctation) – 19.1 percent

●Systemic venous abnormalities – 8.1 percent

●Ventricular septal defects – 5.2 percent

●Pulmonary venous abnormalities – 4 percent

●Hypoplastic left heart/single ventricle – 3.5 percent

●Atrial septal defects – 1.7 percent

●Coronary artery abnormalities – 1.6 percent

Coarctation/aortic valve disease — The prevalence of cardiovascular malformations in patients with Turner syndrome is variable across studies. Approximately 30 percent have aortic valve disease, while up to 30 percent have coarctation. Patients with the relatively common anomaly of a bicuspid aortic valve are more likely to have other cardiovascular abnormalities, such as aortic arch defects. The variability among estimates could be due to differences in the age group examined, the degree of mosaicism in the population, or to technical difficulty in visualizing

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