Growth-promoting strategies in Turner's syndrome.

Abstract

T syndrome is an important cause of short stature in girls and primary amenorrhea in young women. First described in 1930 by Otto Ullrich (1) in Germany and subsequently in 1938 by Henry Turner (2) in the United States, it is the most common sex-chromosome abnormality in females, affecting an estimated 3% of all females conceived. However, only 1 in 1000 embryos with a 45,X karyotype survives to term, accounting for about 15% of all spontaneously aborted fetuses (3). Thus, the incidence of the loss of all or part of an X chromosome varies from 1:2000 to 1:5000 in liveborn phenotypic females (3–8). In a recent prospective study of 17,038 newborn girls born in Aarhus, Denmark, nine karyotypes consistent with Turner’s syndrome were detected, for an incidence of 1:1893 live female births (8). There are currently estimated to be from 50,000 to 75,000 girls and women with Turner’s syndrome in the United States alone (9). Molecular studies have shown that the maternal X is retained in two thirds of patients with Turner’s syndrome and the paternal X in the remaining one third (10, 11). More than half of all patients with Turner’s syndrome have a mosaic chromosomal complement, (e.g., 45,X/46,XX) (12–14). Mosaicism with a normal cell line in the fetal membranes may be necessary for adequate placental function and fetal survival (15, 16). The identification of mosaicism depends directly on the method of ascertainment. It varies from 34% with conventional cytogenetic techniques to 60% with fluorescence in situ hybridization techniques to 74% in a study in which RT-PCR assays were used (17). Many patients with Turner’s syndrome lack only part of one X chromosome, and the Turner’s syndrome phenotype can be seen with a variety of structural abnormalities, such as rings, isochromosomes, or terminal deletions. A rare but very informative class of Turner’s syndrome includes patients who have deletions of the Y chromosome that remove the testes determining gene SRY. These individuals develop as females. Based on this finding and the fact that males require only one X chromosome for normal development, Ferguson-Smith (13) hypothesized more than 30 yr ago that copies of Turner’s syndrome genes are also present on the Y chromosome. Specific localization of Turner’s syndrome genes proved elusive until recently when one group successfully demonstrated that a gene located in the pseudoautosomal region (PAR 1) at the tip of the short arm of the X chromosome (Xp 22.3) is related to short stature in Turner’s syndrome. This pseudoautosomal deletion encompassing a novel homeobox gene, SHOX (short stature homeobox containing gene on the X chromosome), is associated with short stature in Turner’s syndrome and also with some cases of idiopathic short stature (18). Independently, the same gene was identified by a different group and was termed pseudoautosomal homeobox-containing osteogenic gene (PHOG). The SHOX gene encodes a homeodomain-containing protein that most likely functions as a transcription regulator. Dosage sensitivity is a common feature of such regulatory genes in the pseudoautosomal region. They escape X inactivation and have functional homologs on the Y chromosome (19–21). It is, therefore, hypothesized that haploinsufficiency of the SHOX gene is the underlying cause of growth impairment in patients with Turner’s syndrome (18, 22). The tips of the short arms of the chromosomes X and Y are logical sites for Turner’s syndrome genes, as sex chromosomes undergo meiotic recombination within the pseudoautosomal 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’s 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 pseudoautosomal region are present. It is not surprising that these patients attain normal stature despite the presence of features consistent with Turner’s syndrome. A 700-kb interval in the pseudoautosomal region is, therefore, the most probable site for a Turner’s syndrome stature locus, and SHOX is an excellent candidate for a Turner syndrome stature gene (18, 23). Studies that have examined the relationship between the chromosomal and karyotypic abnormalities and clinical findings in patients with Turner’s syndrome have been disappointing.