The chromosome constitution 47, XXX was first described by Jacobs et al. (1959) in a woman of average intelligence with secondary amenorrhea. Since that time, several hundred cases have been reported in the medical literature. The phenotype of infants who are prenatally diagnosed with 47, XXX is significantly different from infants who are diagnosed by newborn screening or clinical symptomatology (Robinson et al., 1992; Linden and Bender, 2002). In general, the prenatally diagnosed infants have a more normal developmental profile. This may be due to factors unrelated to the chromosomes, such as socioeconomic status and level of parental education.

The sex chromosome aneuploidies are the most common group of abnormalities found in prenatal karyotypes, with an incidence of 1 in 250 amniocenteses (Robinson et al., 1992). Despite their frequency, sex chromosome aneuploidy is rarely discussed in preprocedural genetic counseling. Thus, the finding of a fetal sex chromosome abnormality is usually not expected by the pregnant patient (Krone et al., 1975). This diagnosis prompts anxiety and ambivalence because, although the karyotype is abnormal, the phenotype of the affected child can be quite variable. Trisomy X can be associated with a normal outcome. In fact, most cases of 47, XXX are undiagnosed (Ratcliffe, 1999).

The incidence of 47, XXX is approximately 1 in 1000 at midtrimester amniocentesis (Hook and Hamerton, 1977) and 0.7 in 1000 livebirths (Tennes et al., 1975). These differences reflect different study populations and are not thought to reflect an increased perinatal mortality for 47, XXX fetuses. Using X-linked restriction fragment length polymorphisms, May et al. (1990) determined the parental origin of the extra X chromosome in 28 individuals with 47, XXX. Maternal nondisjunction was demonstrated in 26 of 28 cases. Seventy percent of these cases were due to an error in meiosis I. Thus, the etiology of trisomy X more closely resembles the autosomal trisomies. In this regard, trisomy X differs from the other sex chromosome aneuploidies, in that there is a maternal age effect. Mitotic errors do not play a significant role in 47, XXX (May et al., 1990).

In general, there is no characteristic phenotype associated with trisomy X. The overwhelming majority of fetuses with trisomy X will have normal results on sonographic examination. The diagnosis is typically made at amniocentesis for advanced maternal age. In one study, the fetal nuchal translucency measurement was above the 95th percentile in 40% of the cases with 47, XXX, 47, XYY, or 48, XXXY (Sebire et al., 1998). In rare cases, structural abnormalities of the genitourinary tract have been described. These include bilateral renal agenesis and developmental arrest of the mesonephric and paramesonephric systems (Hogge et al., 1989); ovarian dysgenesis (Figure 136-1), urinary tract malformation, meconium peritonIt is, and nonimmune fetal ascites (Spear and Porto, 1988); exstrophy of the cloaca with unilateral renal agenesis (Lin et al., 1993); and unilateral renal agenesis, hydrometrocolpos, ovarian dysgenesis, laryngeal atresia, pulmonary hypoplasia, and craniofacial anomalies (Hood et al., 1990). Because of the apparent clustering of cases with abnormalities in the genitourinary system, it has been suggested that the developing urogenital field may be affected by the presence of an extra X chromosome (Lin et al., 1993).

When the karyotype is 47, XXX, the main consideration in the differential diagnosis is whether the abnormality is present in all cells or in a fraction of the cells (mosaicism). A 46, XX/47, XXX mosaic karyotype will result in a significantly reduced likelihood of clinical symptoms (Salbenblatt et al., 1989; Robinson et al., 1992).