Klinefelter syndrome (47, XXY karyotype) is the spectrum of phenotypic features resulting from a sex chromosome complement that includes two or more X chromosomes and one Y chromosome (Figure 135-1). It results from meiotic nondisjunction occurring during gametogenesis of the egg or sperm with subsequent fertilization of an XX ovum by a Y bearing sperm, or fertilization of an X ovum by a sperm bearing both the X and Y chromosomes (Mandoki et al., 1991). There are no known predisposing factors except advanced maternal age in some, but not all, cases. The condition was first described in nine men with gynecomastia, infertility with normal Leydig cells, a normal to low 17-ketosteroid level, and a high follicle stimulating hormone level in the urine (Klinefelter et al., 1942); Schwartz and Root, 1991). It was not until 1956 that the chromosomal basis of this abnormality was appreciated by noting the presence of the Barr body on buccal smears obtained from affected patients, which represented the inactive extra X chromosome (Arens et al., 1988). The specific chromosomal abnormality reponsible for the disorder was not known until 1959.

The phenotype in Klinefelter syndrome is extremely variable and may be subtle. Most cases are never diagnosed. In general, affected males are identified by age-related clinical concerns (Table 135-1). Infant patients are identified by either prenatal cytogenetic testing for advanced maternal age or by the presence of mild genital abnormalities (Schwartz and Root, 1991). During school-age years, affected patients may be identified by the occurrence of learning disabilities and behavioral problems, whereas in adolescence, the clinical diagnosis is usually suspected from gynecomastia, a taller than average stature, and a possible delay in pubertal development. However, a large number of patients with Klinefelter syndrome are identified as adults when they present during a workup for infertility (Schwartz and Root, 1991).

A study of 34,910 newborns performed over 13 years in Arhus, Denmark, put the incidence of Klinefelter syndrome at 1 in 576 newborn male infants (Nielsen and Wohlert, 1991). 47, XXY is generally described as occurring in 1 in 500 to 1 in 800 live male births (Mandoki et al., 1991). About 7% of cases are mosaic (46, XY/47, XXY) (Bojesen et al., 2003). Other variants of Klinefelter syndrome include the karyotypes 48, XXXY, which occurs in 1 in 20,000 live male births, and the karyotype 49, XXXY, which occurs in 1 in 85,000 live male births (Kleczkowska et al., 1988). For a review of the more severe clinical manifestations of 48, XXY, the reader is referred to a study by Linden et al. (1995). In the variant Klinefelter karyotypes, it has been shown that a single parent contributes all of the extra chromosomes present.

The incidence of 47, XXY is increased in twins. In one large study of fetal karyotypes obtained at amniocentesis performed primarily for advanced maternal age, 2 cases of 47, XXY were seen in 1821 singleton fetuses. Three cases of 47, XXY were seen in 21 pairs of twins, giving an incidence of 7.1% in the twin population (Flannery et al., 1984).

Two large, population based studies using national cytogenetic registries have shown that most boys and men with Klinefelter syndrome are not clinically recognized. In the United Kingdom, Abramsky and Chapple (1997) demonstrated that 10% of 47, XXY cases are diagnosed prenatally and 26% are diagnosed in adolescence or adulthood. In Denmark, where all karyotype results are recorded in a central registry, a marked discrepancy between the prevalence of prenatally ascertained cases (153/100,000 male fetuses) and postnatally ascertained cases (40/100,000 males) was shown (Bojesen et al., 2003). Thus, only about a fourth of cases are diagnosed postnatally, which suggests that symptoms are mild.

No sonographic findings are characteristic for a fetus with Klinefelter syndrome. In a review of 35 cases of fetal omphalocele, one fetus had a 47, XXY karyotype, but this is probably unrelated (Gilbert and Nicolaides, 1987). Another study has suggested that the median nuchal translucency measurement is increased in cases of sex chromosome abnormalities (Spencer et al., 2000). In general, the fetal phenotype is extremely mild and difficult to distinguish from normal.

In cases of 47, XXY, the phenotype is not distinctly recognizable, even in fetuses studied at autopsy. In one fetus terminated at 20 weeks of gestation, the clinical features of Klinefelter syndrome noted in the fetus included an arm span less than its height, a minor ear abnormality, fifth-finger clinodactyly, and undescended testes (which is not unusual for a fetus at this point in gestation). Significantly, the testicular histology was normal (Flannery et al., 1984). Amniotic fluid testosterone levels do not differ between 46, XY and 47, XXY fetuses (Ratcliffe, 1999).

Using older data, there is a suggestion that there is a slightly increased risk of miscarriage in fetuses with Klinefelter syndrome (Simpson et al., 2003). The risk was derived by comparing the incidence of 47, XXY at amniocentesis and at birth in newborn studies. However, a more recent Danish dataset did not find any cases of spontaneous abortions or stillbirths among prenatally diagnosed cases that were not electively terminated (Bojesen et al., 2003).

Fetuses with Klinefelter syndrome are most commonly identified during amniocentesis performed for advanced maternal age, where it is the third most common chromosomal abnormality diagnosed, after trisomies 21 and 18 (Robinson et al., 1992; Linden and Bender, 2002). It is unlikely that an affected fetus will be identified on the basis of an abnormal sonographic finding. Occasionally, Klinefelter syndrome is associated with abnormalities in maternal serum screening. Reported maternal serum abnormalities include elevated lev-els of α-fetoprotein (Fejgin et al., 1990) and human chorionic gonadatropin (hCG) (Ben-Neriah et al., 1991; Barnes-Kedar et al., 1993).

The main concern regarding management of pregnancy is the parental decision whether to continue or terminate the pregnancy. One of the difficulties in this area has been the ascertainment bias that exists in the medical literature, overreporting of the more extreme phenotypic aspects of Klinefelter syndrome, and underreporting of patients who have few or no symptoms related to the condition. Ongoing studies regarding developmental outcome for children who have been prenatally diagnosed with 47, XXY suggests a milder phenotype and considerable variability in physical and psychologic development (Robinson et al., 1992; Linden and Bender, 2002). Approximately 30 to 55% of well-informed couples opt to continue their pregnancy after an antenatal diagnosis of 47, XXY (Holmes-Siedle et al., 1987; Lancet editorial, 1988; Robinson et al., 1992; Meschede et al., 1998; Marteau et al., 2002). The most significant factors that influence the decision to terminate the pregnancy include the presence of sonographic abnormalities (Christian et al., 2000; Hamamy and Dahoun, 2004) and the medical specialty of the person providing the genetic counseling following the karyotype results. In general, the pregnancy is more likely to be continued if the counseling is provided by a geneticist instead of an obstetrician (Hall et al., 2001; Marteau et al., 2002). Robinson et al. (1992) suggest that the following information be given to prospective parents during prenatal counseling for a fetal diagnosis of 47, XXY: