Tetrasomy 12p is a multiple congenital anomaly syndrome characterized by the tissue-specific presence of a marker chromosome in fibroblasts, but not lymphocytes, of affected patients. The clinical symptoms associated with this condition were first recognized in 1977, when Pallister described two adults, aged 19 and 37, who had profound retardation, severe hypotonia, coarse facial features, and pigmentary abnormalities. Both of these patients had an extra chromosome that was identified as a probable isochromosome of the short arm of chromosome 12 (Pallister, 1977). Independently, Teschler-Nicola and Killian (1981) reported a 3-year-old with severe mental retardation, dysmorphic facies, and sparse, dystrophic hair. Buyse and Korf (1983) were the first to suggest that these two seemingly disparate clinical presentations actually represented different manifestations of the same syndrome. The discrepancy between the two was explained by the fact that the isochromosome 12p was demonstrable in fibroblasts but not lymphocytes from affected patients. The interesting and unique aspect of this syndrome is that mosaicism exists for the chromosomal abnormality, and diagnosis usually depends on performing a chromosome analysis on amniocytes or fibroblasts from a skin biopsy.

From the prenatal perspective, tetrasomy 12p is usually diagnosed in one of two ways: either it is a karyotype abnormality found at amniocentesis performed for advanced maternal age (32% of cases) or it is detected when karyotyping is performed because fetal anomalies have been detected on sonography (52% of cases) (Wilson et al., 1994; Doray et al., 2002). Advanced maternal age is known to be a risk factor for the development of the isochromosome 12p. In a review of 30 case reports of Pallister–Killian syndrome, Wenger et al. (1988) found that the average age of the mothers of affected patients was 30 years. It is currently thought that there is an initial nondisjunctional event that results in trisomy 12. This is then followed by a centromeric misdivision at meiosis I or II (Struthers et al., 1999). The abnormal extra isochromosome is progressively lost in vivo during embryogenesis and in vitro during tissue culture. This hypothesis has been proven in several cases using molecular markers (Cormier-Daire et al., 1998; de Ravel et al., 2004).

The diagnosis of tetrasomy 12p is made by karyotype (Figure 138-1). The extra chromosome in this syndrome was originally thought to be derived from the long arm of chromosome 21 based on similarities in the cytogenetic banding patterns between the short arm of chromosome 12 and the long arm of chromosome 21 (Zhang et al., 1989). Identification of the marker chromosome as 12p was initially based on the twice-normal expression of the lactate dehydrogenase-B (LDH-B) isoenzyme gene, which maps to chromosome 12. Normal levels of superoxide dismutase 1 (SOD-1), which maps to chromosome 21, ruled out an increased dosage effect from extra copies of chromosome 21 (Gilgenkrantz et al., 1985). Fluorescence in situ hybridization (FISH) studies using DNA markers specific to the short arm of chromosome 12 have now definitively identified the marker chromosome as the short arm of chromosome 12 (Tejuda et al., 1992; Larramendy et al., 1993; Ohashi et al., 1993; Butler and Dev, 1995). The ability to detect the isochromosome 12p is affected by the tissue type studied, the patient’s age (fetal versus infant versus adult) and the in vitro age of the cells (Priest et al., 1992). Peripheral blood lymphocytes are continually dividing, and it has been hypothesized that they lose the extra chromosome with their frequent divisions. In contrast, fibroblasts obtained from a skin biopsy normally cycle less frequently. In addition, a time-dependent in vitro selection occurs against cells that contain the isochromosome. In one study, the percentage of cells containing the isochromosome went from 100% to 20% after only five passages in tissue culture (Speleman et al., 1991). Detection of the isochromosome 12p may be difficult in peripheral blood lymphocytes, although the marker has been seen in bone marrow aspirates obtained from newborns (Ward et al., 1988). Several authors have suggested the use of FISH analysis to detect the presence of the extra chromosome 12 short arm interphase nuclei as opposed to metaphase chromosomes (Reeser and Wenger, 1992; Larramendy et al., 1993).

The incidence of Pallister–Killian syndrome or tetrasomy 12p is unknown. Tetrasomy 12p is the most frequent autosomal tetrasomy in humans (Bresson et al., 1991). The disorder is being increasingly recognized in clinical medicine.

The sonographic findings for fetuses with tetrasomy 12p are summarized in Table 138-1. The most consistent prenatal findings include polyhydramnios, short femurs, and diaphragmatic hernia (Figure 138-2) (Priest et al., 1992; Wilson et al., 1994). Wilson et al. reviewed 15 cases of tetrasomy 12p diagnosed prenatally. In six of the cases that were ascertained by amniocentesis performed for advanced maternal age, only one had fetal anomalies detected between 16 and 18 weeks of gestation. In the cases that were ascertained by the presence of fetal structural anomalies, the gestational age was more advanced, between 16 and 32 weeks (Wilson et al., 1994). The extensive range of sonographic findings described varies from normal to a large diaphragmatic hernia with shift of the heart to right side of the chest (see Chapter 37). Additional sonographic findings reported include congenital heart disease (Wilson et al., 1994) and increased cisterna magna, suggesting agenesis of the vermis or cerebellar hypoplasia (Gilgenkrantz et al., 1985; McLean et al., 1992). An additional clinical finding in fetuses with Pallister–Killian syndrome is hypertelorism. Many fetuses with tetrasomy 12p also have nuchal edema or other hydropic changes (Figure 138-3). In 2002, Doray et al. summarized the existing literature on 63 prenatally diagnosed cases of Pallister–Killian syndrome (Doray et al., 2002). Sonographic abnormalities were described in 31 cases. The three most commonly found abnormalities were: polyhydramnios (26/31, 84%), diaphragmatic hernia (5/31, 16%), and rhizomelic micromelia (3/31, 10%). Other anomalies detected at a frequency of less than 10% included: hydrops fetalis, cystic hygroma, increased nuchal translucency measurement (see Langford et al., 2000), fetal overgrowth, ventriculomegaly, dilated cavum pellu-cidum, absent stomach visualization, and presence of a sacral appendix. Importantly, intrauterine growth restriction has never been described in this syndrome.