Prenatal diagnosis of Pallister-Killian syndrome using cord blood samples

Abstract

Background: Pallister-Killian syndrome (PKS) (OMIM:#601803) is a rare sporadic genetic disorder characterized by multi-malformations which is caused by the presence of the extra isochromosome 12p. PKS is featured by the tissue-limited mosaicism of the isochromosome 12p [i(12p)]. There were a wide spectrum of prenatal ultrasound findings of PKS, which made it difficult to be found in first or second trimester. Polyhydramnios, diaphragmatic hernia, and rhizomelic limb shortening were the most common prenatal ultrasound abnormalities in PKS. This study retrospectively analyzed the ultrasound findings and molecular cytogenetic results of four PKS fetuses diagnosed by using cord blood samples.

Results: The ultrasound anomalies of four PKS fetuses are described as follows: fetal macrosomia, cerebral ventriculomegaly, increased NT thickness, rhizomelic limbs shortening, polyhydramnios. Biparietal diameter (BPD), head circumference (HC), abdominal circumference (AC), femur length (FL) measurements were above the mean in three fetuses,while one fetus showed rhizomelic limbs shortening. Combined with this study and previous literature, polyhydramnios was the most frequent anomaly observed in prenatal ultrasound examination of PKS, which accounted for 48% (94/194). Fetal macrosomia was present in 15% (29/194), cerebral ventriculomegaly in 13% (25/194), thickened nuchal fold in 9% (18/194), rhizomelic limbs shortening in 26% (51/194). I(12p) was found in the karyotype analysis of cultured cord blood lymphocytes and the mosaic ratios ranged from 2 to 5%. Single nucleotide polymorphisms array (SNP-array) results suggested that the whole short arm of chromosome 12 was duplicated with 2~3 copies. Fluorescence in situ hybridization (FISH) was performed to confirm the results of karyotype and SNP-array.

Conclusions: In case non-specific indicators such as fetal macrosomia, polyhydramnios and rhizomelic limbs shortening are observed meanwhile in prenatal ultrasound, targeted detection of PKS should be considered. In the prenatal diagnosis of PKS, the combination of SNP-array and FISH with conventional karyotype are the key to seek i(12p) and for precise diagnosis.

Keywords: Cord blood; Isochromosome 12p; Pallister-Killian syndrome; Prenatal diagnosis; Ultrasound findings.

Fig. 1

Ultrasound image of 4 fetuses with PKS. a: 2 of 4 fetuses’ biparietal diameter and head circumference were large for gestational age and (b) polyhydramnios; c: Besides mild polyhydramnios, fetus2’s left ventricle approximate to dilatation. d: Fetus4 has hydropic forehead and (e) shorten length of humerus and femur. f: There are no sinificant positive characteristics in all the fetuses’profiles of 3D ultrasound images

Fig. 2

Fetal biometry charts of fetal growth based on INTERGROWTH-21st International Standards for Fetal Growth (v1.6.4). Biparietal diameter, head circumference, abdominal circumference and femur length measurements were above the mean in three fetuses, while fetus4 showed rhizomelic limbs shortening. a: Z-scores and centile of head circumference. b: Z-scores and centile of biparietal diameter. c: Z-scores and centile of abdominal circumference. d: Z-scores and centile of femur length

Fig. 3

a: GTG-banding karyotype of PKS fetus in cord blood lymphocytes. Red arrow shows a supernumerary isochromosome 12p. b: Metaphase FISH using 12p telomere probe labeled green and 16 centromere probe labeled orange. Blue arrows show the normal chromosome 12. White arrows show the chromosome 16. Red arrow shows the isochromosome 12p. c: SNP-array analysis of uncultured cord blood. Blue arrow shows the log2 ratio. Red arrow shows the lines of copy number variants of 12p were between 2 and 3