Prenatal diagnosis of Pallister‐Killian syndrome and literature review

Abstract

Pallister‐Killian syndrome (PKS) is a rare sporadic genetic disorder usually caused by mosaicism of an extra isochromosome of 12p (i(12p)). This retrospective study analysed the prenatal ultrasound manifestations and molecular and cytogenetic results of five PKS foetuses. Samples of amniotic fluid and/or cord blood, skin biopsy and placenta were collected. Conventional karyotyping and single nucleotide polymorphism array (SNP array) were performed on all the amniotic fluid or cord blood samples. Copy number variants sequencing (CNV‐seq) and fluorescence in situ hybridization (FISH) were also used for the validation for one foetus. All the five foetuses were from pregnancies with advanced parental age. Two foetuses involved structural abnormalities and one foetus had only soft markers, all of which included increased nuchal translucency. The rest two foetuses had normal ultrasounds in the second trimester, which has rarely been reported before. The karyotype revealed typical i(12p) in four cases and a small supernumerary marker chromosome consisting of 12p and 20p in the remaining one case. The proportion of cells with i(12p) ranged from 0 to 100% in cultural cells, while SNP array results suggested 2−4 copies of 12p. For one foetus, metaphase FISH showed normal results, but the interphase FISH suggested cell lines with two, three and four copies of 12p in the amniotic fluid. Advanced parental age may be an important risk factor for PKS, and there were no typical ultrasound manifestations related to PKS. A combination of karyotype analysis and molecular diagnosis is an effective method for the diagnosis of PKS.

Underlying genetic etiologies of congenital diaphragmatic hernia

“…8,49,50 The ability to perform array-based CNV analyses on uncultured samples can also result in improved detection rates for mosaicism when compared to techniques that require cells to be grown in culture. 54,55 Given its relatively low resolution, the need to culture cells, and the time required for manual scoring, chromosome analysis-which involves the generation of a karyotype, or picture of the number and visual appearance of the chromosomes in a cell-is not considered a first-line test for most cases of CDH. However, chromosome analysis is considered the test of choice for determining if a fetus has Note: + CDH is a relatively rare feature of this syndrome with an incidence estimated at <10% or, for less extensively characterized syndromes, CDH is not generally considered to be a component of the syndrome.…”

“…Array‐based CNV analysis—often referred to as chromosomal microarray analysis (CMA)—with its relatively fast turnaround time, is the test of choice for identifying the location and extent of CNVs in isolated and non‐isolated cases of CDH 8,49,50 . The ability to perform array‐based CNV analyses on uncultured samples can also result in improved detection rates for mosaicism when compared to techniques that require cells to be grown in culture 54,55 …”

“…56 Similarly, fluorescent in situ hybridization (FISH) is not a first-line test, but may be employed if there is a need to rapidly obtain evidence in support of the presence of a chromosomal abnormality that would change medical management, to test for a previously defined familial cytogenetic anomaly, or as an adjunct test when mosaicism is suspected. 54 Since sequence variants can also cause both isolated and nonisolated CDH, the genetic evaluation of a fetus with CDH cannot be considered complete unless it includes a screen for these variants.…”

“…However, chromosome analysis is considered the test of choice for determining if a fetus has Down syndrome due to trisomy 21 or a Robertsonian translocation affecting chromosome 21, and can be used to detect balanced chromosomal anomalies that cannot be detected by array‐based CNV analysis 56 . Similarly, fluorescent in situ hybridization (FISH) is not a first‐line test, but may be employed if there is a need to rapidly obtain evidence in support of the presence of a chromosomal abnormality that would change medical management, to test for a previously defined familial cytogenetic anomaly, or as an adjunct test when mosaicism is suspected 54 …”

Molecular and cytogenetic analysis of small supernumerary marker chromosomes in prenatal diagnosis

“…Two markers of our study were i(12p). Cases with i(12p) are known to be associated with Pallister–Killian syndrome, which has highly variable phenotypes involving multiple systems [ 14 ]. Facial dysmorphism, developmental delay, mental retardation, and hypotonia were observed in all i(12p) cases in ChromosOmics database.…”