Pallister–Killian syndrome

PKS is commonly diagnosed by detecting its causative sSMC as defined by identifying the overexpression of its genetic material. This method has detected the sSMC and therefore diagnosed a fetus as having PKS based on genomic analyses of fetal skin fibroblasts, placenta chorionic villi, cells isolated from the amniotic fluid,[4] fibroblasts isolated from the fetus's umbilical cord,[5] and cells isolated from the fetus's umbilical cord blood.[6] PKS can also be diagnose using fetal ultasound imaging methods. Ultrasound imaging in PKS commonly find fetuses that are too large for their gestational age, contain polyhydramnios (excess amniotic fluid in their amniotic sacs), and have rhizomelic limbs (shortening of the proximal part of the limbs). Less commonly, the imaging evidences diaphragmatic hernias and/or various other major PKS structural malformations. In most cases, however, the ultrasound findings are not diagnostic of PKS. Furthermore, ultrasound diagnoses is best applied in the second or third pregnancy trimester when structural anomalies are more clearly defined and detectable.[7]

Because the prenatal diagnosis of PKS using the methods just cited is difficult, often indecisive, and/or best employed later in a woman's pregnancy, prenatal cell-free DNA screening (cfDNA screening), also known as noninvasive prenatal screening, has been used to diagnose PKS. This method can diagnose PKS in 10 week and older fetuses. In cfDNA screening, DNA from a mothers blood is extracted and screened for the presence of specific chromosome abnormalities such as those associated with the Down syndrome, Patau syndrome (also termed trisomy 13[8]), and Edwards syndrome (also termed trisomy 18[9]). (Small amounts of a fetus's DNA escapes through the placenta to circulate in the mothers blood.[10]) A genome-wide association study[11] done in China used genome-wide cfDNA analyses to diagnose various chromosome-related disorders including PKS. The study scanned the DNA in the blood of 29,007 pregnant women and found three cases with abnormal amount of DNA originating from the entire p-arm of chromosome 12. All three cases were confirmed to have a fetus with PKS. Two of these cases were missed by chromosomal microarray analysis of the placenta and chorionic villi. However, the study did not define the rate of false negative cases, i.e. negative results in women actually carrying a fetus with PKS. While further studies are required, this method may turn out to be a critically useful addition for the prenatal detection of PKS, particularly during early pregnancies for the purpose of pregnancy options counseling.[12]

The postnatal diagnosis of PKS is strongly suggested or indicated in most cases based on finding the key defects of PKS in an individual on physical examination and various radiography, ultrasound, and related methods.[3] However, some individuals with this syndrome do not have a sufficient number of these defects or have a set of defects that are also compatible with other birth defect disorders such as Fryns syndrome, trisomy 12p,[13] and Sifrim-Hitz-Weiss syndrome (also termed CHD4 Neurodevelopmental Disorder[14]).[3] The diagnosis can be confirmed in these cases as well as in all cases of PKS by detecting its sSMC using special methods. This sSMC has been successfully detected (>90% of confirmed cases) in the DNA extracted by a buccal swab taken from the inside of an individual's cheek or the DNA extracted form an individual's cultured skin fibroblasts, i.e. fibroblasts from a skin biopsy grown in a laboratory for at least several days. The sSMC in these tissues or cells is identified by multiplex ligation-dependent probe amplification (i.e. MLPA)[3] or microarray-based comparative genomic hybridization (i.e. array CGH).[2] Because of mosaicism, testing an individual's circulating blood lymphocytes only rarely detects (i.e. gives mostly false negative results) in true PKS cases.[3][15][16]