Prenatal profile of Pallister‐Killian syndrome: Retrospective analysis of 114 pregnancies, literature review and approach to prenatal diagnosis

Abstract

Pallister‐Killian syndrome (PKS) is a tissue limited mosaic disorder, characterized by variable degrees of neurodevelopmental delay and intellectual disability, typical craniofacial findings, skin pigmentation anomalies and multiple congenital malformations. The wide phenotypic spectrum of PKS in conjunction with the mosaic distribution of the i(12p) makes PKS an underdiagnosed disorder. Recognition of prenatal findings that should raise a suspicion of PKS is complicated by the fragmentation of data currently available in the literature and challenges in diagnosing a mosaic diagnosis on prenatal testing. Ultrasound anomalies, especially congenital diaphragmatic hernia, congenital heart defects, and rhizomelic limb shortening, have been related to PKS, but they are singularly not specific and are not present in all affected fetuses. We have combined prenatal data from 86 previously published reports and from our cohort of 114 PKS probands (retrospectively reviewed). Summarizing this data we have defined a prenatal growth profile and identified markers of perinatal outcome which collectively provide guidelines for early recognition of the distinctive prenatal profile and consideration of a diagnosis of PKS as well as for management and genetic counseling.

Ductus Venosus Agenesis as a Marker of Pallister–Killian Syndrome

“…Pallister–Killian syndrome (PKS), also known as 12p mosaic tetrasomy, is a multisystemic disease whose prenatal diagnosis is usually an incidental finding when performing a karyotype in cases of increased nuchal translucency or fetal anomaly [10]. According to literature, the most frequent prenatal findings are polyhydramnios (37%), long bone shortening (34%), brain anomalies (20%), congenital diaphragmatic hernia (27%) fetal macrosomia (7%) cardiac malformations (16%), genitourinary malformations (10%), polydactyly and feet anomalies (19%) and gastrointestinal malformations (10%) [9]. Analyzing each of these groups, the most frequent brain malformations reported were ventriculomegaly (71%), Dandy Walker malformation (6%) and cerebellar anomalies (12%), whilst regarding cardiac malformations the most frequent ones were left ventricular hypoplasia (29%) and anomalies in aortic and pulmonary valves (28%), among others [9].…”

“…According to literature, the most frequent prenatal findings are polyhydramnios (37%), long bone shortening (34%), brain anomalies (20%), congenital diaphragmatic hernia (27%) fetal macrosomia (7%) cardiac malformations (16%), genitourinary malformations (10%), polydactyly and feet anomalies (19%) and gastrointestinal malformations (10%) [9]. Analyzing each of these groups, the most frequent brain malformations reported were ventriculomegaly (71%), Dandy Walker malformation (6%) and cerebellar anomalies (12%), whilst regarding cardiac malformations the most frequent ones were left ventricular hypoplasia (29%) and anomalies in aortic and pulmonary valves (28%), among others [9]. Other more sporadic anomalies are: fetal hydrops (6%), cystic hygroma (7%), increased nuchal translucency (9%) and presence of sacral appendix (3%) [9,10].…”

“…PKS is an unusual genetic syndrome, with an estimated prevalence of 5.1 cases per million live births [8], and it is severe, as it usually involves serious mental retardation. Its main postnatal clinical features are moderate to severe intellectual disability/neuromotor delay, skin pigmentation abnormalities, typical facial appearance, variable association with multiple congenital malformations and epilepsy [8,9,10,11]. Though prenatal findings (including congenital diaphragmatic hernia, ventriculomegaly, congenital heart disease, polyhydramnios, and rhizomelic shortening) have been described in the literature, prenatal diagnosis is difficult as there are no distinctive or pathognomonic signs, and some of the associated malformations are hard to identify prenatally [9,10,12,13].…”

“…Though prenatal findings (including congenital diaphragmatic hernia, ventriculomegaly, congenital heart disease, polyhydramnios, and rhizomelic shortening) have been described in the literature, prenatal diagnosis is difficult as there are no distinctive or pathognomonic signs, and some of the associated malformations are hard to identify prenatally [9,10,12,13]. Regarding serum markers, neither B-HCG nor PAPP-A have demonstrated to be useful to diagnose this syndrome [9]. Prenatal diagnosis of PKS is also a challenge due to difficulties in detecting the extra iso (12p) chromosome, the variable level of mosaicism and the rapid decrease of the supernumerary marker isochromosome during amniocyte sub-culturing [9,13,14].…”

“…Regarding serum markers, neither B-HCG nor PAPP-A have demonstrated to be useful to diagnose this syndrome [9]. Prenatal diagnosis of PKS is also a challenge due to difficulties in detecting the extra iso (12p) chromosome, the variable level of mosaicism and the rapid decrease of the supernumerary marker isochromosome during amniocyte sub-culturing [9,13,14]. Here, we report a case of prenatally diagnosed PKS with DVA as the main sonographic guide sign.…”