Discussion
Rh immunization has significantly decreased the incidence of immune hydrops fetalis. Therefore it was found that the most common association with hydrops has become fetal cardiovascular abnormalities (Bellini, C et al, 2015). Which includes cardiac structural malformations, fetal, arrhythmias, high output heart failure, cardiac tumors, cardiomyopathy, myocarditis, myocardial infarction, and idiopathic arterial calcification (Knilans, T. K, et al 1995). Our patient presented with nonimmune hydrops at 36 weeks gestational age. Prenatal ultrasound detected poor cardiac contractility with no associated structural fetal anomalies. Post-natal echocardiogram showed severely decreased right and left ventricular systolic function, moderate tricuspid valve insufficiency, prominent right ventricle muscle bundle, dilated right ventricle, mild, normal left ventricle structure and size and small restrictive membranous ventricular septal defect. These findings support the pathogenicity of the right ventricular insufficiency as the most likely causative factor for the patient’s hydrops.
PKP2 (#602861) gene encodes plakophilin-2, an essential armadillo repeat protein of the cardiac desmosome, on chromosome 12p11. Molecules that contribute to desmosomes’ formation are: desmosomal cadherins, armadillo-repeat proteins, and plakophilins. Armadillo repeat protein function to link desmosomal cadherins with desmoplakin and the intermediate filament system (Hamosh, A et al, 2004). PKP2 gene alteration was found to cause disrupted intercellular connections resulting in myocyte cell death and an inflammatory repair process. They were also found to cause fibro-fatty replacement of the right ventricle myocardium, which results in dysfunctional dilated right ventricle. PKP2 pathogenesis is an example of pleiotropic gene that it is known to be associated in different inherited cardiac arrhythmias ranging from arthromogenic cardiomyopathy, Brugada syndrome, idiopathic ventricular fibrillation dilated and hypertrophic cardiomyopathy (Novelli, V et al, 2018). A study showed that several PKP2 variants could be found in high percentage of healthy controls, increasing the complexity of interpretation of the variability of this protein (Petrovski, S et al, 2013). So far more than 1000 variants have been reported in ClinVar including deletions, duplications and missense. More than 500 of those were listed as variants of unknown significance.
A study confirmed a high percentage (43 %, 25/58) of cases of ARVD/C caused by mutations in PKP2 (Dalal, D et al, 2006). In addition, earlier disease manifestation was observed in this group.
Whole Exome sequencing trio was conducted including the patient and his parents detected tow heterozygous c.2274del p(Asn759llefs*41)/ c.1688+1G>A variants in the PKP2 gene in the patient. The mother was heterozygous for the c.2274del p(Asn759llefs*41) variant and the father was heterozygous c.1688+1G>A variant. Both of those variants were listed as likely pathogenic according to the ClinVar in a heterozygous state. Those two variants were not detected in the older two healthy sibling. Both heterozygous parents cardiac evaluation including EKG and echocardiogram were unremarkable. Given the autosomal dominant inheritance of the ARVC/D-PKP2-related gene, incomplete penetrance and variable expressivity could well explain the parent’s normal phenotype (12. Leone MP, et al 2021).
Homozygous deletion of PKP2 gene resulted in a lethal defect in cardiac morphogenesis in mice. The author concluded that plakophilin 2 is important for the assembly of junctional protein and an essential morphogenesis factor and architectural component of the heart. We assumed that the bialletic inheritance of PKP2 variants in our patient has resulted in a lethal phenotype (Grossmann, K. S, et al 2004).
.