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).
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