Introduction
Hydrops fetalis occurs in approximately 1 to 1700 to 3000 pregnancies. It is defined as an abnormal fluid accumulation in two or more fetal compartments, including ascites, pleural effusion and skin edema detected in prenatal ultrasound. The widespread use of anti-D immune globin has rendered the majority of cases to be non-immune in nature (NIHF) (Almomani, R, etal 2016).
Cardiovascular etiologies, including structural cardiac anomalies, cardiac dysrhythmias, cardiac tumors, cardiomyopathy and myocarditis are the leading causes for NIHF. Cardiomyopathy in particular has been described in several genetic disorders in association with non-immune hydrops e.g. mitochondrial disorders such as Barth syndrome, RASopathies such as Noonan and Costello syndrome, lysosomal storage disorders such as mucopolysaccharidosis type VII and other single gene disorders (Bellini, C, et al 2015). Severe cardiomyopathy in association with NIHF has been described in biallelic truncating ALPK3 mutation (Almomani, R, etal 2016).
Here, we describe a severe congenital cardiomyopathy that resulted in NIHF in a male infant born to a healthy non-consanguineous Saudi Arab young couple. Whole-exome sequencing detected two heterozygous variants in the PKP2 gene; c.1688+1G>A and c.2274del p(Asn759llefs*41) (Fressart, V et al, 2010) )variants were inherited from the father and the mother respectively. No other variants that could have explained the patient phenotype were detected. The cardiac evaluation including EKG and echocardiogram of the parents was unremarkable.
PKP2 encodes for plakophilin-2, an essential armadillo repeat protein of the cardiac desmosome plaque and cell nucleus. Heterozygous alteration in PKP2 gene is known to cause arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) #609040 (Gerull, B et al, 2004. The estimated prevalence of ARVC/D is 1:2,500 to 1:5,000 (Burke, A. P et al, 2021). Homozygous deletion of PKP2 deletion was described in two siblings with a severe noncompaction cardiomyopathy starting prenatally and leading to rapid cardiac failure (Ramond F et al., 2017), (Katanyuwong P et al 2022)
In addition, Balletic inheritance of PKP2 variant was reported in children presenting with acute viral myocarditis (Belkaya, S et al 2017). Hypoplastic left heart syndrome (15. Verhagen JMA,et al 2018)
A homozygous missense c.C2519Tp.A840V & compound heterozygous c.T2062C p.D829N/c.G2485Ap.D829N unreported variants were detected in those patients retrospectively. The author hypothesized that acute myocarditis is more commonly related to defect to cardiac protein structure and common viral infections merely and indirectly destabilize inherently vulnerable hearts
Our present case the supports the severe phenotype of the biallelic inheritance of PKP2 cardiac disease and extends its clinical spectrum.