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.