Microdeletion of 16p11.2 associated with endocardial fibroelastosis

2010-09-01 21:49:49

American Journal of Medical Genetics Part A; 2010 Sept; 152(9):2383-86

Surasak Puvabanditsin, Michael S. Nagar, Meera Joshi, George Lambert, Eugene Garrow, and Erik Brandsma


Endocardial fibroelastosis (EFE) was first described by Weinberg and Himmelfarb [1943] and is characterized by a porcelain-like thickening of the ventricular endocardium. It presents as unexplained heart failure in infants and children; with most patients progressing to end-stage heart failure and death [Nield et al., 2002]. With improvement in prenatal ultrasonography examination, EFE can be suspected in utero on the basis of ventricular enlargement, poor ventricular contractility, and marked echodensity of the endocardial surface. Although the etiology of EFE is poorly understood, it is conventionally classified into two types: congenital (primary) and acquired (secondary). The congenital type is usually sporadic, but may be inherited as an autosomal recessive (EFE1) or X-linked (EFE2) genetic trait [Sjoberg et al., 2007]. Array comparative genomic hybridization (array CGH) has revolutionized the cytogenetic testing available for patients with dysmorphic features and multiple anomalies leading to the discovery of many novel microdeletions. 16p11.2 microdeletion has recently been detected
by array CGH [Ghebranious et al., 2007] and is associated with autism spectrum. In contrast, we report on a case of 16p11.2 deletion associated with EFE.

The mother was a 21-year-old, gravida 2, para 1 woman whose pregnancy had been normal until 35 weeks' gestation when a fetal sonogram showed cardiac abnormalities. A fetal echocardiogram at 38 weeks' gestation showed massive cardiomegaly with cardiothoracic ratio of approximately 0.74. The right ventricle was severely dilated, but still contracting. The left ventricle (LV) was slightly enlarged; the LV wall was hypertrophic and trabeculated and barely contractile. The RV outflow tract wrapped around the LV. The pulmonary valve annulus was dilated and pulmonary valve tissue was not identifiable. Aortic and ductal arches were not visualized. There was severe pulmonary parenchymal hypoplasia. Mild ascites was noted. The provisional prenatal diagnoses were a primary dilated cardiomyopathy or an absent pulmonary valve syndrome. Due to massive cardiomegaly and virtual absence of lung tissues, the parents decided against aggressive intervention. A repeat cesarean was performed at 39 weeks' gestation; a female infant weighing 3,055g was delivered. Apgar scores were 5 and 5 at 1 and 5?min, respectively. Chest X-ray showed massive cardiomegaly. Comfort care was initiated after delivery; the infant died at 3.5hr of age.

Autopsy showed a dilated right ventricle and small left ventricle. The heart weighed 50 g (normal 19.84.8 g). The endocardium, thickened bilaterally, was lined with a white porcelain-like layer that was consistent with EFE (Fig. 1). The diagnosis was confirmed by microscopic examination (Fig. 2). The right ventricle showed more severe EFE than the left. The inflow/outflow tracts of the heart were normal; the heart valves were normal. The ductus arteriosus and
foramen ovale were patent. Viral tissue cultures of lung and heart were negative. PCR for parvovirus B19 on the heart and lung tissues was negative. TORCH, enterovirus, adenovirus and parvovirus antibodies (IgG and IgM) were negative. A comparative genomic hybridization array analysis (aCGH) of a peripheral blood sample obtained before death revealed a deletion of chromosome 16 (517kb) involving 8 oligonucleotides within 16p11.2 (Fig. 3). The findings were confirmed using a FISH probe (RP11-279M12, Empire Genomics) within the deleted region. aCGH or FISH for the deletion were not performed for the parents.

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