Early-onset Marfan syndrome with a novel missense mutation: A case report

Abstract

Early-onset Marfan syndrome (eoMFS) progresses rapidly, starting during the neonatal period, causes severe clinical disease, and has a poor prognosis. The genetic abnormality associated with eoMFS is located in a so-called critical neonatal region in exons 25-26 of the fibrillin-1 (FBN1) gene. A female neonate was delivered by emergency cesarean section at 37 weeks gestation due to fetal distress with bradycardia, cyanosis, and no spontaneous breathing. On examination, the patient had multiple musculoskeletal deformities, including loose redundant skin, arachnodactyly, flat soles, and joint contractures. Echocardiography showed poor cardiac contractility with multiple valvular abnormalities. She died 13 h after birth. We identified a novel missense variant c.3218A>G (p.Glu1073Gly) in exon 26 of the FBN1 gene by targeted next-generation sequencing. A literature review revealed that arachnodactyly and aortic root dilatation in the fetus are predictive of eoMFS. However, the predictive potential of ultrasonography alone is limited. Genetic testing of the FBN1 gene restriction region associated with short life expectancy and characteristic fetal ultrasound findings could be important for prenatal diagnosis of eoMFS, postnatal management, and parental preparedness.

Learning objective: We identified a novel missense mutation located in exons 25-26 of the Fibrillin-1 gene in a neonate with early-onset Marfan syndrome (eoMFS) who died of severe early heart failure shortly after birth. This mutation was located in a narrowly defined critical neonatal region, recently reported to cause eoMFS, and its clinical profile was consistent with early-onset severe heart failure. In addition to ultrasonography, genetic analysis of this region is important for predicting prognosis in eoMFS.

Keywords: Aortic root dilatation; Arachnodactyly; Early-onset Marfan syndrome; FBN1 gene; Missense variant; Next-generation sequencing.