Genotype–Phenotype Correlations, Treatment, and Prognosis of Children With Early‐Onset (Neonatal) Marfan Syndrome

TL;DR

This study examines the genetic and clinical factors affecting survival in children with early-onset Marfan syndrome, a rare and severe condition marked by heart valve issues.

Contribution

The study identifies genetic variants and surgical timing as key factors influencing survival in early-onset Marfan syndrome.

Findings

Survival is better in individuals with single amino acid substitutions or small deletions compared to those with large deletions.

Cardiovascular surgery at an older age (13 months) is associated with better survival than surgery at younger ages (2 months).

Most deaths occur before 5 months of age, highlighting the critical early period for intervention.

Abstract

Early‐onset Marfan syndrome (eoMFS) is a severe and rare form of Marfan syndrome characterized by severe atrioventricular valve insufficiency developing before or shortly after birth. It is unclear which factors (interventions and/or genotype) influence survival. Forty‐one individuals with eoMFS with a fibrillin‐1 gene (FBN1) variant in exon 24–32 (CRCh37) were included. At the last follow‐up, 14/41 (34%) were alive (8 months‐18 years) and 27/41 (66%) were deceased. Median age of death was 1 month and 88% of the deaths occurred before 5 months of age. More individuals alive past the age of 16 months versus those who were deceased before that age had undergone cardiovascular surgery at an older age (13 months, range 3–72, vs. 2 months, range 2–2, p = 0.03). Survival was better in those with single amino acid substitutions/small in‐frame deletions than in those with large in‐frame deletions (p = 0.007), but variants involving a cysteine substitution in an EGF‐like domain versus those involving other amino acids did not significantly influence survival. EoMFS ranges from a (pre‐)neonatal life‐threatening disorder to a disorder with enhanced survival, creating a window for cardiovascular surgery. Individuals with single amino acid substitutions/small in‐frame deletions had better survival compared to those with variants significantly impacting exon 24–32 length.

Early‐onset Marfan syndrome (eoMFS) is a rare disorder with atrioventricular valve insufficiency being the most severe symptom. We propose to regard eoMFS as a spectrum, ranging from a severe disorder life‐threatening already before or immediately after birth, to a disorder with a better survival rate, creating a window for atrioventricular valve surgery.

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