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.

Neonatal Marfan syndrome (nMFS) is a rare condition characterized by severe phenotype and poor prognosis. nMFS is caused by mutations in a specific region of the fibrillin 1 gene (FBN1). Prompt recognition of typical signs of neonatal presentation, such as characteristic facial anomalies with senile appearance, arthrogryposis, and campto-arachnodactyly, is fundamental for performing an early cardiological examination. This usually reveals rapidly progressive cardiovascular disease due to severe atrioventricular valve dysfunction. Herein, we report the case of an early-onset cardiac failure in a neonate with Marfan syndrome, with a brief review of the literature of cases with cardiac involvement in neonatal age. Clinical exome sequencing identified the novel heterozygous de novo missense variant c.3152T > G in FBN1 gene (NM_000138.4), causing the aminoacidic change p.Phe1051Cys. Phenotype-genotype correlation led to a multidisciplinary diagnostic and management workflow. The prompt recognition of a typical phenotype such as that of Marfan syndrome should lead to a detailed evaluation and close follow-up of cardiac morphology and function. Indeed, multi-disciplinary evaluation based on genotype-phenotype correlations of nMFS cases is essential to finding out the best medical and surgical approach, predicting the relevant impact on patient prognosis, and adequately counseling their families.

Fibrillin-1 and fibrillin-2, encoded by FBN1 and FBN2, respectively, play significant roles in elastic fiber assembly, with pathogenic variants causing a diverse group of connective tissue disorders such as Marfan syndrome (MFS) and congenital contractural arachnodactyly (CCD). Different genomic variations may lead to heterogeneous phenotypic features and functional consequences. Recent high-throughput sequencing modalities have allowed detection of novel variants that may guide the care for patients and inform the genetic counseling for their families. We performed clinical phenotyping for two newborn infants with complex congenital heart defects. For genetic investigations, we employed next-generation sequencing strategies including whole-genome Single-Nucleotide Polymorphism (SNP) microarray for infant A with valvular insufficiency, aortic sinus dilatation, hydronephrosis, and dysmorphic features, and Trio whole-exome sequencing (WES) for infant B with dextro-transposition of the great arteries (D-TGA) and both parents. Infant A is a term male with neonatal marfanoid features, left-sided hydronephrosis, and complex congenital heart defects including tricuspid regurgitation, aortic sinus dilatation, patent foramen ovale, patent ductus arteriosus, mitral regurgitation, tricuspid regurgitation, aortic regurgitation, and pulmonary sinus dilatation. He developed severe persistent pulmonary hypertension and worsening acute hypercapnic hypoxemic respiratory failure, and subsequently expired on day of life (DOL) 10 after compassionate extubation. Cytogenomic whole-genome SNP microarray analysis revealed a deletion within the FBN1 gene spanning exons 7-30, which overlapped with the exon deletion hotspot region associated with neonatal Marfan syndrome. Infant B is a term male prenatally diagnosed with isolated D-TGA. He required balloon atrial septostomy on DOL 0 and subsequent atrial switch operation, atrial septal defect repair, and patent ductus arteriosus ligation on DOL 5. Trio-WES revealed compound heterozygous c.518C>T and c.8230T>G variants in the FBN2 gene. Zygosity analysis confirmed each of the variants was inherited from one of the parents who were healthy heterozygous carriers. Since his cardiac repair at birth, he has been growing and developing well without any further hospitalization. Our study highlights novel FBN1/FBN2 variants and signifies the phenotype-genotype association in two infants affected with complex congenital heart defects with and without dysmorphic features. These findings speak to the importance of next-generation high-throughput genomics for novel variant detection and the phenotypic variability associated with FBN1/FBN2 variants, particularly in the neonatal period, which may significantly impact clinical care and family counseling.

Neonatal Marfan syndrome is a rare disease with mortality in the first year of life reported as high as 95% predominantly due to progressive heart failure from valvar regurgitation and cardiomyopathy. Multisystem involvement and uncertain prognosis have historically precluded transplant candidacy, and current management options are of limited success. We present a baby girl with a postnatal diagnosis of neonatal Marfan syndrome who at 1 year of age underwent mitral valve and tricuspid valve repair with postoperative profound left ventricular and moderate right ventricular dysfunction necessitating biventricular assist device (BiVAD) support and subsequent heart transplant. A number of noncardiac issues persisted in our patient; however, she enjoyed a good quality of life for the initial 3 years posttransplant. Unfortunately, she subsequently developed rapidly progressive coronary allograft vasculopathy (CAV) with progressive deterioration in function and cardiac arrest. To our best knowledge, this is only the second case of neonatal Marfan syndrome to undergo heart transplant reported in the literature and the first with BiVAD support as a bridge to candidacy. This is also the first case of neonatal Marfan syndrome associated with intragenic duplication. This case though demonstrating that earlier listing, ventricular assist device (VAD) support and even primary transplant as treatment in neonatal Marfan syndrome should all be considered viable options but also portends a cautionary tale given the spectrum of comorbidities in this rare and severe disorder.