Marfan syndrome in a paediatric cohort: the importance of family history

Abstract

Marfan syndrome is a rare connective tissue disorder secondary to mutations in the FBN1 gene, characterised by skeletal, ocular, and cardiovascular manifestations. We present an extensive cohort of paediatric patients with Marfan syndrome highlighting the vital importance of promptly referring paediatric first-degree relatives of Marfan syndrome paediatric patients to a tertiary hospital as our results confirm that they are at higher risk of aortic dilatation.

Marfan syndrome is the most prevalent connective tissue disorder with a prevalence of 2–3:10,000 live births. ¹ It is an autosomal dominant disorder secondary to mutations in the FBN1 gene, which encodes fibrillin-1, a key constituent of the extracellular matrix. ² Its phenotype is characterised by skeletal (pectus carinatum or excavatum, scoliosis), ocular (ectopia lentis), and cardiovascular (mitral valve prolapse, aortic dilatation or dissection) manifestations. ³ Nevertheless, aortic complications account for a substantial portion of the morbidity and mortality in these patients. ³ Its diagnosis is currently based on the revised Ghent nosology from 2010. ² Although beta-blockers are considered the standard treatment to slow down aortic complications, angiotensin receptor blockers have also been reported to be effective. ^2,4 Despite the indication for surgical aortic repair being determined by current international adult guidelines, this has not been validated in the paediatric population. ^1,5

Cases report and discussion

A retrospective observational study was conducted including all paediatric patients (aged ≤18 years) with a diagnosis of Marfan syndrome seen at our institution (April 2004–April 2022). The study was approved by our institutional Research Board and consent waived in view of the retrospective data collection. Non-normally distributed data are presented as a median (interquartile range). Categorical variables are presented as number (n) and percentages (%). Fisher’s exact test and Mann–Whitney U test were used for comparing of categorical and continuous variables, respectively. A P-value <0.05 was considered to be statistically significant. Statistical analysis was performed using Statistical Package of Social Sciences (SPSS, version 21.0, IBM).

Overall, the median age at diagnosis and of follow-up was 7.8 [3.6–13.6] and 4.4 [2.2–9.9] years, respectively. Table 1 shows the main characteristics of patients with Marfan syndrome.

Table 1. Main characteristics of patients with Marfan syndrome.

AA: ascending aorta; AV: aortic valve; BB: betablokers; IQR: interquartile range; MS: Marfan syndrome; SV: sinus of Valsalva.

Thirty-four patients (85.0%) had a confirmed genetic diagnosis, it was not available at the end of the study period in 3 (7.5%) and 3 (7.5%) fulfilled the Ghent criteria without genetic testing confirmation. ² Although not all our patients had a genetic confirmation, it is recommended due to the overlap between Marfan syndrome and other connective tissue disorders. ³ Consistent with previous reports, 25.0% (n = 10) of our patients were secondary to de novo mutations. ⁵

Twenty-two patients (55.0%) had a family history of a first-degree relative with Marfan syndrome (FH). Silverman et al reported the presence of family history in an adult first-degree relative with Marfan syndrome and one severe cardiovascular manifestation (nonischaemic cardiovascular death, history of aortic dissection, or cardiac surgery) to be a risk factor for higher aortic dilatation and decreased survival in patients with Marfan syndrome. ⁶ In our study, among the 22 patients with FH, 8 (36.4%) had a family history of a severe cardiovascular event in an adult first-degree relative. According to Silverman et al, we found a statistically significant difference between the median z-score of the sinus of Valsalva in the FH group with a severe cardiovascular event (3.4 [1.9–5.4]) compared to the one from the patients with FH but without a severe cardiovascular event (1.5 [1.1–2.7]) (p = 0.045).

Around 50-80% of the paediatric Marfan syndrome patients present progressive aortic dilatation mainly affecting at the level of the sinus of Valsalva. ⁷ This concurs with our results, where the main cardiac manifestation was the dilatation at this level (n = 23, 57.5%).

Twenty-six patients (65.0%) were under treatment: 7 (17.5%) on beta-blockers, 16 (40.0%) on angiotensin receptor blockers, and 3 (7.5%) on both. Indications for treatment were aortic dilatation (n = 20, 76.9%), left ventricle dilatation (n = 1, 3.8%), or the diagnosis of Marfan syndrome itself (n = 5; 19.2%). Three (7.5%) required cardiac surgery. One underwent aortic root replacement with valve-sparing operation (David’s procedure) (17.0 years, sinus of Valsalva 50 mm, z-score +6.6). Another underwent Bentall surgery (8.9 years, sinus of Valsalva 45 mm, z-score +11). The latter presented progressive ascending aorta dilatation and aortic dissection type A for which he was reintervened. The remaining patient required mitral valve repair due to mitral valve regurgitation and left ventricular dysfunction, and David’s procedure (11.9 years, sinus of Valsalva 38 mm, z-score +3.5). There were no deaths during follow-up.

Annual ophthalmological evaluation is recommended for prompt ectopia lentis diagnosis, which is the main ophthalmological manifestation of Marfan syndrome patients, which is in line with our results where 17 patients (42,5%) presented this feature. ² Additionally, 24 patients (60.0%) had chest deformities [pectus excavatum (n = 17; 70.8%) and pectus carinatum (n = 7; 29.2%)], and scoliosis was present in 12 (30.0%).

In conclusion, herein, we present an extensive cohort of paediatric patients with Marfan syndrome, a rare connective tissue disorder with multisystem involvement. It has been previously suggested that Marfan syndrome patients with family history of a first-degree relative with Marfan syndrome with one severe cardiovascular manifestation are at an increased risk of aortic dilatation, outcome confirmed by our results. Hence, it is paramount that paediatric patients with family history of Marfan syndrome are promptly referred to a tertiary hospital, regardless of their physical appearance, for timely diagnosis and treatment (medical and/or surgical) along with multidisciplinary surveillance. Further long-term prospective and multicentric paediatric studies are needed to confirm our findings and to better define paediatric Marfan syndrome management.