MFS is a multiorgan disorder affecting eyes, skeleton, heart and arteries, dura and lungs; it is notable for its phenotypic variability in age at onset, organ involved and severity of clinical manifestation, both among and within affected families.

MFS is diagnosed according to the revised Ghent criteria. In 2010 the Ghent Criteria were updated adding genetic testing of FBN1 and the presence of a causative FBN1 variant as key criteria in the diagnosis of MFS besides major clinical features as aortic root dilatation and ectopia lentis [10].

Though the use of revised Ghent Criteria improves the diagnostic yield of MFS, in young children the diagnosing MFS is still very challenging as some of its clinical manifestations are age dependent.

Our patient satisfies the criteria showing aortic root dilatation and causal mutation of FBN1 gene. He also presents a Systemic Score of 3: plain flat foot (1 points); peculiar facial anomalies with dolichocephaly, down-slanting palpebral fissures, malar hypoplasia and retrognathia (1 point) and MVP (1 point). Moreover, arachnodactyly is evident in both hands and feet.

Aortic root dilatation, initially occurring at the sinuses of Valsalva, is the main cardiovascular manifestation of MFS, which can lead to life-threatening sequelae (i.e. aortic dissection).

The reported prevalence in young children with MFS varies among studies from 50 to 83% and increase with time. Aburawi et al. estimated an aortic root dilatation prevalence of 35% at 5 years [16]. In our patient, aortic dilatation was described at 3 years of age, while the previous echocardiography at 16 months of life was normal.

In our report, WES analysis revealed a de novo heterozygous single-base deletion in in exon 26 of FBN1 gene ( NM_000138.4:c.3089del) producing an altered reading frame and generating a premature termination of translation. The mutation appears to be novel; nevertheless, according to the current ACMG/AMP guideline it is possible to definite it causative.

To date, few genotype-phenotype correlations for FBN1 mutations have been uncovered. In a series of 570 adult patient with MFS, those with FBN1 haploinsufficiency mutations had a significantly increased risk for any aortic complications (such as aortic dissection, aortic surgery) than those with missense (dominant-negative) mutations (adjusted hazard ratio 1.6; 95%CI 1.1–2.7) [17]. In addition, Baudhuin L. M. et al. found that the ratio of FBN1 truncation mutations was also higher in the aortic events in patients affected by MFS [18]. It is also reported in some previous studies that patients harbouring truncating mutation show lower likelihood of diagnosis of ectopia lentis versus patients with missense mutations [19]. This data supports the absence of any actual ocular manifestations in our patient.

Variants in exons 24–32 are typically associated with a severe form of MFS rapidly progressive [], previously named nMFS [9]. However, some patients with severe MFS lack mutations in this region and many patients with mutations in this region have classic or mild variants of MFS. Likewise, we identified in our proband a FBN1 pathogenic variant in exon 26 which seems to have a little prognostic value as our patient presents a mild phenotype of MFS.

Although gastrointestinal tract manifestations are not listed in Ghent nosology as a diagnostic sign of MFS, many MFS patients’ present gastrointestinal tract involvement such as liver cysts, biliary duct ectasia, CDH, intussusception, volvulus, as well as functional disorders.

To the best of our knowledge 24 cases of CDH associated with MFS have been reported so far and listed in Table 1. The definitive pathogenetic explanation for the association of CDH and MFS is still limited. However, it is thought that diaphragmatic defect is caused by a deficiency of fibrillin-1 during fetal development of diaphragm that may disrupt mesenchymal cell proliferation, causing malformed muscle tissue as well as abnormally lax oesophageal hiatus and lax gastric ligamentous attachments resulting in diaphragmatic defects, as was documented in the foetuses of rats nitrofen-induced CDH model [20].

As showed in Table 1, PHE is the most common type of diaphragmatic defects reported in patients with MFS. The CDH doesn’t seem to be associated with a specific MFS phenotype. In our case the patient had a MH, of which only 5 cases in association with MFS were previously described. The age of MH diagnoses ranging from 2 month to 53 years with a median age of 22 years as the majority of patients tend to be pauci- or a-symptomatic.

Yetman et al. reported a MH in a 22-year-old man with MFS presented with acute dyspnea secondary to bowel herniation, who, similarly to our case, was initially incorrectly diagnosticated as an acute pneumonia. Later, the diagnosis of MFS in this patient was stated as the presence of aortic root dilatation, mitral valve prolapse, ocular lens subluxation and skeletal anomalies [13]. Similarly, Ayse Esin et al. described the diagnosis of MH in a 9-year-old female presenting with respiratory symptoms. a positive family history of MFS and, at physical examination, MFS facial appearance, tall stature and a systolic murmur that prompts the diagnosis of aortic root dilatation and mitral and tricuspid valve prolapse[4]. Laumonerie et al. described a 3 month-old female with phenotype and family history strongly suggestive for MFS presenting with MH [12]. This case demonstrates an affinity with our report as MH was the first feature of MFS and the infant showed cardiac involvement requiring for targeted therapy already at a young age.

According to cardiological involvement showed in some cases, we cannot say that patients with MFS and MH have less severe clinical phenotype; rather we highlight how an early diagnosis of MFS is essential to prevent cardiovascular complications, in order to increase life expectancy of patients [21].

MFS prognosis is related to aortic root dissection, a complication related to aortic root dilatation. A French multicentre study assessed the incidence of cardiovascular events and their associated risk markers in children with MFS and set that a close follow up and timely prophylactic surgery during childhood prevent dissection and that aortic root Z score and aortic valve regurgitation seem interesting risk markers for cardiovascular events and progressive aortic root dilation [22].

In our case, the child has aortic root dilatation and mitral valve prolapse at the age of 4 years and a prophylactic treatment was started.

Traditionally B-blockers and angiotensin receptor blockers (ARBs) are prescribed at the time of diagnosis with MFS at any age or upon appreciation of progressive aortic dilatation. These drugs are expected to reduce the risk of aortic dissection reducing the systolic ejection impulse and consequently hemodynamic stress on the aortic wall [7]. Chiu et al. demonstrated that the combination of B-blockers and losartan affords better protection against aortic root enlargement than B-blockers alone in children with MFS [23]. In the same yeara study conducted in a small cohort of young patients with MFS proved a significant improvement with losartan monotherapy in all affected proximal aortic segments, with a better response to therapy when started at an earlier age and with a longer therapy duration [24].

As alternative to B-blockers and ARBs, calcium antagonists and ACE inhibitors have been considered. Enalapril has been seen to improve aortic distensibility and reduce the rate of aortic dilatation compared with B-blockers in a small not randomized clinical trial in children and adolescents [25]. According to these findings Enalapril therapy was started in our case.

Our experience teaches the importance of a multidisciplinary follow up, particularly genetic and pediatric one, for a child with an occasional anterior CDH and some minor dysmorphisms. The continuous clinical evaluations of the patient allowed to make diagnosis and to set up an early cardiological therapy in an asymptomatic child that we hope will prevent the even fatal complications of MFS.