Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder due to pathogenic variants in Fibrillin-1 (FBN1) affecting nearly one in every 10,000 individuals. We report a 16-month-old female with early-onset MFS heterozygous for an 11.2 kb de novo duplication within the FBN1 gene. Tandem location of the duplication was further confirmed by optical genome mapping in addition to genetic sequencing and chromosomal microarray. This is the third reported case of a large multi-exon duplication in FBN1, and the only one confirmed to be in tandem. As the vast majority of pathogenic variants associated with MFS are point mutations, this expands the landscape of known FBN1 pathogenic variants and supports consistent use of genetic testing strategies that can detect large, indel-type variants.

BACKGROUND: FBN1 (15q21.1) encodes fibrillin-1, a large glycoprotein which is a major component of microfibrils that are widely distributed in structural elements of elastic and non-elastic tissues. FBN1 variants are responsible for the related connective tissue disorders, grouped under the generic term of type-1 fibrillinopathies, which include Marfan syndrome (MFS), MASS syndrome (Mitral valve prolapse, Aortic enlargement, Skin and Skeletal findings, Acromicric dysplasia, Familial ectopia lentis, Geleophysic dysplasia 2, Stiff skin syndrome, and dominant Weill-Marchesani syndrome.
METHODS: Two siblings presented with isolated skeletal manifestations of MFS, including severe pectus excavatum, elongated face, scoliosis in one case, and absence of other clinical features according to Ghent criteria diagnosis, were screened for detection of variants in whole FBN1 gene (65 exons). Both individuals were heterozygous for the R2726W variant. This variant has been previously reported in association with some skeletal features of Marfan syndrome in the absence of both tall stature and non-skeletal features. These features are consistent with the presentation of the siblings reported here.
CONCLUSIONS: The presented cases confirm that the R2726W FBN1 variant is associated with skeletal features of MFS in the absence of cardiac or ocular findings. These findings confirm that FBN1 variants are associated with a broad phenotypic spectrum and the value of sequencing in atypical cases.

The cooccurrence of Marfan syndrome and psychiatric disorders has been reported for many years. Furthermore, neuropsychological deficits have been shown to be associated with Marfan syndrome. The aim of the present article is to summarize findings from the sparse studies and case reports available. The results hold clinical and therapeutic implications and suggest that psychological and neuropsychological domains in Marfan syndrome patients should be carefully assessed. In particular, some patients may require specific rehabilitation programs. On this basis, a multidisciplinary approach to Marfan syndrome treatment seems mandatory.

Congenital contractural arachnodactyly (CCA) is a connective tissue disease caused by mutations of the FBN2, which encodes fibrillin-2. CCA patients have a marfanoid habitus; however, aortic dilatation and/or dissection as observed in Marfan syndrome have been rarely documented. Here, we report on a Japanese familial case of CCA resulting from a FBN2 splicing mutation (IVS32+5g→a), which leads to exon 32 being skipped, and the patients developed aortic dilatation and type A dissection. Although CCA patients have been believed to have favorable prognoses, repetitive aortic imaging studies must be performed in some patients to detect possible aortic disease early, and genetic testing of FBN2 might be useful to identify such high-risk patients.

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Beals-Hecht syndrome or congenital contractural arachnodactyly (CCA) is a rare, autosomal dominant connective tissue disorder characterized by crumpled ears, arachnodactyly, contractures, and scoliosis. Recent reports also mention aortic root dilatation, a finding previously thought to differentiate the condition from Marfan syndrome (MFS). In many cases, the condition is caused by mutations in the fibrillin 2 gene (FBN2) with 26 mutations reported so far, all located in the middle region of the gene (exons 23-34). We directly sequenced the entire FBN2 gene in 32 probands clinically diagnosed with CCA. In 14 probands, we found 13 new and one previously described FBN2 mutation including a mutation in exon 17, expanding the region in which FBN2 mutations occur in CCA. Review of the literature showed that the phenotype of the FBN2 positive patients was comparable to all previously published FBN2-positive patients. In our FBN2-positive patients, cardiovascular involvement included mitral valve prolapse in two adult patients and aortic root enlargement in three patients. Whereas the dilatation regressed in one proband, it remained marked in a child proband (z-score: 4.09) and his father (z-score: 2.94), warranting echocardiographic follow-up. We confirm paradoxical patellar laxity and report keratoconus, shoulder muscle hypoplasia, and pyeloureteral junction stenosis as new features. In addition, we illustrate large intrafamilial variability. Finally, the FBN2-negative patients in this cohort were clinically indistinguishable from all published FBN2-positive patients harboring a FBN2 mutation, suggesting locus heterogeneity.

OBJECTIVE: Our objective was to describe the features of prenatal Marfan syndrome.
METHODS: Doppler fetal echocardiograms were performed. The morphology and rhythm of the fetal heart were examined sequentially.
RESULTS: The case was referred because of cardiomegaly and dilated great vessels. Sequential Doppler echocardiographic evaluation led to the diagnosis of prenatal Marfan syndrome. The main features are cardiomegaly, dysplastic atrioventricular valves with tricuspid regurgitation and dilated great vessels, which can be aneurysmal at their origin. The fetus died in utero at 39 weeks of gestation because of cardiac failure. Pathological study confirmed the Marfan habitus and complications. Molecular genetic study showed a de novo point mutation in exon 26 of the FBN1 gene.
CONCLUSIONS: We report a case of prenatal Marfan syndrome diagnosed by sequential evaluation of the cardiac signs, which are essential for prenatal diagnosis. The prognosis seems as poor as the neonatal one. The prenatal diagnosis is essential for adequate counselling.

The neonatal Marfan syndrome (nMFS) is a rare condition with a poor prognosis. The relative infrequency of this syndrome hampers the clinical diagnosis at an early age. This report describes the progress of a 4-year-old boy with neonatal Marfan syndrome and severe cardiac involvement. Molecular genetic studies showed a de novo point mutation in exon 29 of the FBN1 gene located on chromosome 15q21.1. This mutation is in the classic region for nMFS and has not been reported before. The literature is reviewed. We stress the importance of early recognition of the phenotype in order to anticipate the development of cardiac abnormalities.

Neonatal Marfan syndrome, the most severe presentation of Marfan syndrome phenotypes (MIM 154700), is characterised mainly by joint contractures, arachnodactyly, loose skin, crumpled ears, severe atrioventricular valve dysfunction and pulmonary emphysema. Death usually occurs within the first 2 years of life from congestive heart failure. We describe here a newborn male with many typical characteristics of neonatal Marfan syndrome associated with a diaphragmatic eventration and a bilateral uretero-hydronephrosis with bladder dilatation. He died from cardiac failure due to severe tricuspid and mitral regurgitation at 62 h of age.
CONCLUSIONS: Molecular analysis showed a heterozygous missense mutation at nucleotide 3165 (3165T>G) in exon 25 of the FBN1 gene, resulting in the substitution of cysteine for tryptophan (C1055W).

Marfan syndrome is an autosomal dominant disorder of connective tissue that affects the cardiac, eye, and skeletal systems. More than 135 mutations have been identified in the fibrillin-1 gene, localized on chromosome 15q21.1 [corrected] and responsible for the clinical manifestations of Marfan syndrome. The major orthopedic manifestations of Marfan syndrome include scoliosis, chest wall deformity, dural ectasia, joint hypermobility, and acetabular protrusion. In addition, decreased bone mineral density has been reported in patients with Marfan syndrome. This review summarizes recent developments in the genetic and orthopedic aspects of Marfan syndrome. Increased practitioner awareness of the clinical features associated with Marfan syndrome may facilitate earlier diagnosis and optimize patient treatment.