Marfan syndrome (MFS)

What is Marfan syndrome (MFS)?

Marfan syndrome is a genetic disorder that affects mainly the connective tissue in the body. Connective tissue can be found throughout the body, meaning the syndrome can affect many different parts of the body too.

Symptoms may vary between sufferers of the syndrome but involve mainly three systems: skeletal, ocular and cardiovascular.

The syndrome is congenital but not all symptoms and features may be obvious at birth. Some become more apparent in childhood or, even in some cases, in adulthood.

Marfan syndrome occurs in around 1 in every 5,000 people.

Syndrome Synonyms:
Marfan Syndrome, Type I; Mfs1 MFS

What gene changes cause Marfan syndrome (MFS)?

Mutations in the FBN1 gene on chromosome 15 cause the disorder. The syndrome is inherited in 75% of cases, while the remaining 25% of recorded cases occur due to spontaneous genetic mutations.

In the case of autosomal dominant inheritance just one parent is the carrier of the gene mutation, and they have a 50% chance of passing it onto each of their children. Syndromes inherited in an autosomal dominant inheritance are caused by just one copy of the gene mutation.

In some cases, a genetic syndrome may be the result of a de-novo mutation and the first case in a family. In this case, this is a new gene mutation which occurs during the reproductive process.

What are the main symptoms of Marfan syndrome (MFS)?

Individuals with the syndrome are usually tall and thin with long arms, legs and fingers. Symptoms may vary between individuals but scoliosis and hyper-flexible joints are common symptoms.

Other health conditions include serious heart defects, as well as issues affecting the eyes, bones and covering of the spinal cord. There are specific clinical criteria purposed for the syndrome and this includes a cardiovascular evaluation with echocardiogram.

Possible clinical traits/features:
Retinal detachment, Congestive heart failure, Downslanted palpebral fissures, Ectopia lentis, Dural ectasia, Emphysema, Deeply set eye, Esotropia, Dolichocephaly, Flexion contracture, Exotropia, Malar flattening, Dental crowding, Decreased muscle mass, Decreased subcutaneous fat, Pulmonary artery dilatation, Mitral annular calcification, Premature osteoarthritis, Protrusio acetabuli, Spondylolisthesis, Tricuspid valve prolapse, Aortic root aneurysm, Aortic regurgitation, Aortic dissection, Arachnodactyly, Dilatation of ascending aorta, Cataract, Autosomal dominant inheritance, Retrognathia, Pneumothorax, Pectus carinatum, Overgrowth, Pes cavus, Pes planus, Striae distensae, Tall stature, Increased axial length of the globe, Narrow palate, Myopia, Mitral regurgitation, Mitral valve prolapse, Narrow face, Long face, Micrognathia, Pectus excavatum, Medial rotation of the medial malleolus, Joint hypermobility, Kyphoscoliosis, Hypoplasia of the iris, High palate, Hammertoe, Incisional hernia, Genu recurvatum, Glaucoma

How does someone get tested for Marfan syndrome (MFS)?

The initial testing for Marfan syndrome can begin with facial analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the need for further testing. A consultation with a genetic counselor and then a geneticist will follow. 

Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing.   

Medical information on Marfan syndrome

Patients with this syndrome have a combination of dolichostenomelia, arachnodactyly, pectus deformities of the chest, mitral or aortic regurgitation, ectopia lentis, and mild joint laxity. Other evidence of a generalized connective tissue disorder may be present, such as scoliosis and skin striae. Marfan syndrome is caused by mutations in the FBN1 gene.

A dilated aortic root can usually be demonstrated by echocardiography, and aortic aneurysms can ensue. Shores et al., (1994) studied the effect of beta-adrenergic blockade and concluded it slowed the rate of aortic dilatation and reduced the development of complications from aortic rupture in some patients with Marfan syndrome.

Erkula et al., (2002) provide growth charts for individuals with Marfan syndrome. Very rarely, multiple cervical spine subluxations occur (Place and Enzenauer, 2006). A myopathy has occasionally been recorded (Behan et al., 2003), although poor muscle development is common. In the Behan et al., (2003) family, a muscle biopsy showed an abnormality in fibrillin immunoreactivity.

Some cases have dural ectasia, defined as a ballooning or widening of the dural sac, often associated with herniation of the nerve root sleeves out of the associated foraminae of the spine (Rose et al., 2000; Ahn et al., 2001). Patient 1, reported by Ades et al., (2006) had major, cranial, dura problems.

Ahn et al., (2000) discuss screening for this condition by MR and CT scans. Of 32 Marfan patients, 20 patients were found to have dural ectasia. These patients may have low back pain, headache, proximal leg pain, and weakness and numbness (Foran et al., 2005). Dural ectasia occurred in 78% of the cohort examined by Soylen et al., (2009). Hispanic families might have few skeletal manifestations (Villamizaret al., 2010).

There have been about 10 case reports (van den Berg et al., 1996) of cerebral aneurysms in Marfan syndrome, but the association is doubted by some (van den Berg et al., 1996).

Multisegment colobomas have also been reported (LeBlanc et al., 2014).

Dental pulp calcification might be fairly frequent in those older than 30 years (Bauss et al., 2008).

Average life expectancy is halved. Ninety-five percent of deaths are due to a cardiovascular cause. Gray et al., (1998) studied life expectancy in British patients. Mean age of death was 45.3 years. Fifty percent median cumulative survival was 53 years for males and 72 years for females.

The condition has been shown to be caused by mutations in the fibrillin-1 gene (FBN1) on chromosome 15 (see Tsipouras et al., (1992) for review). Gray et al., (1994) estimated a prevalence of 1 in 14,000 in Scotland. Twenty-seven percent of cases appeared to be new mutations. Most mutations are unique to individual families. Hayward et al., (1997) screened all 65 exons of the gene and found mutations in 78% of well-characterized familial cases but only about 20% of sporadic cases. Intragenic markers can be used for predictive testing (Rantamaki et al., 1994; Pereira et al., 1994), however, care must be taken because of possible genetic heterogeneity (for example, see Boileau et al., 1993).

Dietz and Pyeritz (1995) provide a good review of mutations in the fibrillin gene in Marfan syndrome. Collod-Beroud et al., (1997) have published a database of mutations in the FBN1 gene in Marfan syndrome.

Rantamaki et al., (1999) provided evidence for parental germ-line mosaicism in a family. A further family with paternal somatic mosaicism was reported by Collod-Beroud et al., (1999).

Liu et al., (1998) reported a 76% detection rate for mutations using denaturing high-performance liquid chromatography. Toudjarska et al., (2001) described a comprehensive approach to the molecular diagnosis of Marfan syndrome that relied on direct analysis of the FBN1 gene at the cDNA level.

Diagnosis by assessment of fibrillin immunofluorescence on skin biopsies or fibroblast cultures is still technically difficult, and the accuracy is not certain (Schaefer and Godfrey, 1995).

De Paepe et al., (1996) discuss the diagnostic criteria. Rose et al., (2000) compare the ""Berlin"" and ""Ghent"" criteria for diagnosis, stressing the importance of looking for dural ectasia in some cases. These ectasias sometimes leak CSF, causing postural headache (Rosser et al., 2005).

Thomas et al., (1996) conclude that the metacarpal index is not a good diagnostic test.

Lipscomb et al., (1997) report the experience of 36 women who had 91 pregnancies. Four had an aortic dissection relating to the pregnancy, and two others required aortic surgery following delivery. The incidence of obstetric complications did not exceed expectation.

Kilpatrick et al., (1996) reported preimplantation diagnosis of Marfan syndrome using linked markers. Note that expression can be very variable, and there might be an overlap with Ehlers-Danlos - kyphoscoliotic type (De Backer et al., 2007). Molecular studies might be needed to sort this out.

Schrijver et al., (1999) provide information on genotype-phenotype correlation in FBN1 mutations. Robinson and Godfrey (2000) and Tiecke et al., (2001) also provided a good review of FBN1 and FBN2 mutations.

Putnam et al., (1996) present data suggesting that cases with mutations in exons 25-27 of the FBN1 gene have relatively severe cardiac manifestations or the neonatal form.

Liu et al., (1996) reviewed cases with exon-skipping mutations of the FBN1 gene resulting in a fibrillin-1 chain lacking EGF-like domains. Lui et al., (1997) reported a further exon-skipping mutation. Many of these cases have the severe neonatal form of the disorder, and a dominant negative effect was postulated.

Schrijver et al., (2002) identified 34 cases with premature termination mutations of the FBN1 gene. In this group, joint hypermobility was more common, but lens dislocation and retinal detachment less common.

Ades et al., (2002) reported a three-generation family apparently segregating for a form of kyphoscoliosis with some skeletal features of Marfan syndrome but no heart defects. A mutation in the FBN1 gene (G1796E) was detected.

de Vries et al., (2007) reported two cousins with transient hypothyroidism, lens dislocation between one and three years of age, mitral valve prolapse, and aortic aneurysm in one. Neither had joint laxity nor striae, but both had high arched palates. Height in one was on the 60th percentile and on the 85th in the other (no pictures were published). There were mild features in one set of parents but not in the other. The cousins were homozygous for a c.1453C>T mutation.

Two patients with severe disease who are compound heterozygotes were reported by Van Dijk et al., (2009).

In an international study (1,013 probands), Faivre et al., (2007) found that mutations in exons 24-32 resulted in a more severe phenotype.

Loeys et al., (2010) have revised the Ghent nosology. They state that in the absence of family history, but in the presence of aortic root aneurysms and ectopia lentis, these two manifestations are sufficient for diagnosis.

A three-generation family reported by Potter et al., (2013) had C-terminal missense mutation - there were no eye signs.

Arnaud et al., (2016) performed sequencing of the FBN1 gene in 2,500 probands with Marfan syndrome. While 1,400 individuals carried a heterozygous mutation in this gene, four patients had homozygous mutations, and five had compound heterozygous mutations. None of the patients carried two premature termination codon mutations in the FBN1 gene. There was a large spectrum of severity of the disease in probands carrying two mutations, but none of them presented with extremely severe manifestations.

Lu et al., (2017) described a pair of siblings with Marfan syndrome diagnosed at the age of 26 years due to homozygous splice site mutations in the FBN1 gene. Clinical characteristics included aortic dilatation that required aortic graft with root replacement, bilateral ectopia lentis, and positive thumb and wrist signs. None had pectus deformity, scoliosis or striae. Parents of the siblings and the daughter of one of them had heterozygous mutations, and neither had skeletal or ocular signs.

Dordoni et al., (2017) described a male patient with a de novo 15q21.1 deletion of 2.17 Mb partly encompassing the FBN1 gene and another 13 genes. Clinical characteristics included developmental delay, motor clumsiness, joint hypermobility, asthma, mild aortic root ectasia (Z-score 2.5) and mild mitral valve regurgitation, slender build, widely spaced eyes, broad nasal bridge, prominent columella, microretrognathia, jaw deviation, short philtrum, and small ears with hypoplastic antihelix and earlobe. Skeletal features were pectus excavatum, scoliosis, asymmetry of the shoulder and pelvic girdles, winged scapulae, contractures, arachnodactyly of fingers and toes, and pes cavus. Mild hyperextensible skin and striae distensae were seen. An additional feature was lower limb dystonia.

Martínez-Quintana et al., (2017) described a female patient with Marfan syndrome due to a novel missense mutation in the FBN1 gene. The father demonstrated gonadal mosaicism. Patterning defects were present including extra phalanx at the first digit in the right hand and the fusion of scaphoid, lunate, and trapezium to trapezoid bones.

Becerra-Muñoz et. al. (2018) reviewed the clinical and molecular characteristics of 90 patients from 58 families. Patients with protein-truncating mutations had higher proportion of aortic events, whereas missense mutations were associated with a more benign course.

* This information is courtesy of the L M D.
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