Disease group Connective tissue disorder
Synonymous FBN1-related Marfan Syndrome
Estimated prevalence Unknown
OMIM 154700
Inheritance Autosomal dominant
Gene (s) FNB1


FBN1-related Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder with a wide range of clinical features. These include ocular manifestations such as myopia, ectopia lentis, and an elevated risk of retinal detachment, glaucoma and cataracts. Bone overgrowth, joint laxity, and characteristic features like disproportionately long extremities as well as pectus deformities are common. The cardiovascular system is a major concern, with aorta dilation, mitral valve issues, tricuspid valve prolapse, and pulmonary artery enlargement leading to significant morbidity and early mortality. 


Clinical Description

MFS is an inherently complex condition, with significant inter- and intrafamilial variability. The disorder manifests as a spectrum of diverse symptoms across various organs, differing greatly from the classical patient profile. Several of the physical findings associated with MFS can also be seen in the general population or in other syndromic Heritable Thoracic Aortic Diseases (H-TAD), such as Loeys–Dietz syndrome (LDS) and Ehlers–Danlos syndrome (EDS).

Cardiovascular features: Cardiovascular complications are the primary causes of morbidity (e.g. aortic dilation at the sinuses of Valsalva (in 80%; commonly with time-related progression), susceptibility to aortic tears and ruptures, mitral and tricuspid valve prolapse, and enlargement of the proximal pulmonary artery. More rarely, intracranial aneuryms (14%) and intracranial dissection (3%) can be found. 

Ocular feautres: Ectopia lentis (in 60%), progressing myopia (34-44%), increased axial globe length, strabismus, exotropia, esotropia, vertical deviations, primary inferior oblique muscle over action, glaucoma. 

Skeletal, bone, muscle features: long and narrow face with deeply set eyes, malar hypoplasia, abnormal ear cartilage, mocro/retrognathia, high arch narrow palate,..

Joint laxity and abnormal linear growth patterns > disproportion (= dolichostenomelia) between limb length and trunk size, leading to an enlarged arm span-to-heigh ratio. Individuals with MFS may not necessarily stand out as tall according to general population standards.

Pectus excavatum, pectus carinatum, scoliosis (63%), lordosis, kyphosis, spondylolisthesis, arachnodactyly (=distinctive thumb and wrist signs), pes planus, pes vacus, reduced joint mobility, protrusio acetabuli; decreased bone mineral density 

Skin features: Skin stretch marks, umbilical hernia, inguinal hernia (often congenital), and rectus abdominal muscle diastasis, insufficiency of muscularity and fat stores

Dura: Dural ectasia (lumbosacral), lower backache, headache, leak in cerebrospinal fluid with hypotension 

Lung and respiratory system features: restrictive lung disease, parenchymal lung disease, upper lobe blebs with spontaneous pneumothorax, asthma, bronchiectasis, sleep-disordered breathing, upper airway obstruction.1



MFS in inherited in an autosomal dominant way (50% chance of transmitting the causing mutation to children). Approximately 75% of MFS patients inherit the disease from an affected parent, while the remaining 25% obtain the disorder due to a de novo pathogenic variant. Pathogenic variants in FBN1 are expected in about 82–83% of patients who meet the 2010 Ghent revised criteria for MFS. 

It is possible that the high phenotypic variability observed in MFS, even among individuals of the same families, may be due to other genetic or epigenetic modifiers.

Elastic fibers, found in various tissues such as the skin, lungs, arteries, and ligaments, are vital for providing elasticity and resilience. Fibrillin microfibrils (like Fibrillin-1, encoded by the FBN1 gene), a critical component of these elastic fibers, interact with various cellular and extracellular matrix components.



The diagnosis of MFS is based on specific clinical criteria according to the 2010 Ghent revisited croteria.2

Clinical findings indicative of Marfan syndrome include

  • aortic root enlargement/dissection (z score ≥2.0) + ectopia lentis
  • aortic root dilatation/dissection + FBN1 mutation
  • ectopia lentis + FBN1 mutation
  • a systemic score ≥7 (see below)

Family history consistent with autosomal dominant inheritance supports the diagnosis.

The definitive diagnosis in a proband without a known family history of Marfan syndrome is contingent on the presence of an FBN1 pathogenic variant linked to Marfan syndrome and either aortic root enlargement (z score ≥2.0) or ectopia lentis. For individuals under 20 with suggestive findings not reaching diagnostic thresholds, temporary diagnostic terms such as "Nonspecific connective tissue disorder" or "Potential Marfan syndrome" are recommended until specific criteria are met.


Molecular Genetic Testing Approaches

  1. Gene-Targeted Testing (Option 1):

    • Single-gene testing: The initial step involves sequencing FBN1 to identify missense, nonsense, and splice site variants. If no variant is found, targeted deletion/duplication analysis follows.
    • Multigene panel: A comprehensive panel, including FBN1 and other relevant genes, offers a more efficient approach to identify the genetic cause while minimizing identification of variants with uncertain significance.
  2. Comprehensive Genomic Testing (Option 2):

  • Exome sequencing or genome sequencing: Considered when the phenotype closely resembles other inherited disorders with features observed in Marfan syndrome. This approach does not require the clinician to predefine the likely involved gene.


Calculation of the Systemic score

3 points: Wrist AND thumb sign

2 points (for each finding): Pectus carinatum, Hindfoot deformity, Pneumothorax, Dural ectasia, Protrusio acetabulae

1 point (for each finding): Wirs OR thumb sign, Pectus excavatum or chest asymmetry, Plain flat foot (Pes planus), Reduced upper segment to lower segment AND increased arm span to height ratios, Reduced elbow extension, 3-5 facial features, skin striae, myopia, mitral valve prolaps

Sum of the total points: ____ (maximum 23 points)

A systemic score calculator and a complete description of each component evaluation can be found at the Marfan Foundation website


Differential diagnosis

In recent years, several phenotypes with similarities to Marfan syndrome, particularly involving the cardiovascular, ocular, or skeletal aspects, have been documented. However, these phenotypes do not meet the diagnostic criteria for Marfan syndrome.1

Neonatal Marfan syndrome: most severe form of MFS, poor prognosis, FBN1 mutation

Weill-Marchesani syndrome: autosomal dominant mutation in FBN1; or autosomal recessive mutation in ADAMTS10, ADAMTS17, LTBP2; microspherophakia, lens subluxation, short stature, brachydactyly, without vascular invovlement

Geleophysic dysplasis 2: rare autosomal dominant skeletal dysplasia, postnatal onset short stature, delayed bone age, short limbs, brachydactyly with markedly short tubular bones and relatively normal epiphyses, progressive joint contractures, progressive thickening of heart valves, facial anomalies, hepatomegaly; rarely tracheal stenosis, respiratory insufficiency

Acromicric dysplasia: similar to geleophysic dysplasia 2; mutations in FBN1 gene, autosomal dominant

Stiff skin syndrome: autosomal dominant mutations in FBN1 gene; progressive, symmetric sclerotic skin changes of shoulders, hips, thighs, joint contracture, relatively short stature without typical skeletal, ocular and cardiovascular features of MFS

Marfanoid progeroid lipodystrophy syndrome: very rare; poor weight gain since birth, postnatal lipodystrophy, muscle wasting, generalized subcutaneous fat reduction, progeroid appearance; marfanoid habitus, hyper extensible joints, arachnodactyly, severe myopia, ectopia lentis, increased aortic root dilatation ris, mitral valve prolaps; FBN1 gene mutation

MASS (Mitral valve-Aorta-Skeleton-Skin) syndrome: mitral valve proplapse, myopia, borderline and non-progressive aortic enlargement, skin/skeletal systemic features

Bicuspid aortic valve: common cardiac defect (0.5-2% of the general population)

Loeys-Dietz syndrome (LDS): aortic root aneurysms, risk of dissection, skeletal features, marfanoid habitus; different facial appearance versus MFS (craniosynostosis, hypertelorism, bifid uvula, cleft palate), no ectopia lentis; arterial tortuosity pronounced, cardiovascular manifestations early in life; joint hyperlaxity, joint contractures, hernias, thin translucent skin, poor wound healing, atrophic scars frequent; mutations in TGFBR1, TGFBR2, SMAD2, SMAD3, TGFB2, TGFB3

Beals syndrome (Congenital contractural arachnodactyly): rare autosomal dominant, marfan-like appearance, crumpled ears, arachnodactyly, contractures, muscular hypoplasia, scoliosis; mutations in FBN2 

Meester-Loyes syndrome: very rare, facial features resembling MFS, joint hypermobility or contractures, early onset thoracic aortic aneurysm, mitral and aortic valve insufficiency; mutation in BGN-gene.

Ehlers-Danlos syndrome (EDS): heterogenous group of inherited connective tissue disorders; joint hypermobility, increased skin elasticity, tissue fragility (see article)

Brittle cornea syndrome: very rare autosomal recessive; mutation in PRDM5 or ZNF469 gene; ocular alterations (thin cornea, progressive keratoconus, high myopia, retinal detachment), marfanoid habitus, scoliosis, arachnodactyly, hypermobility of distal joints, pes planus, hallux valgus, mild contractures of fingers, soft, translucent skin, blute sclerae

Arterial tortuosity syndrome: rare, autosomal recessive mutations in SLC2A10, twisting and elongation of large and medium-sized arteries. Stenosis of arterial and pulmonary valves, increased risk for aortic aneurysms and vascular dissection, hyperextensible skin, mild dysmorphic facial featrues, joint hypermobility

Classical homocystinuria: rare autosomal recessive mutations in CBS gene; accumulation of homocysteine in urine, myopia, ectopia lentis, mitral valve prolapse, accelerated skeletal growth, osteoporosis, skeletal anomalies resembling MFS, thromboembolic events, intellectual disability; one subtype responds to therapy with pyridoxine (vitamin B6) 

Heritable thoracic aortic disease: significant increased risk of thoracic aortic diseases; incidence about 10.4 per 100 000 people / year; in 2% positive family history. 

Autosomal dominant polycystic kidney disease: increased risk of aortic root aneurysms; mutations in PKD1, PDK2


Follow-up in MFS1

Suggested indications for follow-up in MFS

Apparatus/System Diagnostic Criteria and/or Related Diseases Diagnosis and Follow-up
  • Aortic root ectasia 
  • Increased risk of aortic aneurysms and dissection
  • Mitral Valve prolapse
  • Increased risk of valve insufficiency
  • 2D-thransthoracic echocardiography: at first evaluation, then every 6 months
  • Vascular CT/MRI: from the age of 18 years every 2-3 years (thoraco-abdomen) and every 3-5 years (neck and CNS)
  • Cardiac Surgery evaluation: as needed
  • Ectopia Lentis and Dislocation of the lens
  • Myopia
  • High risk for retinal detachment
  • High risk for myopic based retinal degeneration
  • Risk of glaucoma
  • Ophthalmological evaluation: at first evaluation, then every 12 months
  • Kyphosis/Scoliosis
  • Dolichostenomelia
  • Chest deformity
  • Flat-footedness
  • Joint laxity
  • Protrusio Acetaboli
  • Polyarthralgia
  • Orthopedic clinical evaluation: at diagnosis, then every 12 months
  • Physiatric counselling and physiotherapy: as needed
  • Pelvis X-ray: at diagnosis
Neurovascular/ Neurological
  • Dural ectasia
  • CSF Hypotension
  • Neurological evaluation: at diagnosis
  • Spine MRI: if CSF hypotension suspected
  • Hypovitaminosis D
  • Osteopenia/osteoporosis
  • endocrinological evaluation adn Vit D dosage: every 12 months
  • BMD: every 2 years
  • Increased risk for spontaneous penumothorax
  • Reduced aerobic capacity
  • Chest deformity-linked complications
  • Spirometry + breathing function tests: every 12 months
  • Pneumological evaluation: as needed
  • Thoracic surgery evaluation: as needed
Integumentary and skin
  • Recurrent hernias
  • Atrophic skin striae non related to weight increase, stress or pregnancy
  • Surgical evaluation: as needed
  • FBN1 pathogenic variant
  • Counselling and genetic testing: at first evaluation
  • Preconceptional counselling: before pregnancies
Psychological counselling and support  
  • as needed



Medical therapy in MFS should be tailored based on patient tolerance and various risk factors, including age and family history of aortic dissection. Patients diagnosed with aortic root dilatation are advised to receive therapy with adequate doses of either a beta-blocker or angiotensin receptor blocker (ARB), with a consideration for a combination of these therapies in severe cases.

Losartan, among ARBs, is highlighted for its favorable effects in reducing the rate of progressive aortic root dilation in MFS. Studies suggest that losartan, by inhibiting TGF-β signaling, can mitigate abnormal changes in the aortic wall and decrease the rate of aortic root dilatation in MFS mouse models. Clinical trials support the beneficial effects of losartan in adult MFS patients, demonstrating a decreased average rate of aortic root dilation and reduced aortic arch dilatation rate in those who underwent aortic root surgery.

Beta-blockers have been a standard preventive treatment for aortic complications in MFS since the 1970s. Propranolol, atenolol, and metoprolol are current beta-blockers in use, with atenolol being the drug of choice due to its cardioselectivity and longer half-life. However, recent meta-analysis questions the clinical benefits of long-term beta-blockade in MFS, reporting no evidence of significant advantages.3

Inhibitors of Angiotensin converting enzyme (ACEIs) have been shown since 2007 to reduce aortic root dilatation in MFS patients, although they do not significantly attenuate aortic growth velocity compared to beta-blockers. ACEIs improve aortic distensibility and stiffness, potentially delaying the phenotypic expression of MFS by antagonizing TGF-β. Perindopril and verapamil are ACEIs in use, but their use is contraindicated during pregnancy due to potential fetal toxicity.



1. Marelli S, Micaglio E, Taurino J, Salvi P, Rurali E, Perrucci GL, Dolci C, Udugampolage NS, Caruso R, Gentilini D, Trifiro' G, Callus E, Frigiola A, De Vincentiis C, Pappone C, Parati G, Pini A. Marfan Syndrome: Enhanced Diagnostic Tools and Follow-up Management Strategies. Diagnostics (Basel). 2023 Jul 5;13(13):2284.

2. Loeys BL, Dietz HC, Braverman AC, Callewaert BL, De Backer J, Devereux RB, Hilhorst-Hofstee Y, Jondeau G, Faivre L, Milewicz DM, Pyeritz RE, Sponseller PD, Wordsworth P, De Paepe AM. The revised Ghent nosology for the Marfan syndrome. J Med Genet. 2010;47:476-85.

3. Koo, HK, Lawrence KA, Musini VM. Beta-blockers for preventing aortic dissection in Marfan syndrome. Cochrane Database Syst. Rev 2017, 11, CD011103.