Marfan Syndrome

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Clinical features in Marfan syndrome. Tall stature, arachnodactyly, and aortic root dilation are notable features in individuals with Marfan syndrome.
Marfan Syndrome
Inheritance	Autosomal dominant
Genetics	Heterozygous pathogenic variants in the FBN1 gene
Pathophysiology	FBN1 mutations lead to defective fibrillin-1 protein, disrupting connective tissue integrity and resulting in multisystem involvement.
Clinical Features	Tall stature, long limbs, arachnodactyly, pectus deformities, scoliosis, ectopia lentis, aortic root dilation/dissection.
Tests	Genetic testing for FBN1 mutations, echocardiography, slit-lamp examination, and skeletal imaging.
DDX	Homocystinuria, Ehlers-Danlos syndrome, Loeys-Dietz syndrome, and other connective tissue disorders.
Treatment	Regular cardiovascular monitoring, pharmacological management with beta-blockers or ARBs, surgical repair of aortic aneurysms when indicated, and symptomatic management.

Marfan syndrome is an autosomal dominant connective tissue disorder caused by mutations in the FBN1 gene, which encodes fibrillin-1, a critical component of the extracellular matrix. This syndrome exhibits significant clinical variability and affects multiple organ systems, including the cardiovascular, ocular, and skeletal systems.

Clinical Features

Cardiovascular manifestations are the most life-threatening and include aortic root dilatation, aortic aneurysm, aortic dissection, and mitral valve prolapse. Ocular features often include ectopia lentis (dislocation of the ocular lens), myopia, and an increased risk of retinal detachment. Skeletal abnormalities are characterized by overgrowth of the long bones, leading to features such as arachnodactyly (elongated fingers and toes), pectus excavatum or carinatum (chest deformities), scoliosis, and joint hypermobility.

Diagnosis

Diagnosis of Marfan syndrome is based on the revised Ghent criteria (2010), which include a combination of clinical features and genetic testing for FBN1 mutations. It requires careful clinical evaluation due to its significant phenotypic variability, both within and between families, and its overlap with other connective tissue disorders.

The revised Ghent criteria, published in 2010, provide a structured framework that emphasizes key features such as aortic root involvement and ectopia lentis, supported by genetic testing when available. Other manifestations are integrated into a systemic score that helps to stratify patients who may not meet classical diagnostic thresholds. A combination of family history, clinical findings across multiple systems, and molecular testing guides diagnosis and helps distinguish Marfan syndrome from related conditions such as Loeys-Dietz syndrome, Ehlers-Danlos syndrome, and the MASS phenotype.

Revised Ghent Criteria for Diagnosis of Marfan Syndrome and Related Conditions

Criteria	Diagnosis
In the absence of family history
Ao (Z≥2) and EL	MFS
Ao (Z≥2) and FBN1 mutation	MFS
Ao (Z≥2) and Syst (≥7 points)	MFSa
EL and FBN1 mutation with known aortic aneurysm	MFS
EL with or without Syst and with FBN1 mutation not previously associated with aortic root aneurysm/dissection or no FBN1 mutation	ELS
Ao (Z<2) and Syst (≥5 with at least one skeletal feature) without EL	MASS
MVP and Ao (Z<2) and Syst (<5) without EL	MVPS
In the presence of family history
EL and family history of MFS (as defined above)	MFS
Syst (≥7 points) and family history of MFS (as defined above)	MFSa
Ao (Z≥2 above 20 years old, ≥3 below 20 years) and family history of MFS (as defined above)	MFSa
a Caveat: without discriminating features of Sphrintzen-Goldberg syndrome, Loeys-Dietz syndrome or the vascular form of Ehlers-Danlos syndrome and after TGFBR1/2, collagen biochemistry, and COL3A1 testing if indicated. Ao: Aortic root diameter at sinuses; EL: ectopia lentis; Syst: Systemic score; MFS: Marfan Syndrome; ELS: Ectopia lentis syndrome; MASS: A phenotype involving Myopia, Aortic root dimensions < Z2, Skin striae, and Skeletal findings (but not fulfilling MFS criteria); MVPS: Mitral valve prolapse syndrome – MVP with some skeletal/systemic features but insufficient for MFS.; MVP: Mitral valve prolapse

Scoring of Systemic Features in the Revised Ghent Nosology

Systemic Feature	Points
Wrist AND thumb sign	3 (wrist OR thumb sign – 1)
Pectus carinatum	2 (pectus excavatum or chest asymmetry – 1)
Hindfoot deformity	2 (plain pes planus – 1)
Pneumothorax	2
Dural ectasia	2
Acetabular protrusion	2
Reduced upper/lower segment ratio AND increased arm/height AND no severe scoliosis	1
Scoliosis or thoracolumbar kyphosis	1
Reduced elbow extension	1
Facial features (3/5) (dolichocephaly, enophthalmos, down-slanting palpebral fissures, malar hypoplasia, retrognathia)	1
Skin striae	1
Myopia >3 diopters	1
Mitral valve prolapse (all types)	1
Maximum total: 20 points; score ≥7 indicates systemic involvement.

Management

Management involves regular cardiovascular monitoring with imaging techniques such as echocardiography, CT, or MRI to track aortic root size and prevent aortic dissection through prophylactic surgical intervention when necessary. Medical therapy, including beta-blockers or angiotensin receptor blockers, is used to slow the progression of aortic dilatation.

Overall, a multidisciplinary approach is essential for managing the various manifestations of Marfan syndrome and improving patient outcomes.

Resources

Aortic root Z score calculator for adults: https://marfan.org/dx/z-score-adults/

Aortic root Z score calculator for children: https://marfan.org/dx/zscore-children/

Systemic score calculator: https://marfan.org/dx/score/

Scoring of systemic features from Marfan.org website - 560 KB (f)