Marfan syndrome

Marfan syndrome is caused by heterozygous germline pathogenic variants in FBN1 (15q21.1), which encodes fibrillin-1, an extracellular-matrix protein that contributes to microfibrils involved in elastic-matrix formation and homeostasis, matrix-cell attachments, and regulation of selected growth factors. Disease causation involves both dominant-negative effects and haploinsufficiency, with excess TGF-β signalling implicated in cardiovascular, pulmonary, skeletal, and dural manifestations.

Marfan syndrome is inherited in an autosomal dominant manner. Each child of an affected individual has a 50% risk of inheriting the pathogenic variant. Approximately 25% of probands have the disorder as the result of a de novo pathogenic variant. Prenatal molecular testing is technically possible once the familial pathogenic variant has been identified.

The diagnosis of Marfan syndrome is established by , applying clinical, ophthalmologic, and cardiovascular criteria. Meeting these criteria establishes the clinical diagnosis of Marfan syndrome. Key investigations include echocardiography for aortic-root measurement (z-score ≥2.0 supports diagnosis), slit-lamp examination after maximal pupillary dilation for detection of ectopia lentis, systemic-score evaluation (≥7 supports diagnosis), and spinal MRI as indicated for dural ectasia.

Main differential diagnoses include:

• : connective-tissue and aortic-root overlap without ectopia lentis, widely spaced eyes, bifid uvula, arterial tortuosity, SMAD3, TGFBR2 and others.
• : aneurysm/dissection of medium-to-large muscular arteries without preferential aortic root involvement; translucent skin; easy bruising; COL3A1.
• Homocystinuria (cystathionine β-synthase deficiency): Marfanoid habitus with ectopia lentis, intellectual disability, thromboembolic events; approximately 50% pyridoxine-responsive; CBS.
• : overlapping Marfanoid habitus but distinguished by near-uniform developmental delay or mild-to-moderate intellectual disability and less frequent and milder cardiovascular manifestations; SKI

• Establishing the diagnosis: Molecular genetic testing identifies the underlying pathogenic variant and thereby confirms the clinical diagnosis at the molecular level.
• Specific and individualised surveillance: Knowledge of the causative variant enables targeted surveillance for early detection of medically significant complications, particularly potentially life-threatening cardiovascular manifestations, and is the prerequisite for individualised medical care planned by the treating physicians in consultation with the affected individual.
• Family-member testing: Once the familial pathogenic variant has been identified, at-risk relatives can clarify their genetic status by predictive testing, enabling timely surveillance for those who carry the variant.

• Dietz H. FBN1-Related Marfan Syndrome. 2022 Feb 17. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. PMID: 20301510. Available from:
• Harju S, Saari A, Sund R, Sankilampi U. Epidemiology of disorders associated with tall stature in childhood: A 20-year birth cohort study. PloS one. 2025;20(4):e0321798. doi: 10.1371/journal.pone.0321798. PMID: . PMCID: PMC11999151.
• Loeys BL, Dietz HC, Braverman AC, Callewaert BL, De Backer J, Devereux RB, et al. The revised Ghent nosology for the Marfan syndrome. Journal of medical genetics. 2010;47(7):476-85. doi: 10.1136/jmg.2009.072785. PMID: .