The revised Ghent nosology for the Marfan syndrome

Authors, Journal, Affiliations, Type, DOI

• Bart L Loeys, Harry C Dietz, Alan C Braverman, Bert L Callewaert, Julie De Backer, Richard B Devereux, Yvonne Hilhorst-Hofstee, Guillaume Jondeau, Laurence Faivre, Dianna M Milewicz, Reed E Pyeritz, Paul D Sponseller, Paul Wordsworth, Anne M De Paepe
• Journal of Medical Genetics
• Center for Medical Genetics, Ghent University Hospital; McKusick-Nathans Institute, Johns Hopkins University and HHMI; Washington University School of Medicine; Weill Cornell Medical College; Leiden University Medical Center; Hôpital Bichat, Paris; University of Texas Medical School Houston; University of Pennsylvania; and others
• Original article
• DOI: https://doi.org/10.1136/jmg.2009.072785

Overview

The 2010 revised Ghent nosology is the international landmark consensus that superseded the 1996 Ghent criteria for diagnosing Marfan syndrome (MFS). It elevates two cardinal features — aortic root aneurysm (Z-score ≥2) and ectopia lentis — as anchors, introduces a structured systemic score (maximum 20 points; ≥7 = systemic involvement), and grants greater diagnostic weight to a bona fide FBN1 mutation. Four diagnostic routes apply in sporadic cases and three in familial cases; related conditions (ectopia lentis syndrome, MASS phenotype, MVPS) are formally defined as separate entities. Special provisions are made for children under 20. Retrospective analysis showed ~90% concordance with 1996 criteria; the 10% discordance was considered beneficial, enabling earlier diagnosis in children with convincing phenotype and appropriately delayed diagnosis in those lacking clear cardiovascular risk.

Keywords

Marfan syndrome, Ghent nosology, FBN1, fibrillin-1, aortic root aneurysm, ectopia lentis, systemic score, diagnostic criteria, Loeys-Dietz syndrome, differential diagnosis

Key Takeaways

Background and Rationale for Revision

• Berlin nosology (1986) was too permissive; 1996 Ghent nosology introduced major/minor criteria across organ systems and proved more stringent, with FBN1 mutations detectable in up to 97% of patients meeting criteria
• Limitations of 1996 criteria: age-dependent manifestations insufficiently handled (difficult diagnosis in children); some criteria not well validated or requiring expensive tests; inadequate framework for differential diagnosis; MFS diagnosis carries psychosocial burden (career/insurance restrictions, anxiety, exercise restriction in children)
• An international expert panel convened in Brussels 2007, supported by the National Marfan Foundation, to revise the nosology based on large published cohorts and expert experience

Five Major Changes in Revised Nosology

1. More weight to two cardinal features: aortic root aneurysm/dissection + ectopia lentis; all other manifestations contribute to a systemic score only
2. More prominent role for molecular genetic testing (FBN1, TGFBR1/2) — not mandatory but given greater diagnostic weight
3. Less specific manifestations removed or de-weighted (joint hypermobility, highly arched palate, recurrent/incisional herniae removed entirely)
4. Formalised requirement for additional diagnostic evaluation if discriminating features of SGS, LDS, or vEDS are present alongside MFS features
5. Context-specific recommendations for patient counselling and follow-up, including children not yet meeting criteria

Revised Diagnostic Criteria (Box 1)

Without family history — 4 routes to MFS diagnosis:

1. Ao (Z≥2) + EL (ectopia lentis) = MFS
2. Ao (Z≥2) + bona fide FBN1 mutation = MFS
3. Ao (Z≥2) + systemic score ≥7 points = MFS (after excluding SGS/LDS/vEDS features)
4. EL + FBN1 mutation previously associated with aortic disease in a proband = MFS

• EL ± systemic features + FBN1 not known to associate with aortic disease = Ectopia Lentis Syndrome (ELS)
• Ao (Z<2) + systemic score ≥5 (≥1 skeletal feature), no EL = MASS phenotype
• MVP + Ao (Z<2) + systemic score <5, no EL = MVPS

With family history of MFS — 3 routes:
5. Ectopia lentis + family history of MFS = MFS
6. Systemic score ≥7 + family history of MFS = MFS
7. Ao (Z≥2 if ≥20 years; Z≥3 if <20 years) + family history of MFS = MFS

Caveat for starred diagnoses: exclude discriminating features of SGS/LDS/vEDS; perform TGFBR1/2 and collagen testing if indicated

Systemic Score (Box 2 — max 20 points; ≥7 = systemic involvement)

• Wrist AND thumb sign: 3 pts (wrist OR thumb only: 1 pt)
• Pectus carinatum: 2 pts (pectus excavatum or chest asymmetry: 1 pt)
• Hindfoot deformity (hindfoot valgus + forefoot abduction): 2 pts (plain pes planus: 1 pt)
• Spontaneous pneumothorax: 2 pts
• Dural ectasia: 2 pts
• Protrusio acetabuli: 2 pts
• Reduced upper/lower segment ratio AND increased arm/height ratio (no severe scoliosis): 1 pt; US/LS thresholds: white adults <0.85, black adults <0.78; arm/height >1.05
• Scoliosis (Cobb ≥20° or ≥1.5 cm chest hemithorax difference) or thoracolumbar kyphosis: 1 pt
• Reduced elbow extension (angle ≤170° on full extension): 1 pt
• Facial features — 3 of 5 present: 1 pt (dolichocephaly, enophthalmos, downslanting palpebral fissures, malar hypoplasia, retrognathia)
• Skin striae (not weight/pregnancy-related; in uncommon locations): 1 pt
• Myopia >3 diopters: 1 pt
• Mitral valve prolapse (all types): 1 pt
• Removed from 1996 nosology due to lack of specificity: joint hypermobility, highly arched palate, recurrent/incisional herniae

FBN1 Mutation Criteria (Box 3 — what constitutes a "bona fide" pathogenic FBN1 mutation)

• Mutation previously shown to segregate in a Marfan family, OR
• De novo mutation (proven paternity + absence of disease in both parents) in one of:
  • Nonsense mutation
  • Inframe or out-of-frame deletion/insertion
  • Splice site mutations affecting canonical splice sequence or demonstrated to alter splicing on mRNA/cDNA
  • Missense affecting or creating cysteine residues
  • Missense affecting conserved residues of the EGF consensus sequence
• Other missense: family segregation + absence in ≥400 ethnically matched controls; in sporadic cases, absence in ≥400 controls alone
• Linkage of FBN1 haplotype confirmed by ≥6 informative meioses in family

Children (<20 years) — Special Provisions

• Sporadic children with insufficient systemic features (<7) and/or borderline aortic root (Z<3) without FBN1 mutation: classify as "non-specific connective tissue disorder" until follow-up echocardiogram shows aortic root Z≥3
• FBN1 mutation confirmed but aortic root below Z=3: classify as "potential MFS" until aorta reaches threshold
• Aortic Z-score threshold with family history in children: Z≥3 (versus Z≥2 for adults ≥20 years)
• ELS cannot be formally diagnosed before age 20 (ensures adequate surveillance of cardiovascular and other organ systems)
• Neonatal MFS: represents the severe end of the MFS spectrum, not a separate diagnostic category

Cardiovascular Criteria — Technical Standards

• Aortic root measurement at sinuses of Valsalva; parallel to aortic valve plane, perpendicular to blood flow axis; largest correctly measured root diameter from ≥3 transthoracic images
• Inner-wall to inner-wall during systole (patients ≤25 years): Z-score calculator at marfan.org
• Leading-edge to leading-edge in diastole (all ages): Roman et al. 1989 normative reference graphs and Z-score equations
• If TTE provides inadequate visualisation: TOE or CT/MRI with double-oblique images; same normograms required
• MVP: defined as protrusion of one or both leaflets across the mitral annulus during systole; best detected in parasternal long axis or apical long-axis views
• Pulmonary artery dilation (>23 mm in adults) not included in systemic score — insufficient specificity and complications rare
• Descending/abdominal aortic aneurysm: NOT a diagnostic criterion due to low specificity; surveillance indicated in adults with suspected MFS but no aortic root enlargement; widespread vascular disease should prompt consideration of LDS or vEDS

Differential Diagnosis — Discriminating Features

• LDS (TGFBR1/2): Bifid uvula/cleft palate, arterial tortuosity, hypertelorism, diffuse aortic and arterial aneurysms, craniosynostosis, clubfoot, cervical spine instability, easy bruising; more aggressive natural history than MFS (dissections at smaller dimensions <40 mm); LDS2 = no craniofacial features but equally aggressive vascular disease
• SGS (FBN1 and other): Craniosynostosis, mental retardation, Marfanoid habitus; low frequency of vascular disease distinguishes it from LDS
• CCA (FBN2): Crumpled ears, joint contractures; arachnodactyly; mild aortic dilation without progression to dissection/rupture
• WMS (FBN1 or ADAMTS10): Microspherophakia, brachydactyly, joint stiffness, short stature; dominant (FBN1) and recessive (ADAMTS10) forms
• ELS (FBN1/LTBP2/ADAMTSL4): Ectopia lentis without aortic root dilation; cardiovascular imaging follow-up throughout life required; genetically heterogeneous
• Homocystinuria (CBS): Mental retardation, thrombosis; lens dislocates downward (vs upward/temporal in MFS); excluded by urine amino acid analysis
• FTAAD (FBN1/TGFBR1/2/MYH11/ACTA2): Lack Marfanoid skeletal features; ACTA2 accounts for up to 16% of FTAAD; ACTA2 adds iris flocculi, livedo reticularis, cerebral aneurysms/Moyamoya, premature CAD
• BAV: 1% population prevalence; dilation predominantly above sinotubular junction; usually lacks ocular/systemic features
• vEDS (COL3A1): Translucent skin, easy bruising, dystrophic scarring, intestinal/uterine rupture; medium-sized artery dissection; no predisposition at aortic root
• ATS (SLC2A10/GLUT10): Autosomal recessive; generalised arterial tortuosity, stenosis, and aneurysms; skeletal and skin involvement

Management

Echocardiographic surveillance:

• Annual echocardiograms for all confirmed MFS
• More frequent if: diameter approaching 4.5 cm in adults, growth ≥0.5 cm/year, or concerns about valve/ventricular function
• Children <20 years with suggestive features but no CV involvement: annual echo due to potential rapid phenotypic evolution
• Adults with repeatedly normal aortic root: 2–3 year intervals

Medical management:

• Beta-blockers: standard of care in most centres; titrate to heart rate <100 bpm after submaximal exercise; consider in ALL MFS patients including children and those with root <4 cm unless contraindicated
• ARBs (losartan): prevented aortic aneurysm in fibrillin-1-deficient mouse model (Habashi 2006, Science); encouraging results in pilot experience in children with severe MFS (Brooke 2008, NEJM); multicentre trials of losartan versus/on top of atenolol underway (as of 2010)
• ACE inhibitors: insufficient data as standard treatment
• If beta-blockers contraindicated or not tolerated: other antihypertensive agents can be used, but definitive evidence for protection lacking

Surgical management:

• Prophylactic surgery recommended when aortic root diameter approaches 5.0 cm; other factors: family history of early dissection, rate of growth, severity of AR, MVP disease, ventricular dysfunction, pregnancy planning, desire for valve-sparing procedure
• Type A dissection (originating in ascending aorta): emergency surgery
• Type B dissection (originating in thoracic descending aorta; ~10% of all MFS dissections): surgical indications include intractable pain, limb/organ ischaemia, diameter >5.5 cm, rapid aortic diameter increase; open surgery preferred over endovascular stenting (connective tissue may not tolerate stent pressure; adjacent normal-sized aorta may also be diseased or dilated)
• Mitral valve: repair or replacement for severe MR with symptoms or progressive LV dilatation/dysfunction; repair preferred, especially at time of aortic valve-sparing root replacement
• Regular aortic imaging after root surgery and in adulthood

Lifestyle and special situations:

• Exercise: avoid contact sports, exercise to exhaustion, isometric activities involving Valsalva manoeuvre; moderate aerobic activities in most patients is safe and encouraged
• Pregnancy: increased cardiovascular risk; majority of aortic complications in 3rd trimester or early postpartum; risk markedly increased if aortic root diameter >4.0 cm at start of pregnancy
• Ophthalmology: annual evaluation; early aggressive refraction in children to prevent amblyopia; surgical lens extraction indications: lens opacity impairing vision, anisometropia, impending luxation, lens-induced glaucoma/uveitis
• Skeletal: scoliosis and pectus managed per standard orthopaedic rules

Related conditions (MASS/MVPS/ELS):

• Annual cardiovascular imaging and ophthalmological evaluation for all three
• Counsel patients/families about risk of more severe presentation in offspring

Evidence Base for Revised Criteria

• Retrospective analysis of multiple large published MFS cohorts showed ~90% concordance between 1996 and 2010 Ghent criteria
• 10% discordance was generally beneficial: earlier diagnosis in young children with convincing clinical phenotype; delayed/avoided diagnosis in individuals without clear cardiovascular risk
• A web-based diagnostic tool for application of these criteria accessible at marfan.org

Limitations of the document

• Expert consensus based primarily on retrospective cohort review and expert opinion; no prospective RCT validation of revised criteria at time of publication
• ~90% concordance figure derived from retrospective analysis only; prospective validation needed (and has since been provided by subsequent studies)
• ARB evidence from mouse model and one small pilot trial; multicentre trials awaited
• Some systemic score thresholds (particularly in children) lack rigorous prospective validation
• Race/ethnicity caveats documented (Asian populations noted to have lower incidence of enlarged arm/height ratio; Afro-Caribbean differences in arm/height distribution) but population-specific normative data limited
• No standardised method or universally accepted cut-offs for dural ectasia detection (CT or MRI; local standards apply)

Key Concepts Mentioned

• concepts/Marfan-Syndrome — primary topic; full revised 2010 diagnostic framework established
• concepts/Ghent-Nosology — the 2010 revision of the 1996 Ghent criteria is the main contribution

Key Entities Mentioned

• entities/FBN1 — primary causative gene; bona fide mutation criteria defined (Box 3)
• entities/Loeys-Dietz-Syndrome — critical differential; TGFBR1/2 mutations; more aggressive natural history; discriminating features tabulated

Wiki Pages Updated

• wiki/sources/marfan-ghent-jmg-2010.md — created
• wiki/concepts/Marfan-Syndrome.md — expanded Ghent 2010 criteria; added systemic score, FBN1 criteria, children provisions, Type B dissection, pregnancy threshold; source_count 3→4
• wiki/sourceindex.md — added marfan-ghent-jmg-2010 entry
• wiki/wikiindex.md — updated Marfan-Syndrome entry description
• log.md — updated