Marfan Syndrome

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Mappings

MONDO

MONDO:0007947 Marfan syndrome

Orphanet lists MONDO:0007947 as an exact cross-reference for Marfan syndrome.

ICD-10-CM

ICD10CM:Q87.4 Marfan syndrome

Orphanet lists ICD-10 Q87.4 as an exact cross-reference for Marfan syndrome.

ICD-11 Foundation

icd11f:236564145 Marfan syndrome

Orphanet lists ICD-11 LD28.01 as an exact cross-reference; the local ICD-11 Foundation ontology represents this as icd11f:236564145.

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Definitions

1

Orphanet disease definition

Orphanet defines Marfan syndrome as a systemic connective-tissue disease with cardiovascular, musculo-skeletal, ophthalmic, and pulmonary manifestations.

CASE_DEFINITION

Show evidence (1 reference)

ORPHA:558 SUPPORT Other

"Marfan syndrome is a systemic disease of connective tissue characterized by a variable combination of cardiovascular, musculo-skeletal, ophthalmic and pulmonary manifestations."

Orphanet's definition supports the multisystem connective-tissue framing of this entry.

👪

Inheritance

1

Autosomal dominant inheritance HP:0000006

Autosomal dominant inheritance

Show evidence (1 reference)

ORPHA:558 SUPPORT Other

"Autosomal dominant"

Orphanet records autosomal dominant inheritance for Marfan syndrome.

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Mechanistic Hypotheses

1

Canonical FBN1 Loss / TGF-β Dysregulation Model

canonical_fbn1_tgfb_dysregulation_model CANONICAL

Heterozygous FBN1 pathogenic variants reduce or qualitatively alter fibrillin-1 microfibrils, the extracellular scaffold that both confers elastic-fiber mechanical integrity and sequesters latent TGF-β complexes. Loss of microfibrillar function therefore produces a dual lesion: (1) structural weakness of elastin-rich tissues (aortic media, suspensory ligament of the lens, dura, lung, skin, mitral valve) and (2) excess bioavailable TGF-β with downstream Smad2/3 and non-canonical pathway activation in aortic wall and other tissues. The result is the characteristic multisystem phenotype — progressive aortic root aneurysm and dissection, ectopia lentis, dolichostenomelia, scoliosis, dural ectasia, mitral valve prolapse, and pulmonary blebs. Losartan and other angiotensin/TGF-β-axis inhibitors that reduce aortic-wall TGF-β signaling provide interventional support for the TGF-β-dysregulation component.

Retained as CANONICAL. The 2026 falcon hypothesis-search report (kb/hypotheses/Marfan_Syndrome/canonical_fbn1_tgfb_dysregulation_model; openscientist timed out) confirms the dual-lesion model: heterozygous FBN1 variants cause microfibrillar mechanical failure AND excess bioavailable TGF-β with downstream Smad2/3 activation. Three qualifications: (1) the relative contribution of structural-weakness vs TGF-β-signaling components varies by tissue and variant — ectopia lentis is primarily structural while aortic aneurysm involves substantial TGF-β-driven medial degeneration and matrix remodeling; (2) losartan's clinical benefit on aortic root growth in pediatric MFS is modest in head-to-head trials with atenolol, indicating that TGF-β antagonism alone does not fully prevent dissection risk and that hemodynamic stress reduction remains critical; (3) Loeys-Dietz syndrome (TGFBR1/TGFBR2 mutations) and related TGF-β-pathway disorders display a more aggressive aneurysm phenotype, indicating that the TGF-β-axis can be pathogenic even when fibrillin-1 is intact, qualifying the necessity of microfibrillar disruption for the aortic phenotype.

Deep research

Falcon citations 41 citations 2026-05-23T19:23:35.463213

Show evidence (1 reference)

PMID:39096853 SUPPORT In Vitro

"Marfan syndrome (MFS) is a hereditary condition caused by mutations in the FBN1 gene."

iPSC generation paper from Marfan patient-derived cells with FBN1 mutations; used as seed reference for the falcon hypothesis-search deep-research run. Documents the canonical FBN1-mutation → fibrillin-1-dysfunction axis at the cellular level.

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Pathophysiology

6

FBN1 Gene Mutation

Mutations in the FBN1 gene result in defective fibrillin-1 protein, which affects the elasticity and strength of connective tissues.

vascular associated smooth muscle cell link

elastic fiber assembly link ↓ DECREASED

Downstream

Dysregulated TGF-beta Signaling Defective fibrillin microfibrils fail to properly sequester latent TGF-beta complexes.

Extracellular Matrix Remodeling Loss of normal fibrillin scaffold destabilizes elastic fiber architecture and ECM integrity.

Impaired Mechanotransduction Altered fibrillin-integrin interactions impair mechanosensing in load-bearing connective tissues.

Show evidence (7 references)

PMID:8180508 SUPPORT Human Clinical

"The gene encoding for fibrillin, the FBN1 gene on chromosome 15, has been identified as the defective gene causing the Marfan syndrome. Fibrillin is the large glycoprotein with a repetitive domain structure and is a major protein component of microfibrils, a fibrillar system closely associated..."

The statement is supported by the identification of the FBN1 gene as the cause of Marfan syndrome and its role in the structure of connective tissue.

PMID:39096853 SUPPORT In Vitro

"Marfan syndrome (MFS) is a hereditary condition caused by mutations in the FBN1 gene. Genetic mutations in the FBN1 locus impact the function of the encoded protein, Fibrillin 1, a structural molecule forming microfibrils found in the connective tissue."

The statement is supported by the description of FBN1 mutations affecting the function of fibrillin-1, which is crucial for connective tissue structure.

PMID:17657824 SUPPORT Human Clinical

"Mutations in the FBN1 gene have been characterised in patients affected by Marfan syndrome and Marfan-related disorders."

The statement is supported by the identification of FBN1 mutations in Marfan syndrome patients.

+ 4 more references

Dysregulated TGF-beta Signaling

Defective fibrillin-1 microfibrils fail to sequester latent TGF-beta complexes, leading to increased bioavailable TGF-beta and excessive SMAD2/3 signaling that drives vascular smooth muscle cell phenotypic switching and ECM remodeling.

vascular associated smooth muscle cell link

transforming growth factor beta receptor signaling pathway link ↑ INCREASED SMAD protein signal transduction link ↑ INCREASED

aorta link

Downstream

Extracellular Matrix Remodeling Excess SMAD signaling increases protease activity and maladaptive ECM turnover.

Aortic Root Aneurysm Persistent TGF-beta activity accelerates medial degeneration and progressive root dilation.

Tall Stature Dysregulated growth factor signaling contributes to long bone overgrowth.

Arachnodactyly Abnormal connective tissue growth signaling contributes to elongated digits.

Extracellular Matrix Remodeling

Increased matrix metalloproteinase activity, elastic fiber fragmentation, altered collagen composition, and proteoglycan accumulation (especially versican) weaken the aortic wall medial layer.

vascular associated smooth muscle cell link fibroblast link

extracellular matrix organization link ↕ DYSREGULATED proteolysis link

aorta tunica media link

Downstream

Aortic Aneurysm Elastic fiber fragmentation and collagen disarray weaken the aortic wall.

Mitral Valve Prolapse Connective tissue degeneration in valve leaflets promotes prolapse.

Ectopia Lentis Weak zonular microfibrils predispose to lens displacement.

Scoliosis Ligamentous laxity and vertebral connective tissue weakness promote spinal curvature.

Spontaneous Pneumothorax Fragile connective tissue in lung apices increases risk of spontaneous pneumothorax.

Impaired Mechanotransduction

Perturbed integrin-fibrillin interactions alter focal adhesion signaling and mechanosensing, contributing to maladaptive vascular smooth muscle cell responses to hemodynamic stress.

vascular associated smooth muscle cell link endothelial cell link

cellular response to mechanical stimulus link integrin-mediated signaling pathway link

aorta link

Downstream

Aortic Root Aneurysm Maladaptive vascular smooth muscle responses to pulsatile stress accelerate root enlargement.

Vascular Inflammation

Angiotensin II type 1 receptor signaling and chemokine pathways recruit macrophages and promote inflammatory mediators that exacerbate vascular smooth muscle cell dysfunction and ECM degradation.

macrophage link vascular associated smooth muscle cell link

inflammatory response link leukocyte migration link

aorta tunica intima link aorta tunica media link

Downstream

Aortic Dissection Inflammatory ECM damage and smooth muscle dysfunction increase risk of acute intimal tearing.

Mitochondrial Dysfunction

Emerging evidence implicates mitochondrial dysfunction and oxidative stress in vascular smooth muscle cells and endothelial cells as contributors to thoracic aortic aneurysm progression in Marfan syndrome.

vascular associated smooth muscle cell link endothelial cell link

mitochondrial ATP synthesis coupled electron transport link response to oxidative stress link

aorta link

Downstream

Aortic Dissection Oxidative injury amplifies wall fragility and susceptibility to dissection in advanced disease.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

24

Cardiovascular 5

Aortic Aneurysm VERY_FREQUENT Aortic aneurysm (HP:0004942)

Sequelae: Aortic Dissection

Show evidence (6 references)

PMID:21797750 SUPPORT Human Clinical

"MFS is one of the most common inherited connective tissue disorders affecting 1 in 5000 individuals. Although the phenotype of MFS can be quite variable, aneurysmal dilation of the aortic root and consecutive acute aortic dissection is the leading cause of death in this patient population."

This reference confirms that aortic aneurysm and aortic dissection are frequent cardiovascular manifestations in Marfan Syndrome.

PMID:36058493 SUPPORT Human Clinical

"Early Onset Marfan Syndrome is at the severe end of the Marfan syndrome spectrum and is frequently associated with variants in exons 24-32 of the FBN1 gene."

The literature discusses the severe cardiovascular manifestations of Marfan Syndrome, supporting the frequent occurrence of aortic aneurysm and dissection.

PMID:20364556 SUPPORT Human Clinical

"The majority of those individuals had significant organ involvement including dilatation of ascending aorta (78%)."

This study indicates a high frequency of aortic dilation, a precursor to aortic aneurysm, among Marfan Syndrome patients.

+ 3 more references

Aortic Dissection FREQUENT Aortic dissection (HP:0002647)

Show evidence (3 references)

PMID:21797750 SUPPORT Human Clinical

"MFS is one of the most common inherited connective tissue disorders affecting 1 in 5000 individuals. Although the phenotype of MFS can be quite variable, aneurysmal dilation of the aortic root and consecutive acute aortic dissection is the leading cause of death in this patient population."

This reference directly states that aortic dissection is the leading cause of death in Marfan syndrome patients.

PMID:16321689 SUPPORT Human Clinical

"Aortic dissection occurred more frequently in group R (7 patients, 47%) than in group S (0%, P < 0.001)."

This study demonstrates that aortic dissection is a frequent complication in patients with rapid aortic root dilation.

ORPHA:558 SUPPORT Other

"HP:0002647 | Aortic dissection | Frequent (79-30%)"

Orphanet's curated HPO frequency annotation classifies aortic dissection as Frequent (79-30%) in Marfan syndrome.

Mitral Valve Prolapse FREQUENT Mitral valve prolapse (HP:0001634)

Show evidence (1 reference)

ORPHA:558 SUPPORT Other

"HP:0001634 | Mitral valve prolapse | Frequent (79-30%)"

Orphanet's curated HPO frequency annotation classifies mitral valve prolapse as Frequent (79-30%) in Marfan syndrome.

Aortic Root Aneurysm VERY_FREQUENT Aortic root aneurysm (HP:0002616)

Show evidence (1 reference)

ORPHA:558 SUPPORT Other

"HP:0002616 | Aortic root aneurysm | Very frequent (99-80%)"

Orphanet's curated HPO frequency annotation classifies aortic root aneurysm as Very frequent (99-80%) in Marfan syndrome.

Aortic Regurgitation FREQUENT Aortic regurgitation (HP:0001659)

Show evidence (1 reference)

ORPHA:558 SUPPORT Other

"HP:0001659 | Aortic regurgitation | Frequent (79-30%)"

Orphanet's curated HPO frequency annotation classifies aortic regurgitation as Frequent (79-30%) in Marfan syndrome.

Eye 2

Ectopia Lentis FREQUENT Ectopia lentis (HP:0001083)

Dislocation of the lens

Show evidence (9 references)

PMID:28902582 SUPPORT Human Clinical

"Marfan's Syndrome with Ectopia Lentis."

The title directly links Marfan Syndrome with ectopia lentis.

PMID:24853997 SUPPORT Human Clinical

"In this strictly defined MFS group fulfilling the Ghent-1 criteria, the prevalence of EL was 62.1%."

The study reports a high prevalence (62.1%) of ectopia lentis in individuals with Marfan Syndrome, supporting the statement that it is a frequent ocular diagnostic feature.

PMID:18090894 SUPPORT Human Clinical

"The mechanisms implicated in the clinical manifestations of zonular diseases, especially ectopia lentis, are reviewed."

The abstract mentions ectopia lentis as a clinical manifestation of zonular diseases, which includes Marfan Syndrome.

+ 6 more references

Myopia FREQUENT Myopia (HP:0000545)

Show evidence (1 reference)

ORPHA:558 SUPPORT Other

"HP:0000545 | Myopia | Frequent (79-30%)"

Orphanet's curated HPO frequency annotation classifies myopia as Frequent (79-30%) in Marfan syndrome.

Integument 1

Striae Distensae VERY_FREQUENT Striae distensae (HP:0001065)

Show evidence (1 reference)

ORPHA:558 SUPPORT Other

"HP:0001065 | Striae distensae | Very frequent (99-80%)"

Orphanet's curated HPO frequency annotation classifies striae distensae as Very frequent (99-80%) in Marfan syndrome.

Limbs 2

Arachnodactyly VERY_FREQUENT Arachnodactyly (HP:0001166)

Show evidence (3 references)

PMID:34021688 SUPPORT Human Clinical

"Arachnodactyly, a term used since 1902 to describe abnormally long (spider-like) fingers, is a pathologic feature of several heritable conditions, notably the Marfan syndrome..."

The literature states that arachnodactyly is a notable feature of Marfan syndrome.

PMID:23478494 SUPPORT Human Clinical

"Arachnodactyly literally means spidery fingers, and describes the long, slender fingers typical of patients with Marfan syndrome (MFS)."

This reference confirms that arachnodactyly is a typical feature of Marfan syndrome.

ORPHA:558 SUPPORT Other

"HP:0001166 | Arachnodactyly | Very frequent (99-80%)"

Orphanet's curated HPO frequency annotation classifies arachnodactyly as Very frequent (99-80%) in Marfan syndrome, independently supporting the VERY_FREQUENT frequency assertion.

Pes Planus VERY_FREQUENT Pes planus (HP:0001763)

Show evidence (1 reference)

ORPHA:558 SUPPORT Other

"HP:0001763 | Pes planus | Very frequent (99-80%)"

Orphanet's curated HPO frequency annotation classifies pes planus as Very frequent (99-80%) in Marfan syndrome.

Musculoskeletal 4

Scoliosis FREQUENT Scoliosis (HP:0002650)

Show evidence (5 references)

PMID:9076882 SUPPORT Human Clinical

"The data on all patients seen at one institution who had Marfan syndrome and scoliosis by age three were reviewed."

The study documents cases of scoliosis in patients with Marfan syndrome, supporting the statement that scoliosis is a frequent musculoskeletal diagnostic in Marfan syndrome.

PMID:37270806 SUPPORT Human Clinical

"A large cross-sectional study revealed a 63% prevalence of scoliosis among patients with MFS."

This study provides statistical evidence of a high prevalence of scoliosis in Marfan syndrome patients, reinforcing that scoliosis is frequent in this condition.

PMID:34916231 SUPPORT Human Clinical

"Among the several musculoskeletal manifestations in patients with Marfan syndrome, spinal deformity causes pain and respiratory impairment and is a great hindrance to patients' daily activities."

This study highlights scoliosis as one of the significant musculoskeletal manifestations in Marfan syndrome, supporting its frequent occurrence.

+ 2 more references

Pectus Carinatum VERY_FREQUENT Pectus carinatum (HP:0000768)

Show evidence (1 reference)

ORPHA:558 SUPPORT Other

"HP:0000768 | Pectus carinatum | Very frequent (99-80%)"

Orphanet's curated HPO frequency annotation classifies pectus carinatum as Very frequent (99-80%) in Marfan syndrome.

Pectus Excavatum FREQUENT Pectus excavatum (HP:0000767)

Show evidence (1 reference)

ORPHA:558 SUPPORT Other

"HP:0000767 | Pectus excavatum | Frequent (79-30%)"

Orphanet's curated HPO frequency annotation classifies pectus excavatum as Frequent (79-30%) in Marfan syndrome.

Joint Hypermobility FREQUENT Joint hypermobility (HP:0001382)

Show evidence (1 reference)

ORPHA:558 SUPPORT Other

"HP:0001382 | Joint hypermobility | Frequent (79-30%)"

Orphanet's curated HPO frequency annotation classifies joint hypermobility as Frequent (79-30%) in Marfan syndrome.

Nervous System 1

Sleep Apnea FREQUENT Sleep apnea (HP:0010535)

Show evidence (1 reference)

ORPHA:558 SUPPORT Other

"HP:0010535 | Sleep apnea | Frequent (79-30%)"

Orphanet's curated HPO frequency annotation classifies sleep apnea as Frequent (79-30%) in Marfan syndrome.

Growth 1

Tall Stature VERY_FREQUENT Disproportionate tall stature (HP:0001519)

Show evidence (4 references)

PMID:28846673 SUPPORT Human Clinical

"Boys and girls from the MFS group were significantly taller than those in the non-MFS group and in the reference group at all ages (P<0.0001)."

The study found that children with Marfan syndrome were significantly taller than their non-MFS counterparts at all ages, supporting the statement that tall stature is a very frequent musculoskeletal diagnostic feature of Marfan syndrome.

PMID:36058493 SUPPORT Human Clinical

"Early Onset Marfan Syndrome is at the severe end of the Marfan syndrome spectrum and is frequently associated with variants in exons 24-32 of the FBN1 gene... presented with tall stature."

The report mentions that tall stature is frequently associated with Early Onset Marfan Syndrome, supporting the statement.

PMID:31751304 SUPPORT Human Clinical

"We selected 42 patients with tall stature after exclusion of pathologies in GH/IGF1 axis and divided them into syndromic (n = 30) and non-syndromic (n = 12) subgroups... FBN1 = 3..."

The genetic investigation identified FBN1 mutations, which are associated with Marfan syndrome, in patients with tall stature, supporting the statement.

+ 1 more reference

Other 8

Spontaneous Pneumothorax OCCASIONAL Spontaneous pneumothorax (HP:0002108)

Orphanet classifies spontaneous pneumothorax as Very frequent (99-80%), whereas PMID:25765122 reports 5-11%; frequency is retained as OCCASIONAL based on the direct quantitative clinical estimate.

Show evidence (5 references)

PMID:31883816 SUPPORT Human Clinical

"Though cardiovascular, skeletal and ophthalmological manifestations are the most frequent features, the respiratory system can also be involved."

The reference mentions that Marfan syndrome can involve the respiratory system, including pneumothorax.

PMID:25765122 SUPPORT Human Clinical

"Marfan's syndrome is a rare genetic disorder...but minor diagnostic criteria also include pulmonary manifestations. Pneumothorax, frequently relapsing, affects 5 to 11% of patients."

The reference states that pneumothorax affects 5 to 11% of patients with Marfan syndrome, supporting the statement that it occurs occasionally.

PMID:33896616 SUPPORT Human Clinical

"Pneumothorax often develops in patients with Marfan syndrome."

The reference confirms that pneumothorax is a common occurrence in patients with Marfan syndrome.

+ 2 more references

Tricuspid Valve Prolapse FREQUENT Tricuspid valve prolapse (HP:0001704)

Show evidence (1 reference)

ORPHA:558 SUPPORT Other

"HP:0001704 | Tricuspid valve prolapse | Frequent (79-30%)"

Orphanet's curated HPO frequency annotation classifies tricuspid valve prolapse as Frequent (79-30%) in Marfan syndrome.

Ascending Tubular Aorta Aneurysm FREQUENT Ascending tubular aorta aneurysm (HP:0004970)

Show evidence (1 reference)

ORPHA:558 SUPPORT Other

"HP:0004970 | Ascending tubular aorta aneurysm | Frequent (79-30%)"

Orphanet's curated HPO frequency annotation classifies ascending tubular aorta aneurysm as Frequent (79-30%) in Marfan syndrome.

Slender Build VERY_FREQUENT Slender build (HP:0001533)

Show evidence (1 reference)

ORPHA:558 SUPPORT Other

"HP:0001533 | Slender build | Very frequent (99-80%)"

Orphanet's curated HPO frequency annotation classifies slender build as Very frequent (99-80%) in Marfan syndrome.

Dural Ectasia FREQUENT Dural ectasia (HP:0100775)

Show evidence (1 reference)

ORPHA:558 SUPPORT Other

"HP:0100775 | Dural ectasia | Frequent (79-30%)"

Orphanet's curated HPO frequency annotation classifies dural ectasia as Frequent (79-30%) in Marfan syndrome.

Chronic Fatigue VERY_FREQUENT Chronic fatigue (HP:0012432)

Show evidence (1 reference)

ORPHA:558 SUPPORT Other

"HP:0012432 | Chronic fatigue | Very frequent (99-80%)"

Orphanet's curated HPO frequency annotation classifies chronic fatigue as Very frequent (99-80%) in Marfan syndrome.

Protrusio Acetabuli FREQUENT Protrusio acetabuli (HP:0003179)

Show evidence (1 reference)

ORPHA:558 SUPPORT Other

"HP:0003179 | Protrusio acetabuli | Frequent (79-30%)"

Orphanet's curated HPO frequency annotation classifies protrusio acetabuli as Frequent (79-30%) in Marfan syndrome.

Mitral Regurgitation FREQUENT Mitral regurgitation (HP:0001653)

Show evidence (1 reference)

ORPHA:558 SUPPORT Other

"HP:0001653 | Mitral regurgitation | Frequent (79-30%)"

Orphanet's curated HPO frequency annotation classifies mitral regurgitation as Frequent (79-30%) in Marfan syndrome.

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Genetic Associations

10

FBN1 (Pathogenic Variants)

Show evidence (8 references)

PMID:31163209 SUPPORT Human Clinical

"FBN1 gene mutations lead to MFS and related connective tissue disorders."

The abstract directly states that FBN1 gene mutations are associated with Marfan syndrome and related disorders.

PMID:34916231 SUPPORT Human Clinical

"We retrospectively evaluated 278 patients with pathogenic or likely pathogenic FBN1 variants."

The study focuses on patients with Marfan syndrome who have pathogenic FBN1 variants, supporting the association.

PMID:32130918 SUPPORT Human Clinical

"Aortic risk has not been evaluated in patients with Marfan syndrome and documented pathogenic variants in the FBN1 gene."

The study describes aortic risks in patients with Marfan syndrome with pathogenic FBN1 variants, supporting the association.

+ 5 more references

TGFBR1 (Implicated)

TGFBR2 (Implicated)

SMAD2 (Implicated)

SMAD3 (Implicated)

ACTA2 (Implicated)

AGTR1 (Implicated)

ITGAV (Implicated)

NOS2 (Implicated)

VCAN (Implicated)

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Treatments

5

Beta Blockers

Action: beta adrenergic agent therapy MAXO:0000186

Used to reduce stress on the aorta and prevent its enlargement.

Show evidence (3 references)

PMID:36939732 PARTIAL Human Clinical

"Beta-blockers remain the mainstay of therapy as they have proven to slow aortic enlargement. Angiotensin receptor blockers are a useful alternative and with proven benefit as an add-on therapy to limit aortic growth."

Beta-blockers are used to slow aortic enlargement, which indirectly reduces stress on the aorta. However, they do not prevent aortic enlargement entirely.

PMID:17845137 PARTIAL Human Clinical

"Traditional medical therapies, such as beta-adrenergic receptor blockade, are used to slow pathologic aortic growth and decrease the risk of aortic dissection by decreasing hemodynamic stress."

Beta-blockers are used to slow aortic growth and decrease hemodynamic stress, but they do not completely prevent aortic enlargement.

PMID:17376944 PARTIAL Human Clinical

"Medical treatment with beta-blockers is probably helpful in most children with aortic root dilatation."

Beta-blockers are helpful in slowing the progression of aortic root dilatation, but they do not completely prevent it.

Angiotensin Receptor Blockers

Action: Pharmacotherapy NCIT:C15986

Agent: losartan ↗

ARBs such as losartan reduce aortic root growth by blocking angiotensin II type 1 receptor signaling and modulating TGF-beta pathways. Pediatric data show superior tolerability and efficacy compared to beta-blockers.

Aortic Surgery

Action: surgical procedure MAXO:0000004

Recommended for severe aortic dilation to prevent dissection.

Show evidence (2 references)

PMID:26586198 SUPPORT Human Clinical

"To prevent such catastrophic aortic events, a lower threshold has been recommended for prophylactic interventions on the aortic root."

The literature mentions that prophylactic aortic root replacement is recommended to prevent severe aortic events such as dissections.

PMID:29948025 SUPPORT Human Clinical

"Few data exist regarding predictors of rapid aortic root dilation and referral for aortic surgery in Marfan syndrome (MFS)."

The study investigates predictors for referral for aortic surgery in patients with Marfan syndrome, indicating that surgery is recommended for severe aortic dilation.

Orthopedic Interventions

Action: surgical procedure MAXO:0000004

Treatments for scoliosis and other skeletal abnormalities.

Show evidence (5 references)

PMID:11961443 SUPPORT Human Clinical

"The authors recommend arthrodesing both the primary and secondary curves in all patients with Marfan syndrome."

The study discusses surgical treatment of scoliosis in Marfan syndrome and provides guidelines for successful outcomes through orthopedic interventions.

PMID:11880731 SUPPORT Human Clinical

"The major orthopedic manifestations of Marfan syndrome include scoliosis, chest wall deformity, dural ectasia, joint hypermobility, and acetabular protrusion."

This review highlights the orthopedic aspects of Marfan syndrome, including treatments for scoliosis and other skeletal abnormalities.

PMID:34916231 SUPPORT Human Clinical

"We elucidated the genetic risk factors for the development of severe scoliosis in patients with Marfan syndrome."

The study investigates the genetic risk factors for severe scoliosis in Marfan syndrome, which is relevant to orthopedic interventions.

+ 2 more references

Vision Correction

Action: surgical procedure MAXO:0000004

Management of ocular issues such as ectopia lentis with glasses or surgery.

Show evidence (3 references)

PMID:24698610 SUPPORT Human Clinical

"Anterior lensectomy and limited vitrectomy with aphakic correction is safe and provides a consistent visual outcome in patients with lens subluxation secondary to Marfan syndrome."

The study discusses surgical management of ectopia lentis in Marfan syndrome patients, which supports the statement about managing ocular issues with surgery.

PMID:23661206 SUPPORT Human Clinical

"The ocular features were ectopia lentis in 92.3% of the patients... The best corrected visual acuity in 4 out of 5 patients who had cataract extraction at 8 weeks post op. was 6/60 to 6/12."

This study highlights the use of surgical intervention for vision correction in Marfan syndrome patients with ectopia lentis.

PMID:30260057 SUPPORT Human Clinical

"Our study indicates that even though EL typically occurs at an early stage in most MFS patients, there is still a risk of developing EL in adulthood."

The study confirms the management of ectopia lentis (EL) in Marfan syndrome, indicating the necessity for vision correction, which can include glasses or surgery.

🌍

Environmental Factors

1

Physical Activity Restrictions

Avoidance of strenuous isometric exercise and contact sports to reduce hemodynamic stress on the aorta.

Show evidence (3 references)

PMID:9789865 SUPPORT Human Clinical

"The person with Marfan syndrome is often tall and agile and may unknowingly participate in certain physical activities and sports, putting himself or herself at risk for aortic dissection and sudden death."

The article suggests that physical activity restrictions are necessary to prevent aortic dissection in individuals with Marfan syndrome.

PMID:36453629 SUPPORT Human Clinical

"We instructed patients to take 10 000 steps per day, tracked by an activity tracker... AoR Z score in the intervention group had a significantly lower rate of change per year compared with the controls (rate of change, -0.24 versus +0.008; P=0.01)."

The study indicates that controlled physical activity can reduce the rate of aortic root dilation, which is associated with a lower risk of aortic dissection.

PMID:28947563 SUPPORT Model Organism

"Over the 5-month experimental period, aortic root dilation rate was significantly greater in the sedentary MF group, compared with the wild-type group (∆mm, 0.27±0.07 versus 0.13±0.02, respectively). Exercise significantly blunted the aortic root dilation rate in MF mice compared with sedentary..."

Moderate dynamic exercise mitigates the progression of cardiovascular issues in Marfan syndrome, indirectly supporting the idea that physical activity restrictions can help manage aortic dissection risk.

🔬

Biochemical Markers

1

Fibrillin-1 Protein (Abnormal)

Context: Can be used in research settings but not routine diagnostics.

Show evidence (4 references)

PMID:8180508 REFUTE Human Clinical

"Analysis of fibrillin protein or gene defects in individuals with related phenotypes has revealed that a perinatal lethal syndrome, termed neonatal Marfan syndrome, is due to FBN1 gene mutations."

The literature indicates that fibrillin-1 protein abnormalities are directly linked to Marfan syndrome, which is relevant for both research and diagnostic purposes.

PMID:9586151 REFUTE Human Clinical

"New diagnostic insights have eventually led to revised nosologic criteria for the diagnosis of Marfan syndrome."

The literature discusses the importance of fibrillin-1 in the diagnosis of Marfan syndrome, indicating its relevance in routine diagnostics.

PMID:22705998 REFUTE Model Organism

"Although historically Marfan syndrome (MFS) has always been considered as a condition caused by the deficiency of a structural extracellular matrix protein, fibrillin-1, the study of Marfan mouse models and Marfan-related conditions has shifted our current understanding to a pathogenic model..."

The literature highlights the role of fibrillin-1 in the pathogenesis of Marfan syndrome, which is essential for both research and diagnostic purposes.

+ 1 more reference

📊

Related Datasets

2

Advanced Study of Aortic Pathology (ASAP) geo:GSE26155

Advanced Study of Aortic Pathology (ASAP) dataset comparing aortic tissue gene expression from patients with thoracic aortic aneurysms and bicuspid (BAV) vs tricuspid (TAV) aortic valves. Includes mammary artery controls and transplant donor samples.

human MICROARRAY n=96 Affymetrix Human Exon 1.0 ST Array

thoracic aorta tissue

Conditions: dilated aorta BAV dilated aorta TAV non-dilated aorta mammary artery control

Identifies immune response genes elevated in dilated TAV aortic tissue. Relevant for studying aortic aneurysm pathogenesis in connective tissue disorders including Marfan syndrome.

Genome-wide analysis of gene expression of ascending aorta from patients with acute Stanford type A aortic dissection geo:GSE52093

Gene expression profiling comparing dissected ascending aorta tissue from acute Stanford type A aortic dissection patients to normal aorta controls, identifying pathogenesis pathways.

human MICROARRAY n=12 Illumina HumanHT-12 V4.0 expression beadchip

ascending aorta tissue

Conditions: acute aortic dissection normal aorta control

Identifies genes with altered expression in aortic dissection, providing insights into pathogenesis relevant to Marfan syndrome cardiovascular complications

{ }

Source YAML

click to show

name: Marfan Syndrome
creation_date: '2025-12-04T16:57:31Z'
updated_date: '2026-04-27T12:39:26Z'
description: Marfan syndrome is an autosomal dominant connective tissue disorder caused by mutations in FBN1, which encodes fibrillin-1. It affects multiple organ systems including the cardiovascular system (aortic root dilation and dissection), skeleton (tall stature, arachnodactyly, scoliosis), and eyes (ectopia lentis).
category: Genetic
parents:
- Connective Tissue Disorder
mappings:
  icd10cm_mappings:
  - term:
      id: ICD10CM:Q87.4
      label: Marfan syndrome
    mapping_predicate: skos:exactMatch
    mapping_source: ORPHA:558
    mapping_justification: Orphanet lists ICD-10 Q87.4 as an exact cross-reference for Marfan syndrome.
    consistency:
    - reference: ORPHA:558
      consistent: CONSISTENT
      notes: "ICD-10:Q87.4 | Exact"
  icd11f_mappings:
  - term:
      id: icd11f:236564145
      label: Marfan syndrome
    mapping_predicate: skos:exactMatch
    mapping_source: ORPHA:558
    mapping_justification: Orphanet lists ICD-11 LD28.01 as an exact cross-reference; the local ICD-11 Foundation ontology represents this as icd11f:236564145.
    consistency:
    - reference: ORPHA:558
      consistent: CONSISTENT
      notes: "ICD-11:LD28.01 | Exact"
  mondo_mappings:
  - term:
      id: MONDO:0007947
      label: Marfan syndrome
    mapping_predicate: skos:exactMatch
    mapping_source: ORPHA:558
    mapping_justification: Orphanet lists MONDO:0007947 as an exact cross-reference for Marfan syndrome.
    consistency:
    - reference: ORPHA:558
      consistent: CONSISTENT
      notes: "MONDO:0007947 | Exact"
definitions:
- name: Orphanet disease definition
  definition_type: CASE_DEFINITION
  description: >
    Orphanet defines Marfan syndrome as a systemic connective-tissue disease
    with cardiovascular, musculo-skeletal, ophthalmic, and pulmonary
    manifestations.
  evidence:
  - reference: ORPHA:558
    reference_title: "Marfan syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Marfan syndrome is a systemic disease of connective tissue characterized by a variable combination of cardiovascular, musculo-skeletal, ophthalmic and pulmonary manifestations."
    explanation: Orphanet's definition supports the multisystem connective-tissue framing of this entry.
external_assertions:
- name: Orphanet Marfan syndrome record
  source: Orphanet
  assertion_type: Structured disease record
  external_id: ORPHA:558
  url: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=558
  description: >
    Orphanet structured record for Marfan syndrome, including curated
    cross-references to MONDO, ICD-10, ICD-11, OMIM, MeSH, MedDRA, and UMLS
    identifiers.
  evidence:
  - reference: ORPHA:558
    reference_title: "Marfan syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MONDO:0007947 | Exact"
    explanation: The Orphanet cross-reference table exactly maps ORPHA:558 to MONDO:0007947.
  - reference: ORPHA:558
    reference_title: "Marfan syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ICD-10:Q87.4 | Exact"
    explanation: The Orphanet cross-reference table exactly maps ORPHA:558 to ICD-10 Q87.4.
  - reference: ORPHA:558
    reference_title: "Marfan syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ICD-11:LD28.01 | Exact"
    explanation: The Orphanet cross-reference table exactly maps ORPHA:558 to ICD-11 LD28.01.
  - reference: ORPHA:558
    reference_title: "Marfan syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "UMLS:C0024796 | Exact"
    explanation: The Orphanet cross-reference table exactly maps ORPHA:558 to UMLS C0024796.
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: ORPHA:558
    reference_title: "Marfan syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Autosomal dominant"
    explanation: Orphanet records autosomal dominant inheritance for Marfan syndrome.
prevalence:
- population: Global
  percentage: 0.01-0.02
  evidence:
  - reference: PMID:21308160
    reference_title: "Marfan's syndrome: an overview."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: Marfan's syndrome is an autosomal dominant condition with an estimated prevalence of one in 10,000 to 20,000 individuals.
    explanation: The statement is partially supported as the prevalence is given in a range (0.01-0.02) which matches the statement's value range, but it's not explicitly stated as a percentage of the global population.
  - reference: PMID:26631233
    reference_title: "Prevalence, incidence, and age at diagnosis in Marfan Syndrome."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: We identified a total of 1628 persons with possible Marfan syndrome. We confirmed the diagnosis in 412, whereof 46 were deceased, yielding a maximum prevalence of 6.5/100,000 at the end of 2014.
    explanation: This study reports a maximum prevalence of 6.5/100,000, which is lower than the 0.01-0.02 percentage range stated in the question.
- population: Worldwide (Orphanet point prevalence)
  percentage: 0.01-0.05
  notes: Orphanet reports a worldwide point-prevalence class of 1-5 per 10,000.
  evidence:
  - reference: ORPHA:558
    reference_title: "Marfan syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "1-5 / 10 000 | Worldwide | Point prevalence | PMID:20301510"
    explanation: The Orphanet epidemiology table provides a worldwide point-prevalence class for Marfan syndrome.
progression:
- phase: Onset
  age_range: All ages
  evidence:
  - reference: ORPHA:558
    reference_title: "Marfan syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Age of onset: All ages"
    explanation: Orphanet records all ages as the age-of-onset category for Marfan syndrome.
  - reference: PMID:28383843
    reference_title: "[Marfan syndrome in childhood and adolescence]."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: The expression of the Marfan syndrome varies from the severe neonatal presentation to the classical manifestations of the child and young adult, but also comprises isolated features.
    explanation: The reference indicates that Marfan syndrome can manifest from neonatal stages to young adulthood, but it does not fully cover the all-age onset category.
  - reference: PMID:35420547
    reference_title: "A clinical scoring system for early onset (neonatal) Marfan syndrome."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: Distinct from classical Marfan syndrome in phenotype and morbidity, eoMFS can be diagnosed clinically using an objective scoring system encompassing the typical physical features and cardiac disease manifestations.
    explanation: This reference discusses early onset Marfan syndrome (eoMFS), which can be diagnosed in early childhood. However, it does not specify that the onset is restricted to childhood-adolescence.
  - reference: PMID:26631233
    reference_title: "Prevalence, incidence, and age at diagnosis in Marfan Syndrome."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: 'We found a median age at diagnose of 19.0 years (range: 0.0-74).'
    explanation: This study reports a broad age-at-diagnosis range from birth to older adulthood, partially supporting a broad age-of-recognition spectrum while not directly measuring biological onset.
  - reference: PMID:38728377
    reference_title: "Mitral annular disjunction and its progression during childhood in Marfan syndrome."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: MAD was found in children of all ages, increased +0.18 mm/year (95% CI +0.14, +0.22) during a median duration of 5.5 years (IQR 3.1, 7.5 years).
    explanation: This study indicates that mitral annular disjunction (MAD) associated with Marfan syndrome can be detected in children of all ages, but it does not confirm that the onset of Marfan syndrome itself is restricted to childhood-adolescence.
mechanistic_hypotheses:
- hypothesis_group_id: canonical_fbn1_tgfb_dysregulation_model
  hypothesis_label: Canonical FBN1 Loss / TGF-β Dysregulation Model
  status: CANONICAL
  description: >-
    Heterozygous FBN1 pathogenic variants reduce or qualitatively alter fibrillin-1 microfibrils, the extracellular scaffold that both confers elastic-fiber mechanical integrity and sequesters latent TGF-β complexes. Loss of microfibrillar function therefore produces a dual lesion: (1) structural weakness of elastin-rich tissues (aortic media, suspensory ligament of the lens, dura, lung, skin, mitral valve) and (2) excess bioavailable TGF-β with downstream Smad2/3 and non-canonical pathway activation in aortic wall and other tissues. The result is the characteristic multisystem phenotype — progressive aortic root aneurysm and dissection, ectopia lentis, dolichostenomelia, scoliosis, dural ectasia, mitral valve prolapse, and pulmonary blebs. Losartan and other angiotensin/TGF-β-axis inhibitors that reduce aortic-wall TGF-β signaling provide interventional support for the TGF-β-dysregulation component.
  notes: >-
    Retained as CANONICAL. The 2026 falcon
    hypothesis-search report
    (kb/hypotheses/Marfan_Syndrome/canonical_fbn1_tgfb_dysregulation_model;
    openscientist timed out) confirms the dual-lesion model:
    heterozygous FBN1 variants cause microfibrillar mechanical
    failure AND excess bioavailable TGF-β with downstream Smad2/3
    activation. Three qualifications: (1) the relative contribution
    of structural-weakness vs TGF-β-signaling components varies
    by tissue and variant — ectopia lentis is primarily structural
    while aortic aneurysm involves substantial TGF-β-driven
    medial degeneration and matrix remodeling; (2) losartan's
    clinical benefit on aortic root growth in pediatric MFS is
    modest in head-to-head trials with atenolol, indicating that
    TGF-β antagonism alone does not fully prevent dissection
    risk and that hemodynamic stress reduction remains critical;
    (3) Loeys-Dietz syndrome (TGFBR1/TGFBR2 mutations) and
    related TGF-β-pathway disorders display a more aggressive
    aneurysm phenotype, indicating that the TGF-β-axis can be
    pathogenic even when fibrillin-1 is intact, qualifying the
    necessity of microfibrillar disruption for the aortic
    phenotype.
  evidence:
  - reference: PMID:39096853
    reference_title: "Generation of Marfan syndrome-specific induced pluripotent stem cells harboring FBN1 mutations."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Marfan syndrome (MFS) is a hereditary condition caused by mutations in the FBN1 gene."
    explanation: >
      iPSC generation paper from Marfan patient-derived cells with FBN1 mutations;
      used as seed reference for the falcon hypothesis-search deep-research run.
      Documents the canonical FBN1-mutation → fibrillin-1-dysfunction axis at the
      cellular level.
pathophysiology:
- name: FBN1 Gene Mutation
  conforms_to: "aortopathy_tgfbeta_dysregulation#Aortic Wall ECM or Contractile Apparatus Defect"
  description: Mutations in the FBN1 gene result in defective fibrillin-1 protein, which affects the elasticity and strength of connective tissues.
  gene:
    preferred_term: FBN1
    description: Gene encoding fibrillin-1, a structural glycoprotein essential for elastic fiber formation in connective tissue.
    term:
      id: hgnc:3603
      label: FBN1
  cell_types:
  - preferred_term: vascular associated smooth muscle cell
    term:
      id: CL:0000359
      label: vascular associated smooth muscle cell
  biological_processes:
  - preferred_term: elastic fiber assembly
    term:
      id: GO:0048251
      label: elastic fiber assembly
    modifier: DECREASED
  evidence:
  - reference: PMID:8180508
    reference_title: "Identification of defects in the fibrillin gene and protein in individuals with the Marfan syndrome and related disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The gene encoding for fibrillin, the FBN1 gene on chromosome 15, has been identified as the defective gene causing the Marfan syndrome. Fibrillin is the large glycoprotein with a repetitive domain structure and is a major protein component of microfibrils, a fibrillar system closely associated with elastin in connective tissue.
    explanation: The statement is supported by the identification of the FBN1 gene as the cause of Marfan syndrome and its role in the structure of connective tissue.
  - reference: PMID:39096853
    reference_title: "Generation of Marfan syndrome-specific induced pluripotent stem cells harboring FBN1 mutations."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Marfan syndrome (MFS) is a hereditary condition caused by mutations in the FBN1 gene. Genetic mutations in the FBN1 locus impact the function of the encoded protein, Fibrillin 1, a structural molecule forming microfibrils found in the connective tissue.
    explanation: The statement is supported by the description of FBN1 mutations affecting the function of fibrillin-1, which is crucial for connective tissue structure.
  - reference: PMID:17657824
    reference_title: "The importance of mutation detection in Marfan syndrome and Marfan-related disorders: report of 193 FBN1 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Mutations in the FBN1 gene have been characterised in patients affected by Marfan syndrome and Marfan-related disorders.
    explanation: The statement is supported by the identification of FBN1 mutations in Marfan syndrome patients.
  - reference: PMID:12938084
    reference_title: "Update of the UMD-FBN1 mutation database and creation of an FBN1 polymorphism database."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Fibrillin is the major component of extracellular microfibrils. Mutations in the fibrillin gene on chromosome 15 (FBN1) were first described in the heritable connective disorder, Marfan syndrome (MFS).
    explanation: The statement is supported by the role of fibrillin as a major component of microfibrils and the impact of FBN1 mutations on connective tissue.
  - reference: PMID:24555249
    reference_title: "[Marfan syndrome]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Marfan syndrome is a genetic disorder of the connective tissue caused by mutations in FBN1 gene.
    explanation: The statement is supported by the description of Marfan syndrome as a genetic disorder caused by FBN1 mutations.
  - reference: PMID:36004597
    reference_title: "[Ocular manifestations of Marfan syndrome]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Marfan syndrome is an orphan disease that is caused by a mutation in the FBN1 gene located on chromosome 15 (15q21.1) and is usually inherited in an autosomal dominant manner.
    explanation: The statement is supported by the identification of FBN1 mutations as the cause of Marfan syndrome.
  - reference: PMID:25729264
    reference_title: "C596G mutation in FBN1 causes Marfan syndrome with exotropia in a Chinese family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: A C596G mutation in FBN1 was identified in a Chinese family with MFS. Our results expand the spectrum of FBN1 mutations and contribute to the understanding of the role of FBN1 in the pathogenesis of Marfan syndrome.
    explanation: The statement is supported by the identification of specific FBN1 mutations in Marfan syndrome patients and their impact on connective tissue.
  downstream:
  - target: Dysregulated TGF-beta Signaling
    description: Defective fibrillin microfibrils fail to properly sequester latent TGF-beta complexes.
  - target: Extracellular Matrix Remodeling
    description: Loss of normal fibrillin scaffold destabilizes elastic fiber architecture and ECM integrity.
  - target: Impaired Mechanotransduction
    description: Altered fibrillin-integrin interactions impair mechanosensing in load-bearing connective tissues.
- name: Dysregulated TGF-beta Signaling
  conforms_to: "aortopathy_tgfbeta_dysregulation#TGF-beta Signaling Dysregulation"
  description: Defective fibrillin-1 microfibrils fail to sequester latent TGF-beta complexes, leading to increased bioavailable TGF-beta and excessive SMAD2/3 signaling that drives vascular smooth muscle cell phenotypic switching and ECM remodeling.
  biological_processes:
  - preferred_term: transforming growth factor beta receptor signaling pathway
    term:
      id: GO:0007179
      label: transforming growth factor beta receptor signaling pathway
    modifier: INCREASED
  - preferred_term: SMAD protein signal transduction
    term:
      id: GO:0060395
      label: SMAD protein signal transduction
    modifier: INCREASED
  cell_types:
  - preferred_term: vascular associated smooth muscle cell
    term:
      id: CL:0000359
      label: vascular associated smooth muscle cell
  locations:
  - preferred_term: aorta
    term:
      id: UBERON:0000947
      label: aorta
  downstream:
  - target: Extracellular Matrix Remodeling
    description: Excess SMAD signaling increases protease activity and maladaptive ECM turnover.
  - target: Aortic Root Aneurysm
    description: Persistent TGF-beta activity accelerates medial degeneration and progressive root dilation.
  - target: Tall Stature
    description: Dysregulated growth factor signaling contributes to long bone overgrowth.
  - target: Arachnodactyly
    description: Abnormal connective tissue growth signaling contributes to elongated digits.
- name: Extracellular Matrix Remodeling
  conforms_to: "aortopathy_tgfbeta_dysregulation#Aortic Medial Degeneration and Wall Weakening"
  description: Increased matrix metalloproteinase activity, elastic fiber fragmentation, altered collagen composition, and proteoglycan accumulation (especially versican) weaken the aortic wall medial layer.
  biological_processes:
  - preferred_term: extracellular matrix organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: DYSREGULATED
  - preferred_term: proteolysis
    term:
      id: GO:0006508
      label: proteolysis
  cell_types:
  - preferred_term: vascular associated smooth muscle cell
    term:
      id: CL:0000359
      label: vascular associated smooth muscle cell
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  locations:
  - preferred_term: aorta tunica media
    term:
      id: UBERON:0003618
      label: aorta tunica media
  downstream:
  - target: Aortic Aneurysm
    description: Elastic fiber fragmentation and collagen disarray weaken the aortic wall.
  - target: Mitral Valve Prolapse
    description: Connective tissue degeneration in valve leaflets promotes prolapse.
  - target: Ectopia Lentis
    description: Weak zonular microfibrils predispose to lens displacement.
  - target: Scoliosis
    description: Ligamentous laxity and vertebral connective tissue weakness promote spinal curvature.
  - target: Spontaneous Pneumothorax
    description: Fragile connective tissue in lung apices increases risk of spontaneous pneumothorax.
- name: Impaired Mechanotransduction
  description: Perturbed integrin-fibrillin interactions alter focal adhesion signaling and mechanosensing, contributing to maladaptive vascular smooth muscle cell responses to hemodynamic stress.
  biological_processes:
  - preferred_term: cellular response to mechanical stimulus
    term:
      id: GO:0071260
      label: cellular response to mechanical stimulus
  - preferred_term: integrin-mediated signaling pathway
    term:
      id: GO:0007229
      label: integrin-mediated signaling pathway
  cell_types:
  - preferred_term: vascular associated smooth muscle cell
    term:
      id: CL:0000359
      label: vascular associated smooth muscle cell
  - preferred_term: endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  locations:
  - preferred_term: aorta
    term:
      id: UBERON:0000947
      label: aorta
  downstream:
  - target: Aortic Root Aneurysm
    description: Maladaptive vascular smooth muscle responses to pulsatile stress accelerate root enlargement.
- name: Vascular Inflammation
  description: Angiotensin II type 1 receptor signaling and chemokine pathways recruit macrophages and promote inflammatory mediators that exacerbate vascular smooth muscle cell dysfunction and ECM degradation.
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
  - preferred_term: leukocyte migration
    term:
      id: GO:0050900
      label: leukocyte migration
  cell_types:
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  - preferred_term: vascular associated smooth muscle cell
    term:
      id: CL:0000359
      label: vascular associated smooth muscle cell
  locations:
  - preferred_term: aorta tunica intima
    term:
      id: UBERON:0003619
      label: aorta tunica intima
  - preferred_term: aorta tunica media
    term:
      id: UBERON:0003618
      label: aorta tunica media
  downstream:
  - target: Aortic Dissection
    description: Inflammatory ECM damage and smooth muscle dysfunction increase risk of acute intimal tearing.
- name: Mitochondrial Dysfunction
  description: Emerging evidence implicates mitochondrial dysfunction and oxidative stress in vascular smooth muscle cells and endothelial cells as contributors to thoracic aortic aneurysm progression in Marfan syndrome.
  biological_processes:
  - preferred_term: mitochondrial ATP synthesis coupled electron transport
    term:
      id: GO:0042775
      label: mitochondrial ATP synthesis coupled electron transport
  - preferred_term: response to oxidative stress
    term:
      id: GO:0006979
      label: response to oxidative stress
  cell_types:
  - preferred_term: vascular associated smooth muscle cell
    term:
      id: CL:0000359
      label: vascular associated smooth muscle cell
  - preferred_term: endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  locations:
  - preferred_term: aorta
    term:
      id: UBERON:0000947
      label: aorta
  downstream:
  - target: Aortic Dissection
    description: Oxidative injury amplifies wall fragility and susceptibility to dissection in advanced disease.
phenotypes:
- category: Cardiovascular
  name: Aortic Aneurysm
  description: Progressive dilation of the aortic root beginning in childhood, with risk of life-threatening aortic dissection.
  frequency: VERY_FREQUENT
  diagnostic: true
  sequelae:
  - target: Aortic Dissection
    description: Progressive dilation weakens the aortic wall, predisposing to acute dissection.
    evidence:
    - reference: PMID:16321689
      reference_title: "Determinants of rapid progression of aortic root dilatation and complications in Marfan syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Aortic dissection occurred more frequently in group R (7 patients, 47%) than in group S (0%, P < 0.001).
      explanation: This study demonstrates that rapid aortic root dilation significantly increases dissection risk, with 47% dissection rate in rapidly progressing patients.
  evidence:
  - reference: PMID:21797750
    reference_title: "Cardiovascular surgery in Marfan syndrome: implications of new molecular concepts in thoracic aortic disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: MFS is one of the most common inherited connective tissue disorders affecting 1 in 5000 individuals. Although the phenotype of MFS can be quite variable, aneurysmal dilation of the aortic root and consecutive acute aortic dissection is the leading cause of death in this patient population.
    explanation: This reference confirms that aortic aneurysm and aortic dissection are frequent cardiovascular manifestations in Marfan Syndrome.
  - reference: PMID:36058493
    reference_title: "Early Onset Marfan Syndrome with multivalvular insufficiency: Report from a tertiary hospital in Tanzania, and a review of the recurrent c.7606G>A p.0 variant in FBN1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Early Onset Marfan Syndrome is at the severe end of the Marfan syndrome spectrum and is frequently associated with variants in exons 24-32 of the FBN1 gene.
    explanation: The literature discusses the severe cardiovascular manifestations of Marfan Syndrome, supporting the frequent occurrence of aortic aneurysm and dissection.
  - reference: PMID:20364556
    reference_title: "Clinical presentation and echocardiographic findings of Thai patients with Marfan syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The majority of those individuals had significant organ involvement including dilatation of ascending aorta (78%).
    explanation: This study indicates a high frequency of aortic dilation, a precursor to aortic aneurysm, among Marfan Syndrome patients.
  - reference: PMID:32290873
    reference_title: "Clinical significance of family history and bicuspid aortic valve in children and young adult patients with Marfan syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Marfan syndrome is an autosomal dominant disorder of the connective tissue, whose cardinal features affect eyes, musculoskeletal, and cardiovascular system.
    explanation: The study highlights the cardiovascular system as a primary area affected in Marfan Syndrome, supporting the frequent occurrence of aortic aneurysms and dissection.
  - reference: PMID:7911041
    reference_title: "Cardiovascular molecular genetics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The relation between Marfan syndrome and fibrillin mutations and that between supravalvular aortic stenosis and William syndromes and elastin mutations are reviewed.
    explanation: This reference discusses the genetic basis of cardiovascular issues in Marfan Syndrome, supporting the frequent occurrence of aortic aneurysm and dissection.
  - reference: ORPHA:558
    reference_title: "Marfan syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0004942 | Aortic aneurysm | Very frequent (99-80%)"
    explanation: Orphanet's curated HPO frequency annotation classifies aortic aneurysm as Very frequent (99-80%) in Marfan syndrome.
  phenotype_term:
    preferred_term: Aortic Aneurysm
    description: Abnormal dilation of the aorta due to weakening of the vessel wall.
    term:
      id: HP:0004942
      label: Aortic aneurysm
- category: Musculoskeletal
  name: Tall Stature
  description: Disproportionately tall stature with long limbs and increased arm span-to-height ratio.
  frequency: VERY_FREQUENT
  diagnostic: true
  evidence:
  - reference: PMID:28846673
    reference_title: "Skeletal evolution in Marfan syndrome: growth curves from a French national cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Boys and girls from the MFS group were significantly taller than those in the non-MFS group and in the reference group at all ages (P<0.0001).
    explanation: The study found that children with Marfan syndrome were significantly taller than their non-MFS counterparts at all ages, supporting the statement that tall stature is a very frequent musculoskeletal diagnostic feature of Marfan syndrome.
  - reference: PMID:36058493
    reference_title: "Early Onset Marfan Syndrome with multivalvular insufficiency: Report from a tertiary hospital in Tanzania, and a review of the recurrent c.7606G>A p.0 variant in FBN1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Early Onset Marfan Syndrome is at the severe end of the Marfan syndrome spectrum and is frequently associated with variants in exons 24-32 of the FBN1 gene... presented with tall stature.
    explanation: The report mentions that tall stature is frequently associated with Early Onset Marfan Syndrome, supporting the statement.
  - reference: PMID:31751304
    reference_title: "Genetic investigation of patients with tall stature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We selected 42 patients with tall stature after exclusion of pathologies in GH/IGF1 axis and divided them into syndromic (n = 30) and non-syndromic (n = 12) subgroups... FBN1 = 3...
    explanation: The genetic investigation identified FBN1 mutations, which are associated with Marfan syndrome, in patients with tall stature, supporting the statement.
  - reference: ORPHA:558
    reference_title: "Marfan syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001519 | Disproportionate tall stature | Very frequent (99-80%)"
    explanation: Orphanet's curated HPO frequency annotation classifies disproportionate tall stature as Very frequent (99-80%) in Marfan syndrome.
  phenotype_term:
    preferred_term: Disproportionate tall stature
    description: Height significantly above the population mean with disproportionate limb and body proportions.
    term:
      id: HP:0001519
      label: Disproportionate tall stature
- category: Musculoskeletal
  name: Arachnodactyly
  description: Abnormally long, slender fingers and toes (spider-like digits), often demonstrated by positive wrist and thumb signs.
  frequency: VERY_FREQUENT
  diagnostic: true
  evidence:
  - reference: PMID:34021688
    reference_title: "Arachnodactyly represented in art."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Arachnodactyly, a term used since 1902 to describe abnormally long (spider-like) fingers, is a pathologic feature of several heritable conditions, notably the Marfan syndrome...
    explanation: The literature states that arachnodactyly is a notable feature of Marfan syndrome.
  - reference: PMID:23478494
    reference_title: "Arachnodactyly--a key to diagnosing heritable disorders of connective tissue."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Arachnodactyly literally means spidery fingers, and describes the long, slender fingers typical of patients with Marfan syndrome (MFS).
    explanation: This reference confirms that arachnodactyly is a typical feature of Marfan syndrome.
  - reference: ORPHA:558
    reference_title: "Marfan syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001166 | Arachnodactyly | Very frequent (99-80%)"
    explanation: Orphanet's curated HPO frequency annotation classifies arachnodactyly as Very frequent (99-80%) in Marfan syndrome, independently supporting the VERY_FREQUENT frequency assertion.
  phenotype_term:
    preferred_term: Arachnodactyly
    description: Abnormally long and slender fingers and toes resembling spider legs.
    term:
      id: HP:0001166
      label: Arachnodactyly
- category: Ocular
  name: Ectopia Lentis
  description: Superior and temporal displacement of the lens due to weakened zonular fibers, affecting visual acuity.
  frequency: FREQUENT
  diagnostic: true
  notes: Dislocation of the lens
  evidence:
  - reference: PMID:28902582
    reference_title: "Marfan's Syndrome with Ectopia Lentis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Marfan's Syndrome with Ectopia Lentis.
    explanation: The title directly links Marfan Syndrome with ectopia lentis.
  - reference: PMID:24853997
    reference_title: "Ocular findings in 87 adults with Ghent-1 verified Marfan syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In this strictly defined MFS group fulfilling the Ghent-1 criteria, the prevalence of EL was 62.1%.
    explanation: The study reports a high prevalence (62.1%) of ectopia lentis in individuals with Marfan Syndrome, supporting the statement that it is a frequent ocular diagnostic feature.
  - reference: PMID:18090894
    reference_title: "Pathophysiology of zonular diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The mechanisms implicated in the clinical manifestations of zonular diseases, especially ectopia lentis, are reviewed.
    explanation: The abstract mentions ectopia lentis as a clinical manifestation of zonular diseases, which includes Marfan Syndrome.
  - reference: PMID:17134646
    reference_title: "Current concepts of ocular manifestations in Marfan syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Marfan syndrome is a widespread disorder of connective tissue. It is characterized by systemic and ocular features due to mutations in the fibrillin gene.
    explanation: This reference supports the ocular diagnostic aspect of Marfan Syndrome.
  - reference: PMID:11705149
    reference_title: "Management of ectopia lentis in children."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Marfan syndrome, homocystinuria, trauma, and simple ectopia lentis are the most common causes of pediatric lens subluxation.
    explanation: This reference supports the association of Marfan Syndrome with ectopia lentis.
  - reference: PMID:6984233
    reference_title: "Ectopia lentis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Ectopia lentis may cause a marked reduction in visual acuity, which varies with the type and degree of dislocation and the presence of other ocular abnormalities.
    explanation: This reference provides information on the clinical significance of ectopia lentis.
  - reference: PMID:36670079
    reference_title: "Clinical and genetic findings in Chinese families with congenital ectopia lentis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Congenital ectopia lentis (EL) refers to the congenital dysplasia or weakness of the lens suspensory ligament, resulting in an abnormal position of the crystalline lens, which can appear as isolated EL or as an ocular manifestation of a syndrome, such as the Marfan syndrome.
    explanation: This reference supports the statement by linking ectopia lentis as an ocular manifestation of Marfan Syndrome.
  - reference: PMID:38088571
    reference_title: "Uncovering the Hidden World of Aqueous Humor Proteins for Discovery of Biomarkers for Marfan Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Ectopia lentis is a hallmark of Marfan syndrome (MFS), a genetic connective tissue disorder affecting 1/5000 to 1/10 000 individuals worldwide.
    explanation: This reference supports the statement by identifying ectopia lentis as a hallmark of Marfan Syndrome.
  - reference: ORPHA:558
    reference_title: "Marfan syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001083 | Ectopia lentis | Frequent (79-30%)"
    explanation: Orphanet's curated HPO frequency annotation classifies ectopia lentis as Frequent (79-30%) in Marfan syndrome.
  phenotype_term:
    preferred_term: Ectopia Lentis
    description: Displacement or malposition of the crystalline lens from its normal location.
    term:
      id: HP:0001083
      label: Ectopia lentis
- category: Musculoskeletal
  name: Scoliosis
  description: Lateral curvature of the spine occurring in approximately 63% of Marfan syndrome patients, often progressive.
  frequency: FREQUENT
  diagnostic: true
  evidence:
  - reference: PMID:9076882
    reference_title: "Infantile scoliosis in Marfan syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The data on all patients seen at one institution who had Marfan syndrome and scoliosis by age three were reviewed.
    explanation: The study documents cases of scoliosis in patients with Marfan syndrome, supporting the statement that scoliosis is a frequent musculoskeletal diagnostic in Marfan syndrome.
  - reference: PMID:37270806
    reference_title: "Analysis of GPR126 polymorphisms and their relationship with scoliosis in Marfan syndrome and Marfan-like syndrome in Mexican patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: A large cross-sectional study revealed a 63% prevalence of scoliosis among patients with MFS.
    explanation: This study provides statistical evidence of a high prevalence of scoliosis in Marfan syndrome patients, reinforcing that scoliosis is frequent in this condition.
  - reference: PMID:34916231
    reference_title: "Impact of pathogenic FBN1 variant types on the development of severe scoliosis in patients with Marfan syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Among the several musculoskeletal manifestations in patients with Marfan syndrome, spinal deformity causes pain and respiratory impairment and is a great hindrance to patients' daily activities.
    explanation: This study highlights scoliosis as one of the significant musculoskeletal manifestations in Marfan syndrome, supporting its frequent occurrence.
  - reference: PMID:35248143
    reference_title: "Musculoskeletal diseases in Marfan syndrome: a nationwide registry study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'One out of six with Marfan syndrome was registered with scoliosis (HR: 36.7 (27.5-48.9).'
    explanation: The nationwide epidemiological study confirms that scoliosis is a common musculoskeletal diagnosis in Marfan syndrome patients.
  - reference: ORPHA:558
    reference_title: "Marfan syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002650 | Scoliosis | Frequent (79-30%)"
    explanation: Orphanet's curated HPO frequency annotation classifies scoliosis as Frequent (79-30%) in Marfan syndrome.
  phenotype_term:
    preferred_term: Scoliosis
    description: Lateral curvature of the vertebral column.
    term:
      id: HP:0002650
      label: Scoliosis
- category: Respiratory
  name: Spontaneous Pneumothorax
  description: Spontaneous lung collapse occurring in 5-11% of patients due to apical blebs from connective tissue abnormalities.
  frequency: OCCASIONAL
  notes: Orphanet classifies spontaneous pneumothorax as Very frequent (99-80%), whereas PMID:25765122 reports 5-11%; frequency is retained as OCCASIONAL based on the direct quantitative clinical estimate.
  evidence:
  - reference: PMID:31883816
    reference_title: "[Recurrent spontaneous pneumothorax revealing Marfan's syndrome]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Though cardiovascular, skeletal and ophthalmological manifestations are the most frequent features, the respiratory system can also be involved.
    explanation: The reference mentions that Marfan syndrome can involve the respiratory system, including pneumothorax.
  - reference: PMID:25765122
    reference_title: "[Respiratory manifestations of Marfan's syndrome]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Marfan's syndrome is a rare genetic disorder...but minor diagnostic criteria also include pulmonary manifestations. Pneumothorax, frequently relapsing, affects 5 to 11% of patients.
    explanation: The reference states that pneumothorax affects 5 to 11% of patients with Marfan syndrome, supporting the statement that it occurs occasionally.
  - reference: PMID:33896616
    reference_title: "Optimal treatment of pneumothorax in adolescents with Marfan syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Pneumothorax often develops in patients with Marfan syndrome.
    explanation: The reference confirms that pneumothorax is a common occurrence in patients with Marfan syndrome.
  - reference: PMID:21252480
    reference_title: "Pneumothorax and bullae in Marfan syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Increased risk of spontaneous pneumothorax has been described in patients with Marfan syndrome.
    explanation: The reference supports the statement by indicating an increased risk of pneumothorax in Marfan syndrome patients.
  - reference: ORPHA:558
    reference_title: "Marfan syndrome (Orphanet structured-database record)"
    supports: PARTIAL
    evidence_source: OTHER
    snippet: "HP:0002108 | Spontaneous pneumothorax | Very frequent (99-80%)"
    explanation: Orphanet supports the more specific spontaneous pneumothorax phenotype term for Marfan syndrome, but its Very frequent classification conflicts with the 5-11% estimate from PMID:25765122.
  phenotype_term:
    preferred_term: Spontaneous pneumothorax
    description: Pneumothorax occurring without traumatic injury to the chest or lung.
    term:
      id: HP:0002108
      label: Spontaneous pneumothorax
- category: Respiratory
  name: Sleep Apnea
  description: Intermittent cessation of airflow during sleep, reflecting sleep-related breathing involvement reported in Marfan syndrome.
  frequency: FREQUENT
  evidence:
  - reference: ORPHA:558
    reference_title: "Marfan syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0010535 | Sleep apnea | Frequent (79-30%)"
    explanation: Orphanet's curated HPO frequency annotation classifies sleep apnea as Frequent (79-30%) in Marfan syndrome.
  phenotype_term:
    preferred_term: Sleep apnea
    description: Intermittent cessation of airflow at the mouth and nose during sleep.
    term:
      id: HP:0010535
      label: Sleep apnea
- category: Cardiovascular
  name: Aortic Dissection
  description: Life-threatening tear in the aortic wall allowing blood to enter between tissue layers, the leading cause of death in untreated Marfan syndrome.
  frequency: FREQUENT
  evidence:
  - reference: PMID:21797750
    reference_title: "Cardiovascular surgery in Marfan syndrome: implications of new molecular concepts in thoracic aortic disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: MFS is one of the most common inherited connective tissue disorders affecting 1 in 5000 individuals. Although the phenotype of MFS can be quite variable, aneurysmal dilation of the aortic root and consecutive acute aortic dissection is the leading cause of death in this patient population.
    explanation: This reference directly states that aortic dissection is the leading cause of death in Marfan syndrome patients.
  - reference: PMID:16321689
    reference_title: "Determinants of rapid progression of aortic root dilatation and complications in Marfan syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Aortic dissection occurred more frequently in group R (7 patients, 47%) than in group S (0%, P < 0.001).
    explanation: This study demonstrates that aortic dissection is a frequent complication in patients with rapid aortic root dilation.
  - reference: ORPHA:558
    reference_title: "Marfan syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002647 | Aortic dissection | Frequent (79-30%)"
    explanation: Orphanet's curated HPO frequency annotation classifies aortic dissection as Frequent (79-30%) in Marfan syndrome.
  phenotype_term:
    preferred_term: Aortic Dissection
    description: Tear in the inner layer of the aortic wall allowing blood to flow between layers.
    term:
      id: HP:0002647
      label: Aortic dissection
- category: Cardiovascular
  name: Mitral Valve Prolapse
  description: Myxomatous degeneration of mitral valve leaflets causing prolapse into the left atrium during systole, often accompanied by mitral regurgitation.
  frequency: FREQUENT
  evidence:
  - reference: ORPHA:558
    reference_title: "Marfan syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001634 | Mitral valve prolapse | Frequent (79-30%)"
    explanation: Orphanet's curated HPO frequency annotation classifies mitral valve prolapse as Frequent (79-30%) in Marfan syndrome.
  phenotype_term:
    preferred_term: Mitral valve prolapse
    description: Abnormal systolic displacement of mitral valve leaflets into the left atrium.
    term:
      id: HP:0001634
      label: Mitral valve prolapse
- category: Cardiovascular
  name: Tricuspid Valve Prolapse
  description: Abnormal systolic displacement of tricuspid valve leaflets into the right atrium, representing right-sided atrioventricular valve involvement.
  frequency: FREQUENT
  evidence:
  - reference: ORPHA:558
    reference_title: "Marfan syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001704 | Tricuspid valve prolapse | Frequent (79-30%)"
    explanation: Orphanet's curated HPO frequency annotation classifies tricuspid valve prolapse as Frequent (79-30%) in Marfan syndrome.
  phenotype_term:
    preferred_term: Tricuspid valve prolapse
    description: Tricuspid valve leaflets bulge back into the right atrium during right ventricular contraction.
    term:
      id: HP:0001704
      label: Tricuspid valve prolapse
- category: Cardiovascular
  name: Aortic Root Aneurysm
  description: Progressive enlargement of the aortic root diameter, typically measured by echocardiography and tracked using Z-scores adjusted for age and body surface area.
  frequency: VERY_FREQUENT
  diagnostic: true
  evidence:
  - reference: ORPHA:558
    reference_title: "Marfan syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002616 | Aortic root aneurysm | Very frequent (99-80%)"
    explanation: Orphanet's curated HPO frequency annotation classifies aortic root aneurysm as Very frequent (99-80%) in Marfan syndrome.
  phenotype_term:
    preferred_term: Aortic root aneurysm
    description: Abnormal widening of the aortic root.
    term:
      id: HP:0002616
      label: Aortic root aneurysm
- category: Cardiovascular
  name: Ascending Tubular Aorta Aneurysm
  description: Localized widening of the tubular ascending aorta, distinct from the aortic root and relevant to thoracic aortic surveillance.
  frequency: FREQUENT
  evidence:
  - reference: ORPHA:558
    reference_title: "Marfan syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0004970 | Ascending tubular aorta aneurysm | Frequent (79-30%)"
    explanation: Orphanet's curated HPO frequency annotation classifies ascending tubular aorta aneurysm as Frequent (79-30%) in Marfan syndrome.
  phenotype_term:
    preferred_term: Ascending tubular aorta aneurysm
    description: Localized dilatation of the tubular portion of the ascending aorta.
    term:
      id: HP:0004970
      label: Ascending tubular aorta aneurysm
- category: Musculoskeletal
  name: Pectus Carinatum
  description: Protrusion of the sternum and anterior chest wall, a common skeletal manifestation in Marfan syndrome.
  frequency: VERY_FREQUENT
  evidence:
  - reference: ORPHA:558
    reference_title: "Marfan syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000768 | Pectus carinatum | Very frequent (99-80%)"
    explanation: Orphanet's curated HPO frequency annotation classifies pectus carinatum as Very frequent (99-80%) in Marfan syndrome.
  phenotype_term:
    preferred_term: Pectus carinatum
    description: Protrusion of the sternum and ribs.
    term:
      id: HP:0000768
      label: Pectus carinatum
- category: Dermatologic
  name: Striae Distensae
  description: Stretch marks caused by connective-tissue fragility, often occurring without major weight change.
  frequency: VERY_FREQUENT
  evidence:
  - reference: ORPHA:558
    reference_title: "Marfan syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001065 | Striae distensae | Very frequent (99-80%)"
    explanation: Orphanet's curated HPO frequency annotation classifies striae distensae as Very frequent (99-80%) in Marfan syndrome.
  phenotype_term:
    preferred_term: Striae distensae
    description: Linear dermal atrophic streaks caused by skin stretching.
    term:
      id: HP:0001065
      label: Striae distensae
- category: Musculoskeletal
  name: Pes Planus
  description: Flattening of the medial longitudinal arch of the foot.
  frequency: VERY_FREQUENT
  evidence:
  - reference: ORPHA:558
    reference_title: "Marfan syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001763 | Pes planus | Very frequent (99-80%)"
    explanation: Orphanet's curated HPO frequency annotation classifies pes planus as Very frequent (99-80%) in Marfan syndrome.
  phenotype_term:
    preferred_term: Pes planus
    description: Flat foot with reduced or absent medial arch.
    term:
      id: HP:0001763
      label: Pes planus
- category: Constitutional
  name: Slender Build
  description: Thin body habitus with reduced soft-tissue bulk relative to height.
  frequency: VERY_FREQUENT
  evidence:
  - reference: ORPHA:558
    reference_title: "Marfan syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001533 | Slender build | Very frequent (99-80%)"
    explanation: Orphanet's curated HPO frequency annotation classifies slender build as Very frequent (99-80%) in Marfan syndrome.
  phenotype_term:
    preferred_term: Slender build
    description: Thin body habitus.
    term:
      id: HP:0001533
      label: Slender build
- category: Neurological
  name: Dural Ectasia
  description: Widening or ballooning of the dural sac, typically in the lumbosacral spine, reflecting connective-tissue weakness.
  frequency: FREQUENT
  evidence:
  - reference: ORPHA:558
    reference_title: "Marfan syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0100775 | Dural ectasia | Frequent (79-30%)"
    explanation: Orphanet's curated HPO frequency annotation classifies dural ectasia as Frequent (79-30%) in Marfan syndrome.
  phenotype_term:
    preferred_term: Dural ectasia
    description: Abnormal widening of the dural sac.
    term:
      id: HP:0100775
      label: Dural ectasia
- category: Constitutional
  name: Chronic Fatigue
  description: Persistent fatigue disproportionate to activity level, reported as a very frequent quality-of-life burden in Marfan syndrome.
  frequency: VERY_FREQUENT
  evidence:
  - reference: ORPHA:558
    reference_title: "Marfan syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0012432 | Chronic fatigue | Very frequent (99-80%)"
    explanation: Orphanet's curated HPO frequency annotation classifies chronic fatigue as Very frequent (99-80%) in Marfan syndrome.
  phenotype_term:
    preferred_term: Chronic fatigue
    description: Fatigue persisting for six months or longer.
    term:
      id: HP:0012432
      label: Chronic fatigue
- category: Musculoskeletal
  name: Pectus Excavatum
  description: Depression of the sternum and anterior chest wall, producing a caved-in chest-wall contour.
  frequency: FREQUENT
  diagnostic: true
  evidence:
  - reference: ORPHA:558
    reference_title: "Marfan syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000767 | Pectus excavatum | Frequent (79-30%)"
    explanation: Orphanet's curated HPO frequency annotation classifies pectus excavatum as Frequent (79-30%) in Marfan syndrome.
  phenotype_term:
    preferred_term: Pectus excavatum
    description: Depression of the sternum giving the chest a caved-in appearance.
    term:
      id: HP:0000767
      label: Pectus excavatum
- category: Musculoskeletal
  name: Joint Hypermobility
  description: Increased passive or active joint range of motion beyond normal physiological limits.
  frequency: FREQUENT
  diagnostic: true
  evidence:
  - reference: ORPHA:558
    reference_title: "Marfan syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001382 | Joint hypermobility | Frequent (79-30%)"
    explanation: Orphanet's curated HPO frequency annotation classifies joint hypermobility as Frequent (79-30%) in Marfan syndrome.
  phenotype_term:
    preferred_term: Joint hypermobility
    description: Ability of joints to move beyond normal limits along physiological axes.
    term:
      id: HP:0001382
      label: Joint hypermobility
- category: Musculoskeletal
  name: Protrusio Acetabuli
  description: Intrapelvic bulging of the medial acetabular wall, a skeletal feature included in systemic diagnostic scoring.
  frequency: FREQUENT
  diagnostic: true
  evidence:
  - reference: ORPHA:558
    reference_title: "Marfan syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003179 | Protrusio acetabuli | Frequent (79-30%)"
    explanation: Orphanet's curated HPO frequency annotation classifies protrusio acetabuli as Frequent (79-30%) in Marfan syndrome.
  phenotype_term:
    preferred_term: Protrusio acetabuli
    description: Intrapelvic bulging of the medial acetabular wall.
    term:
      id: HP:0003179
      label: Protrusio acetabuli
- category: Ocular
  name: Myopia
  description: Refractive error with clear near vision and blurred distance vision, reflecting ocular involvement in Marfan syndrome.
  frequency: FREQUENT
  diagnostic: true
  evidence:
  - reference: ORPHA:558
    reference_title: "Marfan syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000545 | Myopia | Frequent (79-30%)"
    explanation: Orphanet's curated HPO frequency annotation classifies myopia as Frequent (79-30%) in Marfan syndrome.
  phenotype_term:
    preferred_term: Myopia
    description: Nearsighted refractive error with blurred distance vision.
    term:
      id: HP:0000545
      label: Myopia
- category: Cardiovascular
  name: Mitral Regurgitation
  description: Incompetence of the mitral valve causing retrograde blood flow from the left ventricle into the left atrium during systole.
  frequency: FREQUENT
  evidence:
  - reference: ORPHA:558
    reference_title: "Marfan syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001653 | Mitral regurgitation | Frequent (79-30%)"
    explanation: Orphanet's curated HPO frequency annotation classifies mitral regurgitation as Frequent (79-30%) in Marfan syndrome.
  phenotype_term:
    preferred_term: Mitral regurgitation
    description: Retrograde leaking of blood through the mitral valve upon ventricular contraction.
    term:
      id: HP:0001653
      label: Mitral regurgitation
- category: Cardiovascular
  name: Aortic Regurgitation
  description: Aortic valve insufficiency causing backward blood flow from the aorta into the left ventricle.
  frequency: FREQUENT
  evidence:
  - reference: ORPHA:558
    reference_title: "Marfan syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001659 | Aortic regurgitation | Frequent (79-30%)"
    explanation: Orphanet's curated HPO frequency annotation classifies aortic regurgitation as Frequent (79-30%) in Marfan syndrome.
  phenotype_term:
    preferred_term: Aortic regurgitation
    description: Backward blood flow from the aorta into the left ventricle due to aortic valve insufficiency.
    term:
      id: HP:0001659
      label: Aortic regurgitation
biochemical:
- name: Fibrillin-1 Protein
  presence: Abnormal
  context: Can be used in research settings but not routine diagnostics.
  evidence:
  - reference: PMID:8180508
    reference_title: "Identification of defects in the fibrillin gene and protein in individuals with the Marfan syndrome and related disorders."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: Analysis of fibrillin protein or gene defects in individuals with related phenotypes has revealed that a perinatal lethal syndrome, termed neonatal Marfan syndrome, is due to FBN1 gene mutations.
    explanation: The literature indicates that fibrillin-1 protein abnormalities are directly linked to Marfan syndrome, which is relevant for both research and diagnostic purposes.
  - reference: PMID:9586151
    reference_title: "[Marfan syndrome: diagnosis of cardiovascular manifestations]."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: New diagnostic insights have eventually led to revised nosologic criteria for the diagnosis of Marfan syndrome.
    explanation: The literature discusses the importance of fibrillin-1 in the diagnosis of Marfan syndrome, indicating its relevance in routine diagnostics.
  - reference: PMID:22705998
    reference_title: "Marfan syndrome: from gene to therapy."
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    snippet: Although historically Marfan syndrome (MFS) has always been considered as a condition caused by the deficiency of a structural extracellular matrix protein, fibrillin-1, the study of Marfan mouse models and Marfan-related conditions has shifted our current understanding to a pathogenic model that involves dysregulation of the cytokine-transforming growth factor beta (TGF-beta) signaling.
    explanation: The literature highlights the role of fibrillin-1 in the pathogenesis of Marfan syndrome, which is essential for both research and diagnostic purposes.
  - reference: PMID:37688493
    reference_title: "The usefulness of the genetic panel in the classification and refinement of diagnostic accuracy of Mexican patients with Marfan syndrome and other connective tissue disorders."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: Marfan syndrome (MFS) is a multisystem genetic disorder with over 3000 mutations described in the fibrillin 1 (FBN1) gene.
    explanation: The literature underscores the diagnostic importance of identifying fibrillin-1 mutations in Marfan syndrome.
genetic:
- name: FBN1
  association: Pathogenic Variants
  notes: Primary causative gene encoding fibrillin-1, a structural ECM glycoprotein.
  evidence:
  - reference: PMID:31163209
    reference_title: "FBN1 gene mutations in 26 Hungarian patients with suspected Marfan syndrome or related fibrillinopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: FBN1 gene mutations lead to MFS and related connective tissue disorders.
    explanation: The abstract directly states that FBN1 gene mutations are associated with Marfan syndrome and related disorders.
  - reference: PMID:34916231
    reference_title: "Impact of pathogenic FBN1 variant types on the development of severe scoliosis in patients with Marfan syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We retrospectively evaluated 278 patients with pathogenic or likely pathogenic FBN1 variants.
    explanation: The study focuses on patients with Marfan syndrome who have pathogenic FBN1 variants, supporting the association.
  - reference: PMID:32130918
    reference_title: "Pathogenic FBN1 Genetic Variation and Aortic Dissection in Patients With Marfan Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Aortic risk has not been evaluated in patients with Marfan syndrome and documented pathogenic variants in the FBN1 gene.
    explanation: The study describes aortic risks in patients with Marfan syndrome with pathogenic FBN1 variants, supporting the association.
  - reference: PMID:35419902
    reference_title: "The fibrillinopathies: New insights with focus on the paradigm of opposing phenotypes for both FBN1 and FBN2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Different pathogenic variants in the fibrillin-1 gene (FBN1) cause Marfan syndrome and acromelic dysplasias.
    explanation: The abstract states that pathogenic variants in FBN1 cause Marfan syndrome, supporting the association.
  - reference: PMID:36004597
    reference_title: "[Ocular manifestations of Marfan syndrome]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Marfan syndrome is an orphan disease that is caused by a mutation in the FBN1 gene located on chromosome 15 (15q21.1).
    explanation: The article reviews studies concerning the potential ocular manifestations of Marfan syndrome caused by FBN1 mutations.
  - reference: PMID:30485715
    reference_title: "Autosomal dominant Marfan syndrome caused by a previously reported recessive FBN1 variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Pathogenic variants in FBN1 cause autosomal dominant Marfan syndrome.
    explanation: The abstract states that pathogenic variants in FBN1 cause autosomal dominant Marfan syndrome, supporting the association.
  - reference: PMID:19059503
    reference_title: "Compound-heterozygous Marfan syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We report two families in which the probands have compound-heterozygous Marfan syndrome (MFS).
    explanation: The study reports cases of Marfan syndrome associated with compound-heterozygous FBN1 mutations, supporting the association.
  - reference: CGGV:assertion_d3fc0bea-4d6e-449e-885c-b204e6a0b2bf-2019-03-04T170000.000Z
    reference_title: "FBN1 / Marfan syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "FBN1 | HGNC:3603 | Marfan syndrome | MONDO:0007947 | AD | Definitive"
    explanation: ClinGen classifies the FBN1-Marfan syndrome gene-disease relationship as definitive with autosomal dominant inheritance.
- name: TGFBR1
  association: Implicated
  notes: Type I TGF-beta receptor; variants can cause overlapping Loeys-Dietz syndrome phenotype.
- name: TGFBR2
  association: Implicated
  notes: Type II TGF-beta receptor; mutations alter TGF-beta signaling in aortic disease.
- name: SMAD2
  association: Implicated
  notes: Canonical TGF-beta signaling mediator; nuclear translocation drives ECM remodeling.
- name: SMAD3
  association: Implicated
  notes: TGF-beta effector involved in medial remodeling and inflammatory responses.
- name: ACTA2
  association: Implicated
  notes: Alpha-smooth muscle actin; pathogenic variants cause familial thoracic aortic aneurysm and dissection.
- name: AGTR1
  association: Implicated
  notes: Angiotensin II type 1 receptor; modulates hemodynamic stress and pro-fibrotic signaling.
- name: ITGAV
  association: Implicated
  notes: Integrin alpha-V subunit; mediates cell-ECM adhesion and mechanotransduction.
- name: NOS2
  association: Implicated
  notes: Inducible nitric oxide synthase; upregulated in inflamed aortic tissue.
- name: VCAN
  association: Implicated
  notes: Versican proteoglycan; accumulation drives AKT/NOS2 pathways in aortic disease.
diagnosis:
- name: Genetic Testing for FBN1 Mutations
  description: Sequencing of the FBN1 gene to identify pathogenic variants causing Marfan syndrome.
  presence: Positive in affected individuals
  evidence:
  - reference: PMID:17657824
    reference_title: "The importance of mutation detection in Marfan syndrome and Marfan-related disorders: report of 193 FBN1 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Mutations in the FBN1 gene have been characterised in patients affected by Marfan syndrome and Marfan-related disorders.
    explanation: This study confirms that FBN1 mutations are present in individuals affected by Marfan syndrome.
  - reference: PMID:26903455
    reference_title: "Genetic testing in Marfan syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Genetic testing is aiding rapid diagnosis of Marfan syndrome as a basis for management of eye, heart and skeletal disease.
    explanation: This article supports the presence of genetic testing for FBN1 mutations in individuals with Marfan syndrome.
  - reference: PMID:27234404
    reference_title: "Genetic testing of the FBN1 gene in Chinese patients with Marfan/Marfan-like syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Here, we performed genetic testing of the FBN1 gene in 39 Chinese probands with Marfan/Marfan-like syndrome and their related family members by Sanger sequencing.
    explanation: This research supports the presence of FBN1 mutations in affected individuals through genetic testing.
  - reference: PMID:27906200
    reference_title: "Evaluating the quality of Marfan genotype-phenotype correlations in existing FBN1 databases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Genetic FBN1 testing is pivotal for confirming the clinical diagnosis of Marfan syndrome.
    explanation: The study highlights the importance of FBN1 genetic testing in diagnosing Marfan syndrome.
  - reference: PMID:30166242
    reference_title: "Correction of the Marfan Syndrome Pathogenic FBN1 Mutation by Base Editing in Human Cells and Heterozygous Embryos."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Taking advantage of this technology, we corrected a Marfan syndrome pathogenic mutation, FBN1T7498C.
    explanation: This study demonstrates the presence of a specific FBN1 mutation in individuals with Marfan syndrome.
  - reference: PMID:25652400
    reference_title: "The clinical presentation of Marfan syndrome is modulated by expression of wild-type FBN1 allele."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Marfan syndrome is an autosomal dominant disorder mainly caused by mutations within FBN1 gene.
    explanation: This article supports the presence of FBN1 mutations in individuals with Marfan syndrome.
  - reference: PMID:19059503
    reference_title: "Compound-heterozygous Marfan syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We report two families in which the probands have compound-heterozygous Marfan syndrome (MFS).
    explanation: This study supports the presence of FBN1 mutations in individuals with Marfan syndrome.
  - reference: PMID:20709720
    reference_title: "Cardiovascular manifestations in men and women carrying a FBN1 mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In patients with Marfan syndrome and other type-1 fibrillinopathies, genetic testing is becoming more easily available, leading to the identification of mutations early in the course of the disease.
    explanation: The article supports the identification of FBN1 mutations in individuals with Marfan syndrome through genetic testing.
  - reference: PMID:25652356
    reference_title: "Decreased frequency of FBN1 missense variants in Ghent criteria-positive Marfan syndrome and characterization of novel FBN1 variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Testing yielded 207 pathogenic or likely pathogenic FBN1 variants.
    explanation: This study supports the presence of FBN1 mutations in individuals who meet the Ghent criteria for Marfan syndrome.
- name: Echocardiogram
  description: Ultrasound imaging to measure aortic root diameter and assess cardiac valve function.
  presence: Aortic root dilation
  notes: Often used to monitor cardiovascular complications.
  evidence:
  - reference: PMID:9586151
    reference_title: "[Marfan syndrome: diagnosis of cardiovascular manifestations]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The diagnostic reliability as well as the advantage and limitation of these recent diagnostic strategies are discussed; moreover diagnostic concepts for patients with neonatal as well as classic Marfan syndrome are presented and discussed in the context of the clinical management...
    explanation: The reference discusses the use of echocardiography, among other diagnostic tools, in the evaluation and management of cardiovascular manifestations in Marfan syndrome patients.
  - reference: PMID:33843540
    reference_title: "Comparability of different Z-score equations for aortic root dimensions in children with Marfan syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Aortic root dilation is a major complication of Marfan syndrome and is one of the most important criteria in establishing the diagnosis.
    explanation: The reference highlights that aortic root dilation is a significant complication of Marfan syndrome and is a key criterion for diagnosis, which is typically monitored using echocardiography.
  - reference: PMID:35550817
    reference_title: "Prevalence and Outcomes of Primary Left Ventricular Dysfunction in Marfan Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Even in the absence of significant valvular disease, patients with Marfan syndrome (MFS) have evidence of impaired left ventricular (LV) performance, suggestive of a primary cardiomyopathy.
    explanation: The reference indicates that echocardiography is used to monitor left ventricular performance and other cardiovascular complications in Marfan syndrome patients.
  - reference: PMID:29972109
    reference_title: "Utility of serial 12-lead electrocardiograms in children with Marfan syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Children ≤18 years who met the revised Ghent criteria for Marfan syndrome and received a 12-lead electrocardiogram and echocardiogram within a 3-month period were included.
    explanation: The reference confirms that echocardiograms are routinely used to monitor cardiovascular complications in children with Marfan syndrome.
- name: Slit Lamp Exam
  description: Ophthalmic examination using magnified light to detect lens subluxation and other ocular abnormalities.
  presence: Ectopia lentis
  notes: Used to detect lens dislocation.
  evidence:
  - reference: PMID:24853997
    reference_title: "Ocular findings in 87 adults with Ghent-1 verified Marfan syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The position of the lens was noted by observing the eye in different gaze directions in maximal mydriasis during slit lamp examination.
    explanation: The study confirms that slit lamp examination is used to detect lens dislocation (ectopia lentis) in patients with Marfan syndrome.
environmental:
- name: Physical Activity Restrictions
  description: Avoidance of strenuous isometric exercise and contact sports to reduce hemodynamic stress on the aorta.
  effect: Reduces risk of aortic dissection.
  evidence:
  - reference: PMID:9789865
    reference_title: "Exercise and the Marfan syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The person with Marfan syndrome is often tall and agile and may unknowingly participate in certain physical activities and sports, putting himself or herself at risk for aortic dissection and sudden death.
    explanation: The article suggests that physical activity restrictions are necessary to prevent aortic dissection in individuals with Marfan syndrome.
  - reference: PMID:36453629
    reference_title: "Can 10 000 Healthy Steps a Day Slow Aortic Root Dilation in Pediatric Patients With Marfan Syndrome?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We instructed patients to take 10 000 steps per day, tracked by an activity tracker... AoR Z score in the intervention group had a significantly lower rate of change per year compared with the controls (rate of change, -0.24 versus +0.008; P=0.01).
    explanation: The study indicates that controlled physical activity can reduce the rate of aortic root dilation, which is associated with a lower risk of aortic dissection.
  - reference: PMID:28947563
    reference_title: "Cardiovascular Benefits of Moderate Exercise Training in Marfan Syndrome: Insights From an Animal Model."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Over the 5-month experimental period, aortic root dilation rate was significantly greater in the sedentary MF group, compared with the wild-type group (∆mm, 0.27±0.07 versus 0.13±0.02, respectively). Exercise significantly blunted the aortic root dilation rate in MF mice compared with sedentary MF littermates (∆mm, 0.10±0.04 versus 0.27±0.07, respectively).
    explanation: Moderate dynamic exercise mitigates the progression of cardiovascular issues in Marfan syndrome, indirectly supporting the idea that physical activity restrictions can help manage aortic dissection risk.
  exposure_term:
    preferred_term: Physical activity exposure
    description: Exposure to physical exertion that may impact cardiovascular stress.
    term:
      id: XCO:0000059
      label: physical activity
treatments:
- name: Beta Blockers
  description: Used to reduce stress on the aorta and prevent its enlargement.
  evidence:
  - reference: PMID:36939732
    reference_title: "Drug-based cardiovascular prevention in patients with Marfan Syndrome: a systematic review."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: Beta-blockers remain the mainstay of therapy as they have proven to slow aortic enlargement. Angiotensin receptor blockers are a useful alternative and with proven benefit as an add-on therapy to limit aortic growth.
    explanation: Beta-blockers are used to slow aortic enlargement, which indirectly reduces stress on the aorta. However, they do not prevent aortic enlargement entirely.
  - reference: PMID:17845137
    reference_title: "Therapy of Marfan syndrome."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: Traditional medical therapies, such as beta-adrenergic receptor blockade, are used to slow pathologic aortic growth and decrease the risk of aortic dissection by decreasing hemodynamic stress.
    explanation: Beta-blockers are used to slow aortic growth and decrease hemodynamic stress, but they do not completely prevent aortic enlargement.
  - reference: PMID:17376944
    reference_title: "Marfan's syndrome and the heart."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: Medical treatment with beta-blockers is probably helpful in most children with aortic root dilatation.
    explanation: Beta-blockers are helpful in slowing the progression of aortic root dilatation, but they do not completely prevent it.
  treatment_term:
    preferred_term: beta adrenergic agent therapy
    description: Treatment using medications that block beta-adrenergic receptors to reduce heart rate and blood pressure.
    term:
      id: MAXO:0000186
      label: beta adrenergic agent therapy
- name: Angiotensin Receptor Blockers
  description: ARBs such as losartan reduce aortic root growth by blocking angiotensin II type 1 receptor signaling and modulating TGF-beta pathways. Pediatric data show superior tolerability and efficacy compared to beta-blockers.
  treatment_term:
    preferred_term: Pharmacotherapy
    description: Treatment using medications such as losartan to modulate pathological signaling pathways.
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: losartan
      term:
        id: CHEBI:6541
        label: losartan
- name: Aortic Surgery
  description: Recommended for severe aortic dilation to prevent dissection.
  evidence:
  - reference: PMID:26586198
    reference_title: "Overview of current surgical strategies for aortic disease in patients with Marfan syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: To prevent such catastrophic aortic events, a lower threshold has been recommended for prophylactic interventions on the aortic root.
    explanation: The literature mentions that prophylactic aortic root replacement is recommended to prevent severe aortic events such as dissections.
  - reference: PMID:29948025
    reference_title: "Predictors of Rapid Aortic Root Dilation and Referral for Aortic Surgery in Marfan Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Few data exist regarding predictors of rapid aortic root dilation and referral for aortic surgery in Marfan syndrome (MFS).
    explanation: The study investigates predictors for referral for aortic surgery in patients with Marfan syndrome, indicating that surgery is recommended for severe aortic dilation.
  treatment_term:
    preferred_term: surgical procedure
    description: Operative intervention to repair or replace damaged anatomical structures.
    term:
      id: MAXO:0000004
      label: surgical procedure
- name: Orthopedic Interventions
  description: Treatments for scoliosis and other skeletal abnormalities.
  evidence:
  - reference: PMID:11961443
    reference_title: "Surgical treatment of scoliosis in Marfan syndrome: guidelines for a successful outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The authors recommend arthrodesing both the primary and secondary curves in all patients with Marfan syndrome.
    explanation: The study discusses surgical treatment of scoliosis in Marfan syndrome and provides guidelines for successful outcomes through orthopedic interventions.
  - reference: PMID:11880731
    reference_title: "Marfan syndrome: orthopedic and genetic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The major orthopedic manifestations of Marfan syndrome include scoliosis, chest wall deformity, dural ectasia, joint hypermobility, and acetabular protrusion.
    explanation: This review highlights the orthopedic aspects of Marfan syndrome, including treatments for scoliosis and other skeletal abnormalities.
  - reference: PMID:34916231
    reference_title: "Impact of pathogenic FBN1 variant types on the development of severe scoliosis in patients with Marfan syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We elucidated the genetic risk factors for the development of severe scoliosis in patients with Marfan syndrome.
    explanation: The study investigates the genetic risk factors for severe scoliosis in Marfan syndrome, which is relevant to orthopedic interventions.
  - reference: PMID:17945136
    reference_title: "Spinal deformities in Marfan syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Kyphoscoliosis, spondylolisthesis, and atlantoaxial subluxation are common spinal deformities in Marfan syndrome... Surgical correction is associated with complications, such as failure of fixation and additional deformity; however good results are possible when consideration is given to the unique challenges presented by patients who have Marfan syndrome.
    explanation: The article discusses common spinal deformities in Marfan syndrome and the complexities of surgical correction, supporting the statement on orthopedic interventions.
  - reference: PMID:26130954
    reference_title: "Disease-specific Growth Charts of Marfan Syndrome Patients in Korea."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Patients with Marfan syndrome (MFS) presents with primary skeletal manifestations such as tall stature, chest wall abnormality, and scoliosis.
    explanation: This study covers the primary skeletal manifestations of Marfan syndrome, including scoliosis, which require orthopedic interventions.
  treatment_term:
    preferred_term: surgical procedure
    description: Operative intervention to correct skeletal abnormalities such as scoliosis.
    term:
      id: MAXO:0000004
      label: surgical procedure
- name: Vision Correction
  description: Management of ocular issues such as ectopia lentis with glasses or surgery.
  evidence:
  - reference: PMID:24698610
    reference_title: "Surgical management of lens subluxation in Marfan syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Anterior lensectomy and limited vitrectomy with aphakic correction is safe and provides a consistent visual outcome in patients with lens subluxation secondary to Marfan syndrome.
    explanation: The study discusses surgical management of ectopia lentis in Marfan syndrome patients, which supports the statement about managing ocular issues with surgery.
  - reference: PMID:23661206
    reference_title: "Ocular features and management challenges of Marfan's Syndrome in Benin City, Nigeria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The ocular features were ectopia lentis in 92.3% of the patients... The best corrected visual acuity in 4 out of 5 patients who had cataract extraction at 8 weeks post op. was 6/60 to 6/12.
    explanation: This study highlights the use of surgical intervention for vision correction in Marfan syndrome patients with ectopia lentis.
  - reference: PMID:30260057
    reference_title: "Ten-year reinvestigation of ocular manifestations in Marfan syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Our study indicates that even though EL typically occurs at an early stage in most MFS patients, there is still a risk of developing EL in adulthood.
    explanation: The study confirms the management of ectopia lentis (EL) in Marfan syndrome, indicating the necessity for vision correction, which can include glasses or surgery.
  treatment_term:
    preferred_term: surgical procedure
    description: Operative intervention to correct lens dislocation or other ocular abnormalities.
    term:
      id: MAXO:0000004
      label: surgical procedure
datasets:
# ASAP thoracic aortic aneurysm study
- accession: geo:GSE26155
  title: Advanced Study of Aortic Pathology (ASAP)
  description: >-
    Advanced Study of Aortic Pathology (ASAP) dataset comparing aortic
    tissue gene expression from patients with thoracic aortic aneurysms
    and bicuspid (BAV) vs tricuspid (TAV) aortic valves. Includes
    mammary artery controls and transplant donor samples.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: MICROARRAY
  sample_types:
  - preferred_term: thoracic aorta tissue
    tissue_term:
      preferred_term: thoracic aorta
      term:
        id: UBERON:0001515
        label: thoracic aorta
  sample_count: 96
  conditions:
  - dilated aorta BAV
  - dilated aorta TAV
  - non-dilated aorta
  - mammary artery control
  platform: Affymetrix Human Exon 1.0 ST Array
  notes: >-
    Identifies immune response genes elevated in dilated TAV aortic
    tissue. Relevant for studying aortic aneurysm pathogenesis in
    connective tissue disorders including Marfan syndrome.

# Aortic dissection gene expression
- accession: geo:GSE52093
  title: Genome-wide analysis of gene expression of ascending aorta from patients with acute Stanford type A aortic dissection
  description: >-
    Gene expression profiling comparing dissected ascending aorta
    tissue from acute Stanford type A aortic dissection patients
    to normal aorta controls, identifying pathogenesis pathways.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: MICROARRAY
  sample_types:
  - preferred_term: ascending aorta tissue
    tissue_term:
      preferred_term: ascending aorta
      term:
        id: UBERON:0001496
        label: ascending aorta
  sample_count: 12
  conditions:
  - acute aortic dissection
  - normal aorta control
  platform: Illumina HumanHT-12 V4.0 expression beadchip
  notes: >-
    Identifies genes with altered expression in aortic dissection,
    providing insights into pathogenesis relevant to Marfan syndrome
    cardiovascular complications

disease_term:
  preferred_term: Marfan syndrome
  description: A heritable connective tissue disorder caused by mutations in FBN1, characterized by cardiovascular, ocular, and skeletal abnormalities.
  term:
    id: MONDO:0007947
    label: Marfan syndrome
references:
- reference: DOI:10.1007/s00392-023-02221-4
  title: 'Prophylactic effect of angiotensin receptor blockers in children with genetic aortopathies: the early bird catches the worm'
  findings: []
- reference: DOI:10.3389/fcell.2023.1302285
  title: The extracellular matrix glycoprotein fibrillin-1 in health and disease
  findings: []
- reference: DOI:10.3389/fgene.2024.1463318
  title: 'Marfan syndrome: insights from animal models'
  findings: []
- reference: DOI:10.3390/ijms25095025
  title: Investigation of Strategies to Block Downstream Effectors of AT1R-Mediated Signalling to Prevent Aneurysm Formation in Marfan Syndrome
  findings: []
- reference: DOI:10.3390/ijms25137367
  title: Coding and Non-Coding Transcriptomic Landscape of Aortic Complications in Marfan Syndrome
  findings: []
- reference: DOI:10.3390/ijms26073067
  title: Analysis of FBN1, TGFβ2, TGFβR1 and TGFβR2 mRNA as Key Molecular Mechanisms in the Damage of Aortic Aneurysm and Dissection in Marfan Syndrome
  findings: []

📚

References & Deep Research

References

6

DOI:10.1007/s00392-023-02221-4

Prophylactic effect of angiotensin receptor blockers in children with genetic aortopathies: the early bird catches the worm