Marfan Syndrome

Overview

Pathogenesis

• Serve as scaffolds for tropoelastin in elastic tissues (aorta, lungs, skin)
• Act as anchoring elements in non-elastic tissues (ciliary zonule of the eye, basement membranes)

1. Structural deficiency - loss of microfibril integrity in tissues under mechanical stress (aorta, ligaments, ocular zonules)
2. TGF-β dysregulation - microfibrils normally sequester latent TGF-β; when microfibrils are defective, TGF-β signaling becomes excessive, leading to:
   • Abnormal vascular smooth muscle development
   • ECM disruption
   • Bone overgrowth (not explained by structural loss alone)
   • Mitral valve prolapse, lung abnormalities, and muscle hypoplasia

Clinical Manifestations

Skeletal

• Dolichostenomelia - disproportionately long limbs relative to trunk
• Arachnodactyly - very long, slender fingers
• Arm span-to-height ratio > 1.05; reduced upper-to-lower body segment ratio
• Pectus excavatum ("funnel chest") or pectus carinatum ("pigeon breast") - from rib overgrowth
• Scoliosis (~50% of patients); can be progressive
• Kyphosis, thoracic lordosis
• High-arched palate with crowded teeth
• Joint hypermobility (or, paradoxically, congenital contractures of elbows)
• Long, narrow face; deep-set downward-slanting eyes; flat cheekbones; micrognathia

Ocular

• Ectopia lentis (bilateral lens subluxation) in ~60% - classically displaced superiorly; the zonules remain intact (unlike homocystinuria where lens displaces inferiorly)
• Myopia - the most common ocular feature
• Risk of retinal detachment (especially with high myopia)
• Flat corneas
• Increased risk of glaucoma and early cataracts

Cardiovascular (the major cause of morbidity and mortality)

• Aortic root dilation - begins at the sinuses of Valsalva; the defining life-threatening feature. Most males exceed the upper limit of normal by adolescence
• Aortic dissection - usually type A (starts just above the aortic valve); 10% are type B (descending aorta). Medial degeneration shows elastic fiber fragmentation and increased proteoglycans ("cystic medial necrosis")
• Mitral valve prolapse in ~80%; leaflets become progressively myxomatous and thickened; may progress to mitral regurgitation; annular dilation and calcification possible
• Tricuspid valve prolapse; dilation of the proximal pulmonary artery
• Untreated, patients historically died before age 30-40 from aortic dissection or congestive heart failure

Pulmonary

• Spontaneous pneumothorax (~5%) from rupture of apical blebs
• Sleep apnea (secondary to skeletal deformities)
• Impaired pulmonary function from severe pectus/scoliosis

Neurological / Dural

• Dural ectasia (dilation of the caudal thecal sac) in ~90% - a major diagnostic criterion; increases with age; may cause lumbar radiculopathy
• Anterior sacral meningocele (severe form)
• Intracranial hypotension from CSF leak
• Stroke risk mainly from cardiogenic emboli (prosthetic valves, atrial fibrillation)
• Axonal neuropathy or mild myopathy

Skin / Integument

• Striae atrophicae (stretch marks) over shoulders, breasts, lower back - not related to weight change
• Hernias (inguinal, incisional)

Other

• Liver and kidney cysts
• Obstructive sleep apnea (more common as lifespan has extended with treatment)

Diagnosis: Revised Ghent Nosology

1. Aortic root aneurysm (Z-score ≥ 2 at sinuses of Valsalva)
2. Ectopia lentis

• Aortic root aneurysm + ectopia lentis is present, or
• Aortic root aneurysm + pathogenic FBN1 variant, or
• Aortic root aneurysm + systemic score ≥ 7 (a point-based system for skeletal, skin, dural, and other features), or
• Ectopia lentis + pathogenic FBN1 variant known to cause aortic disease

• Slit-lamp ophthalmology exam with full pupillary dilation
• Transthoracic echocardiogram (aortic root diameter)
• Molecular genetic testing of FBN1 (and TGFBR1/2 if Loeys-Dietz is suspected)
• MRI/CT lumbar spine for dural ectasia assessment

Differential Diagnosis

Management

Cardiovascular

• Beta-blockers (e.g., atenolol, propranolol) - first-line; slow aortic root dilation rate and reduce dissection risk; should be started early and continued lifelong
• Angiotensin receptor blockers (ARBs) (losartan, irbesartan) - inhibit TGF-β signaling via AT1 receptor blockade; meta-analysis shows incremental benefit when added to beta-blockers. Irbesartan (150-300 mg/day) significantly reduces aortic dilation rate, especially in younger patients
• Statins and tetracyclines - inhibit matrix metalloproteinases (MMP-2 and MMP-9), reducing aortic wall degradation
• Avoid fluoroquinolone antibiotics - may increase risk of aortic dissection and rupture

• Prophylactic aortic root replacement strongly considered when maximal aortic diameter reaches 45 mm (adults); earlier if there is a family history of dissection, rapid progression (>5 mm/year), or severe aortic regurgitation
• The traditional Bentall procedure (composite valve-graft + coronary reimplantation) markedly improved survival
• Valve-sparing aortic root replacement is now preferred when feasible to preserve native valve
• Annual transthoracic echocardiogram for surveillance

Ophthalmological

• Corrective lenses or contact lenses for myopia/ectopia lentis
• Surgical lens removal if visual acuity significantly affected
• Annual ophthalmology monitoring

Skeletal

• Bracing or surgery for severe scoliosis
• Pectus repair if causing cardiopulmonary compromise
• Low-impact exercise recommended; strenuous isometric activities, contact sports, and competitive athletics should be avoided (increase aortic wall stress)

Genetic

• Genetic counseling; cascade family screening after FBN1 variant identification
• Prenatal diagnosis is possible once a familial variant is known

Prognosis

• Robbins & Kumar Basic Pathology, pp. 110-111
• Goldman-Cecil Medicine, pp. 2749-2750
• Tietz Textbook of Laboratory Medicine, 7th ed., pp. 2727-2728
• Bradley and Daroff's Neurology in Clinical Practice, p. (block 26)

Catastrophic Antiphospholipid Syndrome (CAPS)

Definition and Overview

Pathogenesis

• Lupus anticoagulant (LA), anti-cardiolipin (aCL), and anti-β2-glycoprotein-I (aβ2GPI) antibodies are the hallmark serologic markers
• aPL bind phospholipid-binding proteins on endothelial cells, platelets, and monocytes, triggering a pro-coagulant state

• Infections (most common - bacterial, viral, fungal)
• Surgical procedures (major or minor)
• Anticoagulation withdrawal or inadequacy
• Trauma
• Malignancy
• Obstetric events (delivery, miscarriage)
• Drugs (e.g., oral contraceptives)

Clinical Manifestations

• Adrenal gland - adrenal hemorrhage and acute adrenal insufficiency; this is highly suggestive of CAPS in an aPL-positive patient and may be the initial presenting event
• Hepatic infarction (Budd-Chiari-like picture)
• Bowel infarction (abdominal pain, distension, ileus)
• Splenic, pancreatic, testicular infarction
• Peripheral gangrene

• Moderate thrombocytopenia (consumption by microthrombosis)
• Schistocytes (microangiopathic hemolytic anemia)
• These TMA features overlap with TTP, HUS, and DIC - making diagnosis challenging

Diagnostic Classification Criteria (Asherson Criteria)

1. Evidence of involvement of 3 or more organs, systems, and/or tissues
2. Development of manifestations simultaneously or within < 1 week
3. Histopathological confirmation of small-vessel occlusion (non-inflammatory vascular occlusion in at least one organ)
4. Laboratory confirmation of antiphospholipid antibodies (LA, aCL IgG/IgM, or aβ2GPI IgG/IgM) - must be positive on two occasions ≥ 12 weeks apart (per international criteria)

• Only 2 organs are involved (but all other criteria met), OR
• Repeat aPL testing not yet performed, OR
• A third thrombotic event occurs > 1 week but within 1 month despite anticoagulation

Practical note: Awaiting repeat aPL confirmation should never delay treatment in a critically ill patient. Clinical suspicion is sufficient to begin therapy immediately.

Differential Diagnosis

Treatment

First-Line: "Triple Therapy"

• Intravenous unfractionated heparin (UFH) - start immediately; therapeutic dosing
• Addresses the ongoing thrombotic process; do not withhold even in thrombocytopenic patients unless platelet count is dangerously low
• Transition to warfarin (target INR 2-3, or 3-4 in high-risk) long-term after acute phase

• High-dose corticosteroids (methylprednisolone IV, 1 g/day for 3 days, followed by oral prednisolone 1-2 mg/kg/day)
• Suppress the inflammatory/cytokine storm component
• Essential in cases with concomitant SLE flare or adrenal insufficiency

• Plasma exchange (therapeutic plasmapheresis) - removes circulating aPL antibodies, inflammatory cytokines, and complement fragments; generally 5-7 sessions on consecutive days
• IVIG (2 g/kg over 2-5 days) - blockade of Fc receptors, anti-idiotype inhibition of aPL; particularly useful when PE is not available or in obstetric CAPS
• May be used together or interchangeably

Second-Line / Refractory CAPS

• B-cell depletion depletes aPL-producing plasma cells
• Particularly effective for refractory microvascular involvement and severe thrombocytopenia (overlap with TTP-like picture)
• CAPS Registry data: rituximab-treated patients had reasonable outcomes
• Typically 375 mg/m² weekly × 4 doses

• Blocks terminal complement (C5a, C5b-9 = MAC), directly interrupting TMA
• Most useful when CAPS overlaps with a prominent TMA picture (thrombocytopenia, hemolytic anemia)
• CAPS Registry data (n=39): 74% recovered, 23% worsened, 5 died
• Now recommended for cases resistant to triple therapy + rituximab

• Reserved for very refractory cases or when CAPS occurs in the context of active SLE
• Risk of infection limits use in already critically ill patients

Supportive Care

• ICU-level care; organ support (renal replacement therapy, ventilation as needed)
• Treat any identified precipitating infection aggressively with antibiotics/antivirals
• Avoid fluoroquinolones - potential for worsening thrombotic risk (analogous to Marfan data)
• Anticoagulation should be lifelong after recovery (high risk of recurrent thrombosis)

CAPS in Pregnancy

• The clinical overlap with HELLP is significant; aPL testing must be part of the workup for severe peripartum multiorgan dysfunction
• Warfarin is contraindicated in pregnancy (teratogenic); use LMWH (or UFH) throughout
• Delivery (if obstetric CAPS at or near viability) can be both a trigger and a potential intervention
• IVIG is preferred over plasma exchange in some obstetric centers; both are used
• Multidisciplinary team essential: maternal-fetal medicine, rheumatology, hematology, critical care

Prognosis

• Historical mortality: >50%
• Modern mortality with triple therapy: ~25-30% (CAPS Registry, 2024 analysis)
• Early diagnosis and rapid initiation of anticoagulation + immunomodulation drive the improvement in outcomes
• Survivors require lifelong anticoagulation (warfarin, target INR 2-3 to 3-4 depending on thrombosis history)
• Role of newer anticoagulants (DOACs) in secondary prevention of APS remains debated; rivaroxaban was inferior to warfarin in high-risk triple-positive APS patients in the RAPS/TRAPS trials - warfarin remains standard

• Firestein & Kelley's Textbook of Rheumatology, 2-Volume Set (blocks 21)
• Rheumatology, 2-Volume Set (Elsevier 2022), pp. CAPS section
• Creasy & Resnik's Maternal-Fetal Medicine, 8th ed., Box 65.2
• Salter & Crowther (2024) - ASH Education Program [PMID: 39644034]
• Rodriguez-Pintó et al. (2024) - CAPS Registry lessons [PMID: 39174151]