Introduction
Marfan syndrome is primarily an autosomal dominant genetic disorder caused either due to an inheritance or a de-novo mutation during fertilization in the FBN1 gene that encodes fibrillin. Fibrillin is a glycoprotein essential in the formation of elastic fibers that are the most important component of almost all the organs of the body including but not limited to the eyes, the heart, blood vessels, and the skeleton.
Who Is Susceptible to Marfan Syndrome?
Marfan affects one in every 3000 to 5000 births worldwide with no racial or gender predilection. Marfan is the most common single-gene malformation syndrome with complete penetrance and variable expression.
What Causes Marfan Syndrome?
Marfan syndrome primarily shows an autosomal dominant inheritance with a small percentage of cases being reported with an autosomal recessive pattern. More than three-quarters of the patients have a parental history of Marfan and less than 25 % of the cases arise from de-novo mutations in the FBN1 gene, which encodes the protein fibrillin-1, during fertilization. FBN1 gene is a large gene consisting of 65 axons present on chromosome 15q-21.1. In less than 10 % of the cases, there is no identifiable mutation in the gene which is probably due to complete allele deletion or altered regulation of the gene. In some cases of atypical presentation, a mutation in the gene encoding for transforming growth factor-beta receptor (TGFBR) may be etiological. Some mutations in TGFBR-1 and TGFBR-2 are phenotypically similar to Marfan or may be characteristic of other syndromes like Loeys-Dietz syndrome (LDS) or familial thoracic aortic aneurysm (FTAA) syndrome.
What Is the Pathophysiology of Marfan Syndrome?
The FBN1 gene that encodes for fibrillin protein is responsible for the bioavailability of TGF-beta. TGF-beta regulates inflammation, fibrosis, and activation of specific matrix metalloproteins (MMPs), MMP-2, and MMP-9. The release of MMPs with cytokines, chemokines, prostaglandin derivatives, and elastin degradation fragments along with an accumulation of mucopolysaccharide cysts lead to loss of smooth muscle cells resulting in weakening and cystic medial degeneration of the aorta. These factors in conjunction with decreased collagen and decreased structural integrity of the aorta lead to aneurysmal dilation.
A reduction in wild fibrillin-1 and increased mutant protein increases TGF-beta release and activity which favors aortic damage through vascular remodeling. Vascular remodeling is a combined effect of structural microfibril changes, excess amounts of TGF-beta, and increased amounts of MMP-2 and MMP-9. The role of TGF-beta is established by the fact that angiotensin-converting enzyme inhibitors (ACE I) and angiotensin 2 receptor blockers (ARBs) medications have improved the symptoms in patients. ACE-inhibitors and ARB-blockers have proven detrimental effects on TGF-beta levels.
What Is the Histopathology of Marfan Syndrome?
A specimen collected from the affected aorta of patients, under microscopic analysis, showed medial necrosis, fibrosis, and loss of smooth muscle cells. Cystic medial necrosis is not characteristic of Marfan syndrome but elastin fragmentation is seen more frequently in Marfan-associated aortic aneurysms than in those without any connective tissue disorder diagnosis.
What Are the Signs and Symptoms of Marfan Syndrome?
A triad of aortic root dilatation, with familial history, and FBN1 mutation associated with the same have been diagnostic of Marfan syndrome.
Cardiac Manifestations: Aortic root disease, aortic regurgitation, aneurysmal dilatation, aneurysmal dissection, proximal ascending aortic dilation, thickening, and prolapse of the atrioventricular valves, thromboembolism, endocarditis, mitral regurgitation, and mitral annular calcification. Dilations are also observed in other segments like the thoracic aorta, the abdominal aorta, the root of the pulmonary artery, or the carotid and intracranial arteries. One or more of the other symptoms may be observed in patients.
Ocular Manifestations: Lens dislocation, myopia, cataract, glaucoma, retinal detachment, ectopia lentis, and flat cornea.
Musculoskeletal Manifestations: Excess linear growth of the long bones, joint laxity, reduced joint mobility, disproportionately long extremities, arachnodactyly, pes planus or flatfoot deformity, ligamentous laxity, longer-narrower feet, scoliosis, exaggerated kyphotic thoracolumbar spinal curvature, cerebrospinal fluid leaks, acetabular protrusion or protrusio-acetabuli, pectus carinatum, dural ectasia, pain associated with periosteal pressure, erosion of lumbosacral elements, traction of the nerve roots, or sacral microfractures secondary to osteopenia.
Pulmonary Manifestations: Lung bullae, emphysematous pulmonary changes, and spontaneous pneumothorax.
Other Non-specific Manifestations: Skin striae or striae atrophicae, weight loss, recurrent or incisional hernia, and high-arched palate.
How to Diagnose Marfan Syndrome?
Marfan is diagnosed based on the fulfillment of certain diagnostic criteria that involve a specific scoring system assigned to observed features where a score greater than seven indicates significant systemic involvement.
-
Wrist and Thumb Sign: Three points.
-
Wrist or Thumb Sign: One point.
-
Pectus Carinatum Deformity: Two points.
-
Pectus Excavatum or Chest Asymmetry: One point.
-
Hindfoot Deformity: Two points.
-
Plain Pes Planus: One point.
-
Pneumothorax: Two points.
-
Dural Ectasia: Two points.
-
Protrusio-acetabuli: Two points.
-
Reduced Upper Segment or Lower Segment Ratio and Increased Arm Span or Height Without Severe Scoliosis: One point.
-
Scoliosis or Thoracolumbar Kyphosis: One point.
-
Reduced Elbow Extension: One point.
-
Three or More of the Following Five Features: Dolichocephaly, enophthalmos, down-slanting palpebral fissures, malar hypoplasia, retrognathia - One point.
-
Skin Striae: One point.
-
Myopia Greater Than Three Diopters: One point.
-
Mitral Valve Prolapse: One point.
In patients without any familial history of Marfan, fulfillment of one of the criteria is diagnostic of Marfan syndrome.
-
Aortic criterion and ectopia lentis.
-
Aortic criterion with a causal FBN1 mutation.
-
Aortic criterion with a systemic score equal to seven or more.
-
Ectopia lentis, FBN1 mutation, and an aortic aneurysm.
In patients with a history of Marfan, fulfillment of one of the criteria is diagnostic of Marfan syndrome.
-
Ectopia lentis.
-
A systemic score of seven or more.
-
Aortic dissection.
Revised criteria for Marfan diagnosis when individuals younger than 20 years with Marfan symptoms but do not meet the traditional criteria.
-
Nonspecific Connective Tissue Disorder: With less than seven systemic scores, borderline aortic measurements, and no FBN1 mutations.
-
Potential Marfan: FBN1 mutation with a familial history but aortic measurements below the diagnostic criteria.
- Heart disorders are diagnosed through ultrasound, ECG (electrocardiogram), transthoracic echocardiography (TTE), CT (computed tomography), and MRI (magnetic resonance imaging).
- Eye exams like the slit-lamp exam and eye pressure test are performed annually.
- Genetic testing is often used to confirm the diagnosis of Marfan syndrome.
How to Treat or Manage Marfan Syndrome?
Marfan syndrome is managed with a combined approach of medications and surgery. Beta-blockers, ACE-inhibitors (angiotensin-converting enzyme inhibitors), and ARB-blockers (angiotensin receptor blockers) are used to relieve the heart and decrease palpitations and decrease arterial pressure. Two surgical techniques can be used to replace the enlarged area of the aorta with a graft:
-
The traditional method is where the aorta is replaced with a graft and the aortic valve is replaced with a mechanical valve.
-
Valve-sparing modified reimplantation method where the aorta is replaced with a tube graft and own aortic valve is put back in place.
Patients with subluxated lenses are treated with glasses or contact lenses. Cataracts, glaucoma, and retinal detachment may require surgeries to correct the ailment.
What Is the Differential Diagnosis of Marfan Syndrome?
-
Loeys-Dietz syndrome.
-
Shprintzen-Goldberg syndrome.
-
Mitral valve prolapse syndrome.
-
Congenital contractural arachnodactyly.
-
Weill-Marchesani syndrome.
-
Ectopia lentis syndrome.
-
Familial thoracic aortic aneurysm and dissection syndrome (FTAAD).
-
FTAAD with the bicuspid aortic valve.
-
FTAAD with patent ductus arteriosus.
-
Homocystinuria.
-
Arterial tortuosity syndrome.
-
Ehlers-Danlos syndrome.
-
Stickler syndrome.
-
Klinefelter syndrome.
-
Congenital bicuspid aortic valve disease with associated aneurysms.
-
Aortic coarctation with associated ascending aortic enlargement.
-
Congenital bicuspid aortic valve disease with associated aneurysms.
-
Aortic coarctation with associated ascending aortic enlargement.
-
Familial thoracic aortic aneurysm.
Prognosis of Marfan Syndrome
The life expectancy of Marfans patients has drastically increased from 32 years in 1972 to about 72 years by 1993. Beta-blockers, noninvasive aortic imaging, and elective aortic root repair have contributed to an uneventful life in patients with good prognostic outcomes. Untreated or undiagnosed cardiac anomalies are the primary reason for mortality due to which the patients have a poor prognosis.
Complications of Marfan Syndrome
-
Aortic aneurysm and dissection.
-
Mitral valve prolapse.
-
Mitral regurgitation.
-
Aortic regurgitation.
-
Lens subluxation (ectopia lentis).
-
Cataract, glaucoma, and retinal detachment.
-
Spontaneous pneumothorax.
-
Inguinal hernias.
-
Scoliosis.
Conclusion
Management of Marfan syndrome is a combined effort of cardiothoracic, ophthalmology, orthopedic, and other specialties. Regular appointments should be scheduled with concerned faculties to prevent any complications. An interdepartmental approach can help in enhancing health outcomes and physiotherapy with non-exhausting exercises is needed post-surgery.
