Marfan syndromeQ87.40

Generalized, autosomal-dominant (25% new mutations) inherited, multi-organ disease (most common hereditary connective tissue disease) caused by degeneration of elastic fibers with involvement of the eye, skeleton, cardiovascular system and skin. The skin lesions are not specific, but can be valuable monitoring evidence. Cardiovascular problems determine disease progression, prognosis and life expectancy. The disease is caused by a mutation in the fibrillin 1 gene. Fibrillin-1 is a component of microfibrils that are important for synthesis and homeostasis of the elastic fiber network and for the sequestration and activation of TGF-beta.

Prevalence: 3-10/10,000 inhabitants. No gender dominance

TypI: Predominantly autosomal dominant inheritance, in 15% sporadic inheritance of mutations of the FBN1 gene(fibrillin1 gene; gene locus: 15q15-21.1) with consecutive disturbance of the structure of microfibrils in the connective and supporting tissue. Age effect of the father is discussed.

In 70% of cases familial clustering, in 25% new mutations with an average increased paternal age (36 versus 29 years).

Type II: In type II (the affiliation to the Marfan syndrome is doubted in the meantime, possibly a Loeys-Dietz syndrome is present) there are mutations in the genes TGFB-receptor-1 and TGFB-receptor-2.

• Skin: Striae cutis distensae (24%) over chest, shoulder, thigh (without overweight!), elastosis perforans serpiginosa.
• Eyes: lensectopy (60% from the 4th year of life), possibly with iridodonesis (= iris flap, not "lens flap"), myopia (34%), cataract, retinal detachment.
• Skeleton: arachnodactyly, long bones of the extremities, olichostenomy = "long narrow limb" (77%), long, narrow head, kyphoscoliosis (44%), gothic palate (60%), long ribs, pectus excavatum or carinatum. Flat feet, genu recurvatum, hyperextensibility of the joints (56%), joint dislocations.
• Cardiovascular system (98%): disorders develop over time as a result of reduced mechanical strength: aortic aneurysms, particularly in the ascending aorta, mitral valve insufficiency (floppy valvae) (66%).
• Lungs: apical lung cysts, recurrent pneumothorax (5%).
• Ectasia of the lumbosacral dura (67% in middle-aged adults aged 36 years).

The diagnosis (guidelines of the revised Ghent-Nosologie/Loeys BL et al. 2010) can be made clinically if the following constellations are present in the case of a negative (or positive) family history:

I. Patient without a positive family history of Marfan syndrome

Aortic root ectasia or dissection and lens luxation

Aortic root ectasia or dissection and FBN1 mutation

Aortic root ectasia or dissection and systemic involvement (score =/>7 points)

Lens luxation and FBN1 mutation with aortic root ectasia or dissection

II Patient with positive family history of Marfan syndrome

Related 1st degree fulfils the diagnostic criteria for Marfan syndrome

Fibrillin-1 mutation detected

Lens Luxation

Systemic participation (points score =/<7)

Aortic root ectasia

Characteristic and point value assignment (system participation at =/>7 points; respective point values in brackets)

Positive hand and thumb sign (3)

Positive hand or thumb sign (1)

Pigeon breast (2)

Funnel chest or thoracic asymmetry (1)

folding foot (2)

flat foot (1)

pneumothorax (2)

Duraektasia, radiological detection (2)

Protusio acetabuli, radiological detection (2)

Ratio of arm span to body size greater than 1.05 (without severe scoliosis) (1)

Reduced elbow extension (=/<170°) (1)

At least 5 facial symptoms (longskull, enophthalmus, laterally sloping / antimongoloid eyelid axes, molar hypoplasia, retrognathia) (1)

Striae of the skin (1)

Myopia (>3 dpt) (1)

Mitral valve prolapse (1)

• Congenital aachnodactyly with contractures(Beals-Hecht syndrome - mutation in the fibrillin-2 gene)
• Homocystinuria (frequent thromboses, no aneurysms, lens ectopy possible)
• Congenital contractural arachnodactyly
• Klinefelter syndrome
• Syndrome of the fragile X chromosome
• Mosaic trisomy 8
• MEN
• Ehlers-Danlos syndrome; osteogenesis imperfecta.

• Primary prophylaxis: Genetic counseling (50% risk of transmission). Prenatal diagnosis is possible by molecular biology if a mutation is known in the family.
• Secondary prophylaxis and treatment: Regular echocardiographic check-ups, especially important during pregnancy; endocarditis prophylaxis in case of aortic and mitral insufficiency; timely cardiosurgical correction, possibly the still experimental prevention of aortic dilatation with β blockers. Conservative and surgical-orthopedic measures; possibly early onset of puberty for growth reduction and better treatment of kyphoscoliosis. Eye checks (retinal detachment). Adapted lifestyle: No physical strain, no team sports with physical contact.

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