syndrome may be underdiagnosed due to its great variability [8–10].

The life expectancy of Marfan patients by 1972 was markedly shortened and the mean age was 32 years, with most deaths being due to cardiovascular causes [11]. Life expectancy by 1993 was increased by >25% and the prognosis of surgically treated patients was significantly improved [12].

Ocular involvement is frequent and accounts for a part of the major and minor diagnostic criteria for Marfan syndrome [13]. Almost every ocular structure can be involved. Forty-one percent of patients with Marfan syndrome are initially seen with ocular pathology and diagnosed by an ophthalmologist [14]. This number stresses the importance of alertness of the ophthalmologist when examining patients with suspicious findings—especially in light of improved surgical options and prophylaxis promising better chances in preservation of sight in Marfan patients.

General

Genetics

Marfan syndrome is inherited in an autosomal dominant manner with almost complete penetrance [3]. About one-fourth of patients with Marfan syndrome do have unaffected parents; i.e., the syndrome is caused by sporadic mutations [9].The majority of cases are induced by a mutation of the gene fibrillin 1 (FBN 1) on chromosome 15, q21.1 locus [15, 16]. The glycoprotein FBN 1 is a main component of the extracellular microfibrils. In Marfan syndrome, its integration into the matrix of connective tissue is impaired [6, 17, 18]. Most of the mutations found are unique to a patient or family. Altogether, more than 500 mutations of the FBN1 gene are known [19].

Beyond the structural function of microfibrils, they play a role in the regulation of cytokines [20]. The homology between FBN 1 and transforming growth factor-b(beta) (TGF-b)-binding proteins gave rise to the hypothesis that

microfibrils are involved in the regulation of TGF-b(beta) activation. Indeed, recently a mutation of a further gene was discovered causing inactivation of the TGF-b(beta) receptor 2 (TGFBR2) [21]. This defect seems to end in a final common pathway for the development of the Marfan phenotype.

Pathogenesis

Elastic fibers are bundles of proteins found in the extracellular matrix of connective tissue, allowing its stretching and expansion. Those fibers are composed of an elastin core and surrounding microfibrils. As explained previously, FBN1 is a main component of the microfibrils, and a mutation of its gene is principally responsible for the pathology in Marfan syndrome. Still, more and more proteins containing pathological microfibrils others than FBN1 have been found, leading to the term microfibrillopathy [22].

Ocular Pathology

As mentioned, almost every part of the eye can be involved in Marfan syndrome. Pathology studies were described as early as 1940 and thereafter. A consistent finding is the increased axial length of the globe in affected patients. Remarkably, Maumenee found a significantly higher axial length in patients with dislocated lens compared to patients without dislocation [23]. The cornea is typically flat with decreased K and corneal thinning when measured by pachymetry. The main cause for corneal flattening seems to be an aberration of the cornea itself due to fibrillin gene mutations in combination with scleral thinning. A megalocornea may exist as well [24].

Dvorak-Theobald described an increased distance of the insertion of the rectus muscles from the limbus in a 27-month-old child, along with an enlarged globe [25].

The anterior chamber angle is typically wide open with an immature ciliary body, a broad trabecular meshwork, and displacement of Schlemm’s canal [26]. The sphincter and dilator muscle of the iris are usually underdeveloped, causing eccentric pupil and poor mydriasis [23].