Marfan syndrome (MFS) is a connective tissue disorder that can affect multiple organ systems including the skeletal, ocular, and cardiovascular systems and is caused by mutations in the FBN1 gene. A diagnosis is based on the presence of major and minor clinical criteria, as established by the Ghent nosology (de Paepe 1996, Loeys 2010). Skeletal features can include chest malformations (pectus carinatum/excavatum), tall stature, increased joint mobility, and scoliosis. Eye findings most commonly include lens dislocation (ectopia lentis) and myopia. The cardiovascular features are typically mitral valve prolapse and/or aortic root dilatation, which can progress to aortic dissection. Patient management and treatment is mainly focused on slowing the progression of aortic root dilation, the most common cause of morbidity and early mortality. Therefore, genetic testing is important for identifying presymptomatic family members who carry a FBN1 mutation, and at risk for developing features of Marfan syndrome, who will benefit from appropriate monitoring for aortic root dilatation.
Mutations in the FBN1 gene have also been observed in families with isolated ectopia lentis and MASS syndrome (myopia, mitral valve prolapse, borderline/non-progressive aortic root dilation, skeletal and skin findings). MASS is a connective tissue disorder related to Marfan syndrome but with milder cardiovascular findings.
Loeys-Dietz syndrome (LDS) is a systemic connective tissue disorder caused by mutations in the TGFBR1 or TGFBR2 genes (also available as part of the 16 gene Marfan syndrome/TAAD sequencing panel). The skeletal features of Loeys-Dietz syndrome, such as joint laxity, arachnodactyly, pectus deformity, and scoliosis, can overlap with the Marfan phenotype, however most individuals with LDS have features in other organ systems not typical of Marfan syndrome (Loeys 2005). Patients with Loeys-Dietz syndrome can exhibit various craniofacial, neurodevelopmental, skeletal and skin abnormalties, however features specific to LDS include hypertelorism, cleft palate or bifid uvula, and arterial or aortic aneurysms and aterial tortuosity (Van Hemelrijk 2010). The primary risk for early mortality is due to aterial tortuosity and/or aortic root dilatation, which results in an increased risk of aterial or aortic aneurysm (Van Hemelrijk 2010). Since patients with LDS can develop potentially lethal arterial aneurysms that would not be detected by echocardiogram, differentiating between Loeys-Dietz and Marfan syndromes is necessary to determine the appropriate clinical management. Similar to Marfan syndrome, genetic testing is important for identifying presymptomatic family members at risk for developing Loeys-Dietz syndrome.
Mutations in the TGFBR1 gene have also been observed in families with multiple self-healing squamous epithelioma (MSSE), also known as Ferguson-Smith disease. MSSE is a skin cancer condition that presents with multiple, locally invasive skin tumors that normally regress, leaving scars. Loss-of-function mutations in the TGFBR1 gene have been reported in individuals with MSSE, while gain-of-function mutations are presumed to result in the Loeys-Dietz syndrome phenotype (Goudie 2011)