Meester-Loeys syndrome

Meester-Loeys syndrome describes an X-linked, syndromic form of aortic aneurysms and dissections with skeletal manifestations such as hypertelorism, thoracic deformities, hypermobile joints, contractures and mild skeletal dysplasia.

Cardiovascular symptoms include early aortic aneurysms and dissections in male patients, and mild mitral and aortic valve insufficiency. Female carriers may be cardiologically normal, but also have aortic aneurysms and dissections. Skeletal manifestations in male index patients such as chest deformities, hypermobile joints, contractures and striae are sometimes non-specific for various connective tissue diseases. A split uvula, hypertelorism and instability of the cervical spine are also found in patients with Loeys-Dietz syndrome. Thus, there are clinical overlaps with Marfan syndrome and Loeys-Dietz syndrome, but also characteristic differences such as enlargement of the ventricles, macrocephaly, hypertrichosis, gingival hyperplasia, and skeletal dysplasias, such as hip dislocation, formation of flat vertebral bodies, dysplasia of finger and toe phalanges and dysplastic epiphyses of the long bones. The non-cardiovascular manifestations are milder in female carriers.

The molecular cause is loss-of-function variants in the BGN gene on chromosome Xq28, which codes for biglycan. Biglycan belongs to the small leucine-rich proteoglycan (SLRP) class I proteins and is involved in the formation and maintenance of the extracellular matrix together with other proteoglycans such as decorin. Biglycan interacts with collagen type I, II, III, VI and elastin and is expressed in bone, skin, heart, lung and arteries. The pathogenic variants described to date in Meester-Loeys syndrome are two genomic deletions of 21 kb and 28 kb that contain large portions of the BGN gene, a nonsense variant, and two missense variants, one of which has been shown to be aberrant splicing and the second predicted to be aberrant splicing. Biglycan deficiency leads to increased TGF-ß signaling within the adventitia of the aortic wall.

References

Meester et al. 2017, Genet Med 19:386 / Cho et al. 2016, Am J Hum Genet 98:1243 / Corsi et al. 2002, J Bone Miner Res 17:1180