These syndromes often affect the connective tissue of various organ systems, including heart, blood vessels, skin, joints, bone, eyes, and lungs. The discovery of these HCTD was followed by the identification of mutations in a wide range of genes encoding structural proteins, modifying enzymes, or components of the TGFβ-signaling pathway. These syndromes show some degree of phenotypical overlap of cardiovascular, skeletal, and cutaneous features.
Marfan Syndrome (MFS)
Marfan Syndrome is an autosomal dominant connective tissue disorder with variable expression of the disease which affects the skeletal, ocular and cardiovascular system. Is caused mainly by mutations in the gene FBN1. Based on the 2010 diagnosis criteria by Loeys, great importance is given to ectopia lentis and aortic root dilation
Ehlers-Danlos syndrome (EDS)
EDS refers to a group of clinically and genetically heterogeneous connective tissue disorders and all subtypes are characterized by variable abnormalities of skin, ligaments and joints, blood vessels, and internal organs. Typical presenting features include joint hypermobility, skin hyperextensibility, and tissue fragility. Up to one quarter of the EDS patients show aortic aneurysmal disease. The latest EDS nosology distinguishes 13 subtypes. Many phenotypic features show overlap between the different subtypes, which makes the clinical diagnosis rather difficult and highlights the importance of molecular diagnostic confirmation.
LDS is caused by mutations in TGBR1/2, SMAD2/3, or TGFB2/3, all coding for components of the TGFβ-signaling pathway. LDS can be distinguished from MFS by the unique presence of hypertelorism, bifid uvula or cleft palate, and widespread aortic and arterial aneurysm and tortuosity. Compared to MFS, LDS cardiovascular manifestations tend to be more severe. In contrast, no association is reported between LDS and the presence of ectopia lentis, a key distinguishing feature of MFS. Overlapping features between MFS and LDS include scoliosis, pes planus, anterior chest deformity, spontaneous pneumothorax, and dural ectasia.
Why to perform genetic testing in cases with HCTD?
- The precise molecular diagnosis have important repercusion in prognosis and expected complications
- To detect family members at risk who may need treatment with betablockers despite being asymptomatic
Our HCTD genetic test panel
ACTA2, CBS, COL3A1, COL5A1, COL5A2, EFEMP2, FBN1, FBN2, MYH11, MYLK, NOTCH1, SLC2A10, SMAD3, SMAD4, TGFB2, TGFBR1, TGFBR2.
Important: All our panels can be modified based on the phenotype. Please contact us if you have questions
- The Ehlers-Danlos syndrome, a disorder with many faces. De Paepe A, Malfait F. Clin Genet. 2012 Jul;82(1):1-11. doi: 10.1111/j.1399-0004.2012.01858.x.
- Cardiovascular manifestations in Marfan syndrome and related diseases; multiple genes causing similar phenotypes. Cook JR, et al. Clin Genet. 2015;87(1):11-20. doi: 10.1111/cge.12436.
- Marfan Syndrome and Related Disorders: 25 Years of Gene Discovery. Verstraeten A, Alaerts M, Van Laer L, Loeys B. Hum Mutat. 2016 Jun;37(6):524-31. doi: 10.1002/humu.22977.
Download here interesting open access manuscripts on genetics of HCTD