SCIENTIFIC BACKGROUND

SMAD2, SMAD3, TGFB2, TGFB3, TGFBR1, TGFBR2

Loeys-Dietz (aortic aneurysm) syndrome (LDS) represents an important clinical entity as a differential diagnosis for diseases with aortic aneurysms such as classic Marfan syndrome and vascular Ehlers-Danlos syndrome (vEDS). Vascular involvement (with cerebral, thoracic and abdominal arterial aneurysms and dissections), skeletal involvement (pectus excavatum or pectus carinatum, scoliosis, joint hypermobilty, arachnodactyly, talipes equinovarus, spinal instabilities), craniofacial involvement (widely spaced eyes, strabismus, split uvula or cleft palate, craniosynostosis) and skin involvement (velvety and translucent skin, easy bruising and dystrophic scars) are characteristic for LDS.

 

Based on molecular genetic data, Loeys-Dietz syndrome is divided into:

 

  • LDS1 (TGFBR1 variants)
  • LDS2 (TGFBR2 variants)
  • LDS3 (SMAD3 variants)
  • LDS4 (TGFB2 variants)
  • LDS5 (TGFB3 variants)
  • LDS6 (SMAD2 variants)

 

The detection of a pathogenic variant in one of the above-mentioned genes can diagnose LDS if it is present in combination with aortic root enlargement (z-score >2.0) or a type A dissection, or additional systemic involvement with characteristic craniofacial, vascular, skeletal or skin manifestations is seen.

 

The severity of the disease depends on which of the genes within the TGFß signal pathway is altered (LDS1=LDS2>LDS3>LDS4>LDS5). Patients with TGFBR1 or TGFBR2 variants are not clinically distinguishable. Patients with SMAD3 variants have a higher risk of osteoarthritis. Patients with TGFB2 variants are usually larger, often have mitral valve insufficiency and overall have many overlaps with Marfan syndrome, while patients with TGFB3 variants show additional clinical overlaps with Shprintzen-Goldberg syndrome and Loeys-Dietz syndrome with cardiovascular involvement.

 

In LDS, 55-60% of patients have so far been identified as having variants in the TGFBR2 gene , 20-25% as having variants in the TGFBR1 gene, 5-10% as having variants in each of the genes SMAD3 and TGFB2, and 1-5% as having variants in each in the genes TGFB3 and SMAD2.

 

The detection rate of TGFBR1/2 variants in patients with LDS1 and LDS2 is 95%, in Marfan syndrome with incomplete symptoms about 10% and in thoracic aortic aneurysms and dissections (TAAD) between 1 and 4%. In patients with TAAD the proportion of SMAD3 variants is 2%, of TGFB2 variants between 0.7 and 7% and of TGFB3 variants 2%.

 

References

Loeys and Dietz in: GeneReviews® (Updated 2018 March 1) / Meester et al. 2017, Ann Cardiothorac Surg 6:582 / Cannaerts et al. 2015, Eur J Med Genet 58:695 / Bertoli-Avella et al. 2015, J Am Coll Cardiol 65:1324 / MacCarrick et al. 2014, Genet Med 16:576 / van Laer et al. 2014, Adv Exp Med Biol 802:95 / Loeys et al. 2005, Nat Genet 3:275 / Dietz et al. 2005, Am J Med Genet 139C:4

GENES
SMAD2, SMAD3, TGFB2, TGFB3, TGFBR1, TGFBR2
How to order