IllnessAortectasia, thoracic; differential diagnosis

NGS +

[Sanger]

Diseases of the thoracic aorta can manifest themselves as an enlargement of the thoracic aorta, as an aneurysm (“outpouching” of the thoracic aorta) and/or as a dissection (tear in the inner vessel wall). Thoracic aortic aneurysms and other dilatations of the thoracic aorta can be asymptomatic for a long time and then develop into aortic dissections or ruptures. Aortic diseases can be diagnosed using imaging methods (ultrasound, CT and MRI). Standardized comparative values based on body surface area are used to assess the extent of an aneurysm and the associated risk of complications.

Thoracic aortic diseases can have different causes; both acquired forms (injuries) and genetic causes are known. The genetic causes are extremely heterogeneous, both *isolated forms (without concomitant diseases) and syndromic forms (with other associated symptoms) have been described.

In about 20-30% of those affected by isolated aortic disease, a genetic cause can be detected. If other typical clinical symptoms of a syndromic disease are present, the probability of detecting a genetic cause is higher. In most cases, HTAD is inherited in an autosomal dominant manner with variable expressivity with regard to the age of first manifestation and the localization of the disease (ascending or descending thoracic aorta).

Reduced penetrance has been described for some of the genes examined in this gene panel, which means that not every carrier develops symptoms of aortic disease. However, this gene panel also contains genes that are associated with autosomal recessive (e.g. EFEMP2-ass. Cutis laxa syndrome) or X-linked inherited diseases (e.g. Meester-Loeys syndrome). If no pathogenic variant can be detected in the genes examined, a genetic cause cannot be ruled out due to the heterogeneity of the disease.

If a disease-causing gene variant is detected, the diagnosis of hereditary thoracic aortic disease (HTAD) can be confirmed. The clinical (suspected) diagnosis of HTAD can be made if an affected person has at least one family member with thoracic aortic disease or has other clinical features of a hereditary syndromic disease that is typically associated with aortic disease (e.g. Marfan syndrome or Loeys-Dietz syndrome).

Molecular genetic testing should be offered to all affected individuals with a positive family history (regarding aortic disease or intracranial/peripheral aneurysms and/or sudden death at a young age in a first or second-degree relative), clinical symptoms of a hereditary syndrome with an increased risk of aortic disease (Marfan, Loeys-Dietz, Ehlers-Danlos) or young age at first manifestation of thoracic aortic disease (<60 years).

If a genetic aortic disease has been identified in a family through the detection of a pathogenic variant, relatives can be offered predictive testing for the familially identified variant(s) as part of genetic counseling. Persons in whom HTAD-associated, disease-causing variant(s) have been identified should undergo regular cardiological examinations and treatment if necessary.

https://www.ncbi.nlm.nih.gov/books/NBK1120/

Duarte et al. 2023 https://pmc.ncbi.nlm.nih.gov/articles/PMC10000331/

Chou et al. 2022 https://www.nature.com/articles/s41569-022-00763-0

• Alias: Aortic aneurysm, familial thoracic
• Alias: Familial TAAD
• Alias: Familiäre TAAD
• Alias: Heritable thoracic aortic aneurysm or dissection, HTAD
• Alias: Thoracic aortic aneurysm or dissection, TAD
• Allelic: Acromicric dysplasia (FBN1)
• Allelic: Bone mineral density variation QTL, osteoporosis (COL1A1)
• Allelic: Caffey disease (COL1A1)
• Allelic: Colorectal cancer, hereditary nonpolyposis, type 6 (TGFBR2)
• Allelic: Colorectal cancer, somatic (FLCN)
• Allelic: Craniosynostosis 7, susceptibility to (SMAD6)
• Allelic: Ectopia lentis et pupillae (ADAMTSL4)
• Allelic: Ectopia lentis, familial (FBN1)
• Allelic: Ectopia lentis, isolated, AR (ADAMTSL4)
• Allelic: Esophageal cancer, somatic (TGFBR2)
• Allelic: Geleophysic dysplasia 2 (FBN1)
• Allelic: Leukemia, Philadelphia chromosome +, resistant to imatinib (ABL1)
• Allelic: MASS syndrome (FBN1)
• Allelic: Macular degeneration, age-related, 3 (FBLN5)
• Allelic: Macular degeneration, early-onset (FBN2)
• Allelic: Marfan lipodystrophy syndrome (FBN1)
• Allelic: Megacystis-microcolon-intestinal hypoperistalsis syndrome (MYLK)
• Allelic: Moyamoya disease 5 (ACTA2)
• Allelic: Multiple self-healing squamous epithelioma, susceptibility to (TGFBR1)
• Allelic: Multisystemic smooth muscle dysfunction (ACTA2)
• Allelic: Neuropathy, hereditary, +/- age-related macular degeneration (FBLN5)
• Allelic: Opitz-Kaveggia syndrome (MED12)
• Allelic: Osteogenesis imperfecta, type I-IV (COL1A1)
• Allelic: Polymicrogyria with or without vascular-type EDS (COL3A1)
• Allelic: Radioulnar synostosis, nonsyndromic (SMAD6)
• Allelic: Renal carcinoma, chromophobe, somatic (FLCN)
• Allelic: Spondyloepimetaphyseal dysplasia, XL (BGN)
• Allelic: Stiff skin syndrome (FBN1)
• Allelic: Supravalvar aortic stenosis (ELN)
• Allelic: Thrombosis, hyperhomocysteinemic (CBS)
• Allelic: Weill-Marchesani syndrome 2, AD (FBN1)
• Alport syndrome 1, XL (COL4A5)
• Aortic aneurysm, familial thoracic 10 (LOX)
• Aortic aneurysm, familial thoracic 11, susceptibility to (FOXE3)
• Aortic aneurysm, familial thoracic 4 (MYH11)
• Aortic aneurysm, familial thoracic 6 (ACTA2)
• Aortic aneurysm, familial thoracic 7 (MYLK)
• Aortic aneurysm, familial thoracic 8 (PRKG1)
• Aortic aneurysm, familial thoracic 9 (MFAP5)
• Aortic valve disease 2 (SMAD6)
• Birt-Hogg-Dube syndrome (FLCN)
• Combined osteogenesis imperfecta + Ehlers-Danlos syndrome 1 (COL1A1)
• Congenital heart defects + skeletal malformations syndrome (ABL1)
• Contractural arachnodactyly, congenital (FBN2)
• Cutis laxa, AD 2 (FBLN5)
• Cutis laxa, AR, type IA (FBLN5)
• Cutis laxa, autosomal dominant (ELN)
• Cutis laxa, autosomal recessive, type IB (EFEMP2)
• Ehlers-Danlos syndrome, arthrochalasia type, 1 (COL1A1)
• Ehlers-Danlos syndrome, classic type, 1 (COL5A1)
• Ehlers-Danlos syndrome, classic type, 2 (COL5A2)
• Ehlers-Danlos syndrome, kyphoscoliotic type, 1 (PLOD1)
• Ehlers-Danlos syndrome, kyphoscoliotic type, 2 (FKBP14)
• Ehlers-Danlos syndrome, vascular type (COL3A1)
• Familial thoracic aortic aneurysm, aortic dissection (FOXE3, MFAP5)
• Homocystinuria, B6-responsive + nonresponsive types (CBS)
• Loeys-Dietz syndrome 1 (TGFBR1)
• Loeys-Dietz syndrome 2 (TGFBR2)
• Loeys-Dietz syndrome 3 (SMAD3)
• Loeys-Dietz syndrome 4 (TGFB2)
• Lujan-Fryns syndrome (MED12)
• Marfan syndrome (FBN1)
• Meester-Loeys syndrome (BGN)
• Ohdo syndrome, XL (MED12)
• Pneumothorax, primary spontaneous (FLCN)
• Polycystic kidney disease 1 (PKD1)
• Polycystic kidney disease 2 (PKD2)
• VISS syndrome (IPO8)