Bicuspid aortic valve with thoracic aortic aneurysm
This checklist is meant to guide genetic testing for Heritable Thoracic Aortic Disorders (H-TAD) and/or Heritable Arterial Disorders (HAD). Both syndromic and non-syndromic entities are under consideration.
Since the introduction of Next Generation Sequencing (NGS) techniques, genetic testing has evolved from serial single gene testing to parallel panel testing and is gradually evolving to whole exome (genome) sequencing. This evolution has many advantages, especially in the setting of HTAD since important clinical overlap between the different genetic entities does not allow selection of the underlying causal gene based on clinical features in many instances. This is why genetic testing has evolved from screening for one particular entity (e.g screening of the FBN1 gene in case of suspicion of Marfan syndrome) to screening of a disease entity (e.g panel sequencing for HTAD).
While this strategy will undoubtedly result in the identification of the underlying defect in more patients and families, we do want to emphasize that clinical evaluation remains essential. The NGS techniques will for example not allow mutation detection in case of (small) deletions or insertions and if there is a strong clinical suspicion for a specific disease (e.g suspicion for Marfan syndrome in case of ectopia lentis and aortic aneurysm), we will complement the NGS test with additional testing if no defect is identified.
The two clinical constellations for which specifically targeted genetic testing can/should be considered are:
Aortic root dilatation in combination with lens luxation: Marfan syndrome – FBN1 mutation screening
Recurrent arterial rupture/dissection at distinct vascular beds in young patients with no significant risk factors – vascular Ehlers Danlos syndrome - vEDS
In order to perform the appropriate set of gene tests, we are requesting clinical data. We kindly ask you to be as precise and specific as possible.
The differential diagnosis in patients referred for additional genetic testing with a clinical presentation characterized by aortic (root) aneurysm/dissection and/or arterial tortuosity is extensive. You will find an overview of possible diagnoses below. Please indicate what diagnosis you suspect in your patient and/or make sure to fill out the checklist as complete as possible so that we can set up the appropriate genetic testing.
General recommendations for patient/family evaluation in the setting of HTAD/HAD Target group
Patients younger than 60 - 65 years of age with Thoracic Aortic Aneurysm (aortic diameter Z-score >2 in adults and >3 in children or aortic dissection or arterial aneurysm/dissection and without other risk factors.
Procedures Multidisciplinary Evaluation
Clinical examination of proband:
Facial characteristics (hypertelorism, high plate, bifid uvula)
Revised Ghent Criteria for Diagnosis of Marfan syndrome and related conditions
In the absence of family history:
(1) Ao (Z≥2) + EL = MFS
(2) Ao (Z≥2) + FBN1 = MFS
(3) Ao (Z≥2) + Syst (≥7pts) = MFS
(4) EL + FBN1 with known Ao = MFS
In the presence of family history:
(5) EL + FH of MFS (as defined above) = MFS
(6) Syst (≥7 pts) + FH of MFS (as defined above) = MFS
(7) Ao (Z≥2 in adults, Z≥3 in children) + FH of MFS (as defined above) = MFS
Z: Z-score (aortic root diameter corrected for age and BSA); EL: ectopia lentis; FBN1: Fibrillin 1 mutation; Syst: systemic score (see below); FBN1 with known Ao: FBN1 mutation linked to aortic aneurysm in other patients/families (Loeys et al, Journal of Medical Genetics 2010)
Required clinical data
Aortic diameter at the level of the sinus of Valsalva