The HTAD Working Group, is built upon Multidisciplinary Centres of Excellence that have been collaborating and originating much of the recent progress in understanding Heritable Thoracic Aortic Diseases

The HTAD-WG is chaired by Prof. Dr. Julie De Backer, Center for Medical Genetics and Department of Cardiology, Aorta team, Ghent University Hospital, Belgium. Prof. Dr. Guillaume Jondeau, CNMR Syndrome de Marfan et apparentés, Filière FAVAMulti, INSERM LVTS U1148, is co-chair.

The HTAD-WG cooperates with the Patient-WG, whose representative participating in  the WG is Valentina FAVALLI, Magica Onlus.

Much of the recent progress in understanding HTAD has originated from our centers:

Description of

  • MFS2 (Nat Genet. 1994 Nov;8(3):264-8; Nat Genet. 2004 Aug;36(8):855-60),
  • Loeys Dietz Syndrome (N Engl J Med. 2006 Aug 24;355(8):788-98; Nat Genet. 2005 Mar;37(3):275-81),
  • Arterial Tortuosity syndrome (Nat Genet. 2006 Apr;38(4):452-7),
  • Aneurysm Osteoarthritis Syndrome (Nat Genet. 2011 Feb;43(2):121-6)
  • MFS diagnostic criteria (J Med Gen)

Mutations in

Description of the

  • natural history of these diseases including in MFS (2009 Dec 22;120(25):2541-9),
  • supporting the surgical threshold at 50 mm and not 45 mm for MFS patients (2012 Jan 17;125(2):226-32),
  • natural history of patients having aortic dissection secondary to rare diseases.

Randomised studies with losartan have been performed and published by several groups also included in this ERN or Centers cooperating with VASCern (Eur Heart J. 2016 Mar 21;37(12):978-85; Eur Heart J. 2015 Aug 21;36(32):2160-6; Eur Heart J. 2013 Dec;34(45):3491-500; Eur Heart J. 2016 Mar 21;37(12):978-85), including the European centers participating in the American study (N Engl J Med. 2014 Nov 27;371(22):2061-71).

Heritable Thoracic Aortic Disease (HTAD) covers disease entities with as common denominator Thoracic aortic aneurysms or –dissections that are familial and/or caused by genetic defects. Both syndromic and nonsyndromic entities exist. Although the number of genes involved in HTAD is steadily increasing, a large number of patients/families with HTAD have no identifiable defect, indicating that other genes must be involved. Genetic defects identified so far have can be categorized  into (1) genes encoding components of the extracellular matrix (FBN1, MFAP5, MAT2A); (2) genes encoding components of the TGFbeta signaling pathway (TGFBR1/2, TGFB2/3, SMAD2/3); (3) genes encoding compnents of the smooth muscle cell contractile apparatus (ACTA2, MYH11, MYLK, PRKG1).

Clinical entities covered by this WG include:

  • syndromic entities such as Marfan Syndrome (ORPHA558), Loeys Dietz Syndrome (ORPHA60030), Aneurysm Osteoarthritis syndrome (ORPHA284984), Arterial tortuosity syndrome (ORPHA3342), Multisystemic smooth muscle dysfunction syndrome (ORPHA404463) and Neonatal Marfan syndrome (ORPHA284979)
  • As well as nonsyndromic entities such as Familial Thoracic Aortic Aneurysms Dissections (Familial TAAD) (ORPHA91387), Familial aortic dissection (ORPHA229),
  • caused by mutations in
    • actin, alpha 2, smooth muscle, aorta – ACTA2
    • fibrillin 1 – FBN1
    • microfibrillar associated protein 5 – MFAP5
    • myosin, heavy chain 11, smooth muscle – MYH11
    • myosin light chain kinase – MYLK
    • protein kinase, cGMP-dependent, type I – PRKG1
    • SMAD family member 3 – SMAD3
    • transforming growth factor beta 2 – TGFB2
    • transforming growth factor beta 3 – TGFB3
    • transforming growth factor beta receptor I – TGFBR1
    • transforming growth factor beta receptor II – TGFBR2

While our knowledge of clinical and genetic charactistics of MFS and related H-TAD has increased substantially, already resulting in a better outcome in these patients, further efforts are needed to improve management and increase awareness of these rare disorders since knowledge of the disease appears to be the most important factor influencing outcome. Next stages require formal acknowledgement, status and funding to ensure personalised medicine and therapeutics.

Bases for the following estimated incidence and prevalence numbers: 500 Million inhabitants within European union with about 6 million newborns annually.

sub-thematic areas of expertise Rare or complex disease(s) or condition(s) or highly specialized interventions Code/ICD/ Orphacode / Group of Codes

Incidence (Number of cases / year)

(in general in the EU)


 (in general in the EU)

HTAD Marfan Syndrome type 1 and 2

ICD 10

171 / ORPHA558

3 300 150 000
HTAD Loeys Dietz Syndromes 1-6

ICD 10

171 / ORPHA60030

180 15 000
HTAD Aneurysm Osteoarthritis syndrome

ICD 10

171 / ORPHA284984

60 5 000
HTAD Arterial Tortuosity Syndrome

ICD 10

171 / ORPHA3342

unknown unknown
HTAD Ectopia Lentis in Marfan syndrome ICD 10 H27.1; ORPHA 558 900 75000  ca 1/5000 – 50% lens luxation
HTAD Familial thoracic Aortic Aneurysms Dissections (FTAA(D)) with mutations in FBN1, TGFB2, TGFB3, SMAD2, SMAD3, TGFBR1, TGFBR2, ACTA2, MYH11, MYLK, PRKG1 ICD10 171 1200 100 000
HTAD FTAA(D) with mutations in FOXE3, MAT2A, MFAP5 ICD 171 Unknown Unknown
HTAD Familial forms of bicuspid aortic valve with aortopathy ORPHA402075 Unknown Unknown
HTAD Ascending Aortic Dissection in Marfan syndrome ICD 10 I7101; ORPHA558 90 7500 (prevalence 1/5000 – 5% type A dissection)

All HCP in the HTAD-WG are covering this sub-thematic area of expertise.









Pr. Sebastian DEBUS, FEBS, FEBVS, Chairman
Dr. Christian-Alexander BEHRENDT
Department of Vascular Medicine
Department of General and Interventional Cardiology
University Heart Center Hamburg
University Medical Center Hamburg-Eppendorf
Hamburg, Germany



Dr. Kalman BENKE
Semmelweis University, Heart and Vascular Center
Budapest, Hungary



Pr. Guglielmina PEPE
Regional Tuscany Reference Center for Marfan Syndrome and related disorders
Careggi Hospital, University of Florence
Florence, Italy



Dr. Marlies KEMPERS
Klinisch Geneticus
Radboud university medical center
Nijmegen, Netherlands



Clinical Genetics
Karolinska Universitetslaboratoriet
Karolinska University Hospital
Stockholm, Sweden

ePAG Co-chair


In addition to the general mission of the ERN:

  • Reducing the delay in diagnosing the diseases
  • Improve awareness for the disease among caregivers (general practitioners, school doctors,general public)
  • Reduce care gaps/lost-to-follow up during the transition phase from paediatric to adult care
  • Improve the quality of family counselling
  • Reducing redundant tests – Increasing the use of relevant tests for the disease
  • Improve medical knowledge by sharing experience, conducting clinical trials and registries

Our HTAD-WG specific Goals are to

  • continue to assist patients in their choices, by evaluating the natural history of the various subtypes of H-TAD and the benefits and complications of diagnostic tests and treatments;
  • obtain funding for the Clinical Trials that we see as essential to provide further improvements in clinical care;
  • educate our international colleagues in the management of this challenging but highly rewarding disorder;
  • consolidate the position of H-TAD at the high-table of Rare Diseases, as benefits its prevalence (circa 1 in 5,000, yet subject to substantial under ascertainment)
  1. 2017 ESVS Guidelines on the Management of Descending Thoracic Aorta Diseases
  2. Goldstein SA, Evangelista A, Abbara S, Arai A, Asch FM, Badano LP, Bolen MA,Connolly HM, Cuéllar-Calàbria H, Czerny M, Devereux RB, Erbel RA, Fattori R,Isselbacher EM, Lindsay JM, McCulloch M, Michelena HI, Nienaber CA, Oh JK, Pepi M, Taylor AJ, Weinsaft JW, Zamorano JL, Dietz H, Eagle K, Elefteriades J, Jondeau G, Rousseau H, Schepens M. Multimodality imaging of diseases of the thoracic aorta in adults: from the American Society of Echocardiography and the European Association of Cardiovascular Imaging: endorsed by the Society of Cardiovascular Computed Tomography and Society for Cardiovascular Magnetic Resonance. J Am Soc Echocardiogr. 2015 Feb;28(2):119-82.
  3. Erbel R, Aboyans V, Boileau C, Bossone E, Bartolomeo RD, Eggebrecht H, Evangelista A et all. 2014 ESC Guidelines on the diagnosis and treatment of aortic diseases: Document covering acute and chronic aortic diseases of the thoracic and abdominal aorta of the adult. The Task Force for the Diagnosis and Treatment of Aortic Diseases of the European Society of Cardiology (ESC). Eur Heart J. 2014 Nov 1; 35(41):2873-926.
  4. Vahanian A, Alfieri O, Andreotti F, Antunes MJ, Baron-Esquivias G, Baumgartner H, Borger MA, Carrel TP, De Bonis M, Evangelista A, Falk V, Iung B, Lancellotti P, Pierard L, Price S, Schafers HJ, Schuler G, Stepinska J, Swedberg K, Takkenberg J, Von Oppell UO, Windecker S, Zamorano JL, Zembala M. [Guidelines on the management of valvular heart disease (version 2012). The Joint Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS)]. Eur Heart J (2012) 33, 2451–2496
  5.   Grabenwöger M, Alfonso F, Bachet J, Bonser R, Czerny M, Eggebrecht H, Evangelista A, Fattori R, Jakob H, Lönn L, Nienaber CA, Rocchi G, Rousseau H,Thompson M, Weigang E, Erbel R; European Association for Cardio-Thoracic Surgery EACTS); European Society of Cardiology (ESC); European Association of Percutaneous Cardiovascular Interventions (EAPCI). Thoracic Endovascular Aortic Repair (TEVAR) for the treatment of aortic diseases: a position statement from the European Association for Cardio-Thoracic Surgery (EACTS) and the European Society of Cardiology (ESC), in collaboration with the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur J Cardiothorac Surg. 2012 Jul;42(1):17-24.

Guidelines for the diagnosis of Marfan syndrome

Loeys, B.L. et al., 2010. The revised Ghent nosology for the Marfan syndrome. J Med Genet, 47(7), pp.476–485.

Guidelines for genetic testing in HTAD

Arslan-Kirchner, M. et al., 2015. Clinical utility gene card for: Hereditary thoracic aortic aneurysm and dissection including next-generation sequencing-based approaches. European Journal of Human Genetics.

Clinical Validity of Genes for Heritable Thoracic Aortic Aneurysm and Dissection. Renard M, Francis C, Ghosh R, Scott AF, Witmer PD, Adès LC, Andelfinger GU, Arnaud P, Boileau C, Callewaert BL, Guo D, Hanna N, Lindsay ME, Morisaki H, Morisaki T, Pachter N, Robert L, Van Laer L, Dietz HC, Loeys BL, Milewicz DM, De Backer J. J Am Coll Cardiol. 2018 Aug 7;72(6):605-615. doi: 10.1016/j.jacc.2018.04.089.PMID: 30071989

Several International Guidelines for the diagnosis and management of aortic disease:

Evangelista, A. et al., 2010. Echocardiography in aortic diseases: EAE recommendations for clinical practice. European Journal of Echocardiography, 11(8), pp.645–658.

Erbel, R. et al., 2014. 2014 ESC Guidelines on the diagnosis and treatment of aortic diseases: Document covering acute and chronic aortic diseases of the thoracic and abdominal aorta of the adult. The Task Force for the Diagnosis and Treatment of Aortic Diseases of the European Society of Cardiology (ESC).European Heart Journal, 35(41), pp.2873–2926.

Hiratzka, L.F. et al., 2010. 2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM guidelines for the diagnosis and management of patients with Thoracic Aortic Disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, American Association for Thoracic Surgery, American College of Radiology, American Stroke Association, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of Thoracic Surgeons, and Society for Vascular Medicine. Circulation, 121(13), pp.e266–369.

Guidelines on management of aortic disease in pregnancy

European Society of Gynecology (ESG) et al., 2011. ESC Guidelines on the management of cardiovascular diseases during pregnancy: the Task Force on the Management of Cardiovascular Diseases during Pregnancy of the European Society of Cardiology (ESC). European Heart Journal, 32(24), pp.3147–3197.

Wanga, S. et al., 2016. Pregnancy and Thoracic Aortic Disease: Managing the Risks. The Canadian journal of cardiology, 32(1), pp.78–85.

  1. Planned Guidelines

Guidelines on diagnosis and management of HTAD

Consensus statement of the VASCERN HTAD Working Group: 

In patients with HTAD, Fluoroquinolones should be used with caution because of a possible risk for exacerbation of aortic disease.  The use of alternatives is preferred while awaiting further evidence.

Patient Pathways aim to improve the care and management of patients with a rare disease. They include the “red flags” that may lead to the suspicion of the disease, how to reach a definite diagnosis and the management and follow-up recommendations. They are a very important tool used in defining the best patient care and will be further validated and updated when needed.

The HTAD Patient Pathway is available here

Pills of Knowledge (PoK) are the deliverable for VASCERN Work Package 4 on Pills of Knowledge, defined as short single video lessons (of approximately 3-5 minutes long) in which an expert talks about a specific topic that has been selected and validated by the Rare Disease Working Groups (RDWGs).

Link to the playlist for the HTAD-WG on our YouTube Channel is here

Marfan Syndrome -Diagnosis by HTAD-WG Chair Prof Julie De Backer (Cardiologist, Ghent University Hospital, Ghent, Belgium).

This PoK gives an overview of the diagnosis of Marfan syndrome with its main clinical manifestations and diagnostic criteria described. The genetics of this rare disease are also briefly outlined in a clear and comprehensible manner. This video is a great introduction to Marfan syndrome that is suitable for both the general public and the medical community.

Video in English. Subtitles available in 7 European languages.

See the video here

3 a week – the importance of exercise in Marfan and related Heritable Thoracic Aortic Diseases (HTAD)

Created by Prof. Guillaume Jondeau (Cardiologist, Assistance Publique-Hôpitaux de Paris, Hôpital Bichat-Claude Bernard, Paris, France) and Lise Murphy (European Patient Advocacy Group (ePAG) Patient Advocate Co-Chair for HTAD, Svenska Marfanföreningen, Sweden).

This Pill of Knowledge (PoK) features a conversation between a patient and doctor about the importance of physical activity and what exercise is suitable for patients with Marfan syndrome. It aims to encourage Marfan syndrome patients to participate in a suitable form of exercise 3 times a week. This message will be further shared via the 3 a week campaign. Video in English subtitles available in 7 European languages.

See the video here

Le Sport et le Syndrome de Marfan (Sport and Marfan syndrome)

Created by Prof. Guillaume Jondeau (Cardiologue, Assistance Publique-Hôpitaux de Paris, Hôpital Bichat-Claude Bernard, Paris, France).

This Pill of knowledge talks about how physical activity is beneficial for Marfan syndrome patients and the types of sports that are adapted for these patients and which to avoid. It is meant for patients and gives clear and simple explanations for why certain sports are well tolerated in Marfan patients and others are not. Video in French. Subtitles available in 7 European languages.

See the video here

What is Heritable Thoracic Aortic Disease (HTAD)?

Created by Prof. Julie De Backer (Cardiologist, Ghent University Hospital, Ghent, Belgium).

This Pill of knowledge (PoK) talks about the group of vascular diseases known as Heritable Thoracic Aortic Diseases. Both syndromic and non-syndromic forms are described and the genetics of HTAD are also explored. It is suitable for healthcare professionals and anyone wishing to learn more about HTAD. Video in English. Subtitles in 5 European languages

See the video here

The PubMed List of HTAD 318 publications from the Working Group Members is provided, and emphasizes the importance of continued clinician education.


de Paepe, A. et al., 1996. Revised diagnostic criteria for the Marfan syndrome. American journal of medical genetics, 62(4), pp.417–426.

Dietz, H.C. et al., 1991. Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature, 352(6333), pp.337–339.

Loeys, B.L. et al., 2005. A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nature Genetics, 37(3), pp.275–281.

Loeys, B.L. et al., 2010. The revised Ghent nosology for the Marfan syndrome. J Med Genet, 47(7), pp.476–485.

Marfan, AB, 1896. Un cas de déformation congénitale des quatres membres, plus prononcée aux extrémités, caractérisée par l“allongement des avec un certain degré d”amincissement. Bull mem Soc Med Hop Paris, 13, pp.220–226.

Mizuguchi, T. et al., 2004. Heterozygous TGFBR2 mutations in Marfan syndrome. Nature Genetics, 36(8), pp.855–860.

Pyeritz, R.E., 2014. Heritable thoracic aortic disorders. Current opinion in cardiology, 29(1), pp.97–102.

van de Laar, I.M.B.H. et al., 2011. Mutations in SMAD3 cause a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis. Nature Genetics, 43(2), pp.121–126.

Renard, M. et al., 2018. Clinical Validity of Genes for Heritable Thoracic Aortic Aneurysm and Dissection. JAC, 72(6), pp.605–615.

Muiño Mosquera, L. et al., 2018. Tailoring the American College of Medical Genetics and Genomics and the Association for Molecular Pathology Guidelines for the Interpretation of Sequenced Variants in the FBN1 Gene for Marfan Syndrome: Proposal for a Disease- and Gene-Specific Guideline. Circulation. Genomic and precision medicine, 11(6), p.e002039.

Extramiana F, Milleron O, Elbitar S, Uccellini A, Langeois M, Spentchian M, Delorme G, Arnoult F, Denjoy I, Bouleti C, Fressart V, Iserin F, Maison-Blanche P, Abifadel M, Leenhardt A, Boileau C, Jondeau G. High prevalence of ventricular repolarization abnormalities in people carrying TGFβR2 mutations. Sci Rep. 2018
Aug 29;8(1):13019. doi: 10.1038/s41598-018-31298-5. PubMed PMID: 30158670.

Benarroch L, Aubart M, Gross MS, Jacob MP, Arnaud P, Hanna N, Jondeau G, Boileau C. Marfan Syndrome Variability: Investigation of the Roles of Sarcolipin and Calcium as Potential Transregulator of FBN1 Expression. Genes (Basel). 2018 Aug 21;9(9). pii: E421. doi: 10.3390/genes9090421. PubMed PMID: 30134586.

Aubart M, Gazal S, Arnaud P, Benarroch L, Gross MS, Buratti J, Boland A, Meyer V, Zouali H, Hanna N, Milleron O, Stheneur C, Bourgeron T, Desguerre I, Jacob MP, Gouya L, Génin E, Deleuze JF, Jondeau G, Boileau C. Association of modifiers and  other genetic factors explain Marfan syndrome clinical variability. Eur J Hum Genet. 2018 Aug 7. doi: 10.1038/s41431-018-0164-9. [Epub ahead of print] PubMed PMID: 30087447.

Wallace SE, Regalado ES, Gong L, Janda AL, Guo DC, Russo CF, Kulmacz RJ, Hanna N, Jondeau G, Boileau C, Arnaud P, Lee K, Leal SM, Hannuksela M, Carlberg B, Johnston T, Antolik C, Hostetler EM, Colombo R, Milewicz DM. MYLK pathogenic variants aortic disease presentation, pregnancy risk, and characterization of pathogenic missense variants. Genet Med. 2018 Jun 20. doi: 10.1038/s41436-018-0038-0. [Epub ahead of print] PubMed PMID: 29925964.

Michel JB, Jondeau G, Milewicz DM. From genetics to response to injury: vascular smooth muscle cells in aneurysms and dissections of the ascending aorta. Cardiovasc Res. 2018 Mar 15;114(4):578-589. doi: 10.1093/cvr/cvy006. PubMed PMID: 29360940.


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