Specifieke vragenlijst (checklist) Marfan syndroom en aanverwante syndromale an niet syndromale erfelijke aorta- en arteriele -aandoeningen



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H9.1-B9

Specifieke vragenlijst (checklist)

Marfan syndroom en aanverwante syndromale an niet syndromale erfelijke aorta- en arteriele -aandoeningen


sleutelwoorden: MFS, AA, checklist, website, Marfan syndroom, aortic aneuysm, informatie voor zorgverleners, informatie voor aanvragers, criteria voor aanvaarden van testen, instructies voor stalen, bindweefsellabo, bindweefselziekten, HTAD, HAD
leesgroepen: KLINIEK, BW, ADM, DIENSTH





Naam

Functie

Datum

auteur

Julie De Backer

arts

28/06/2016

auteur

Bert Callewaert

arts

28/06/2016

auteur

Marjolijn Renard

Post-doctoraal medewerker

28/06/2016

auteur

Sofie Symoens

Supervisor Bindweefsellaboratorium

28/06/2016

nazicht

Annelies De Jaegher

Kwaliteitsmedewerker, technische supervisor DNA-labo

30/06/2016

machtiging

Paul Coucke

Hoofd Bindweefsellaboratorium

19/07/2016

machtiging

Bruce Poppe

Diensthoofd CMGG

01/08/2016



Wijzigingen ten opzichte van vorige uitgave:

Wijzigingen werden traceerbaar aangeduid m.b.v “track changes”



GEBRUIKSAANWIJZING:
DE CHECKLIST MAG VRIJ AFGEDRUKT WORDEN.

DRUK EERSTE PAGINA NIET MEE AF.

De tekst op volgende bladzijden is opgenomen op de website van

Het CMGG.



CLINICAL INFORMATION SHEET
Syndromic and nonsyndromic Heritable Thoracic Aortic and Arterial Diseases

Patient information
Name:

First Name(s):



Sex:

M

F




Date of Birth (dd/mm/yyyy):     /     /     

Address:
Referring Physician:

Referring Center:


SAMPLE:

EDTA blood

DNA

Skin biopsy

Chorionic villi




Heparin blood

RNA

Aortic biopsy

Amniocytes




Buccal swab

Fibroblasts

Paraffin embedded material




Other:      

Date (dd/mm/yyyy):      /     /     

Sample arrived:      

Suspected diagnosis
Marfan syndrome

Ehlers-Danlos syndrome – vascular type

Loeys-Dietz syndrome

Shprintzen-Goldberg syndrome

Beals-Hecht syndrome or congenital contractural arachnodactyly

Arterial tortuosity syndrome

Other syndromic heritable (thoracic) aortic aneurysm disease



Nonsyndromic heritable thoracic aortic aneurysm disease

Heritable arterial aneurysm/dissection disease

Bicuspid aortic valve with thoracic aortic aneurysm

Other:      

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:


  1. Aortic root dilatation in combination with lens luxation: Marfan syndrome – FBN1 mutation screening

  2. 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

  1. Multidisciplinary Evaluation

    1. Clinical examination of proband:

      1. Facial characteristics (hypertelorism, high plate, bifid uvula)

      2. Skeletal manifestations (armspan, pectus, arachnodactylia, flat feet, club, feet, scoliosis)

      3. Cardiovascular manifestations (mitral valve prolapse, bicuspid aortic valve, patent ductus arteriosus)

    2. 3 generation pedigree

    3. If necessary, additional examination:

      1. Ocular examination: lens luxation, iris flocculi

      2. X-ray, CT/MRI: osteoarthritis, arterial tortuosity, arterial aneurysms

  2. Clinical evaluation in 1st degree relatives

    1. Clinical examination as described above

    2. If necessary, additional examination:

      1. Echocardiography: aortic diameters, mitral valve prolapse, bicuspid aortic valve, patent ductus arteriosus

      2. Ocular examination: lens luxation, iris flocculi

      3. X-ray, CT/MRI: osteoarthritis, arterial tortuosity, arterial aneurysms

Once these two steps are completed, patients can be classified in 4 distinctive groups. The specific recommendations for each of these groups is explained below:




  1. Positive family history and very specific syndromic features for MFS or vEDS as defined above: Sanger sequencing of a single gene (FBN1 or COL3A1 resp)

  2. Positive family history and no or less specific syndromic features: H-TAD panel by NGS

  3. Negative family history and very specific syndromic features for MFS or vEDS as defined above: Sanger sequencing of a single gene (FBN1 or COL3A1 resp)

  4. Negative family history and no or less specific syndromic features (isolated TAD): Clinical follow up and in some cases consider H-TAD panel by NGS


CLINICAL SUMMARY





PEDIGREE






Differential diagnosis

Gene

Discriminating features

Marfan syndrome (MFS)

FBN1

Aortic root dilatation, ectopia lentis, systemic features (table 1) (diagnostic criteria Box 1)

Loeys-Dietz syndrome (LDS)

TGBR1/2

TGFB2


SMAD3

Bifid uvula/cleft palate, arterial tortuosity, hypertelorism, diffuse aortic and arterial aneurysms, craniosynostosis

Vascular Ehlers Danlos syndrome (vEDS)

COL3A1

Arterial dissection/rupture in multiple vascular beds, including the aorta; bowel rupture; atrophic scarring

Ehlers Danlos syndrome – valvular type

COL1A2

Severe valvular insufficiency, translucent skin

Multisystemic Smooth Muscle Cell Dysfunction Syndrome

ACTA2 p.(R179H)

Patent ductus arteriosus, congenital mydriasis, cerebrovascular lesions (Moya Moya like vascular abnormalities, white matter lesions)

Shprintzen-Goldberg syndrome (SGS)

SKI (FBN1)

Mild aortic root dilatation, mitral valve prolapse, craniosynostosis, mild-to-modertate intellectual disability

Congenital contractural arachnodactyly (CCA)

FBN2

Crumpled ears, contractures

Arterial tortuosity syndrome (ATS)

SLC2A10

Generalised arterial toruosity, arterial stenosis, facial dysmorphism

Cutis laxa

ELN (AD)


Cutis laxa with variable involvement of internal organs (lung, aorta), association with BAV




FBLN4 (AR)

Cutis laxa, emphysema, arterial tortuosity, aortic aneurysm, joint laxity, pectus excavatum, diaphragmatic hernia, bone fragility

Weill-Marchesani syndrome (WMS)

FBN1 and ADAMTS 10

Microspherophakia, brachydactyly, joint stiffness, short stature

Ectopia lentis syndrome (ELS)

FBN1, LTBP2,

ADAMTS4


Lack of aortic root dilatation

Homocystinuria

CBS

Thrombosis, mental retardation

Nonsyndromic Heritable Thoracic Aortic aneurysm/Dissection (H-TAD) (syndromal and non-syndromal)

TGFBR1/2

Lack of Marfanoid skeletal features,

ACTA2

Livedo reticularis, iris flocculi, CVA

SMAD3

Osteoarthritis, arterial tortuosity, arterial aneurysms and dissections, intracranial aneurysms

TGFB2/3

Mitral Valve Prolapse, cerebrovascular disease, arterial tortuosity

MYLK

Gastro-intestinal abnormalities




PRKG1

Arterial aneurysms and dissections, arterial tortuosity




MAT2A

Bicuspid aortic valve




MFAP5

Lone atrial Fibrillation

H-TAD with bicuspid aortic valve (BAV)

ACTA2

BAV, lack of Marfanoid skeletal features, levido reticularis, iris flocculi

SMAD6

BAV, lack of Marfanoid skeletal features, coarctatio aortae

H-TAD with patent ductus arteriosus (PDA)

MYH11

PDA, lack of Marfanoid skeletal features

Checklist for Syndromic and nonsyndromic Heritable Thoracic Aortic and Arterial Diseases


Suspected clinical diagnosis (see list above):

Maximal aortic diameter

mm

Age at measurement

yrs

Localisation of the maximum dilatation




Sinus Valsalva



Sinotubular Junction



Ascending Aorta



Aortic arch



Descending Aorta



Abdominal Aorta



Aortic dissection:

thoracic type A – type B

A -B

abdominal



Arterial tortuosity



Peripheral arterial dissection: please specify

Bicuspid Aortic Valve



Other cardiovascular lesions (please specify):



Other systemic features (please specify):

  • Ocular:

  • Osteo-articular:

  • Central Nervous:

  • Skin:

  • Gastro-intestinal:

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

mm

Age at measurement

yrs

Height

cm

Weight

kg

Ectopia Lentis

Y/N

Systemic score

/20

Family History: please specify



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