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  1. Marfan, Loeys-Dietz Syndrome and Related Disorders Panel

Marfan, Loeys-Dietz Syndrome and Related Disorders Panel

November 15, 2018

Disease summary:

Marfan syndrome (MFS), Loeys-Dietz syndrome (LDS), Ehlers-Danlos syndrome (EDS) and related disorders are all heritable connective-tissue disorders (HCTD). Many genes have been identified as a cause of a HCTD, most commonly they encode structural proteins, modifying enzymes or components of the TGFβ-signaling pathways1.

HCTDs affect the connective tissue of various organ systems, including heart, blood vessels, skin, joints, bone, eyes, and lungs, and there is phenotypic overlap of cardiovascular, skeletal, craniofacial and cutaneous features between them1,2. Cardiovascular manifestations in all related disorders can lead to complications associated with high morbidity and mortality rates.1,3 Clinical overlap between the different syndromes and numerous subtypes makes accurate diagnosis challenging and molecular diagnostic confirmation is a key part of diagnosis and disease management.


  • Autosomal dominant
  • Autosomal recessive

MFS: 11 – 17/ 100,0004

EDS: 1:5,000 to 1:25,0005

The major clinical symptoms common to Marfan, Loeys-Dietz syndrome and related disorders affect numerous systems in the body, namely skeletal, pulmonary and ophthalmological. Below is not an exhaustive list but lists key symptoms that either overlap or differentiate between disorders (where specified).

Major clinical symptoms

  • Skeletal

    • Joint hypermobility
    • Long bone overgrowth (MFS, LD)
    • Anterior chest deformities (MFS, LD)
    • Vertebral column deformity (MFS, LD).

  • Pulmonary

    • Aortic aneurism1,2, mitral valve prolapse (MFS, LD).6

  • Craniofacial characteristics7

    • Maxillary overbite
    • Highly arched palate with crowding of teeth
    • Dolichocephaly
    • Exophthalmos
    • Down-slanting palpebral fissures
    • Malar hypoplasia
    • Ocular hypertelorism, Cleft palate (specific to LD, not MFS)
    • Ectopia lentis (MFS, not LD).

  • Cutaneous

    • Striae distensae (MFS, LD)
    • Velvety, thin and translucent skin with visible veins, easy bruising, poor wound healing and dystrophic scars are observed (LD)8
    • Skin hyperextensibility (EDS)
    • Tissue fragility (EDS).

MFS

  • Diagnosis is made based on the revised Ghent nosology, established in 20109
  • Genetic screening of FBN1.

LDS

No formal diagnostic criteria currently exist. A combination of a mutation in one of the known LDS genes and the presence of aortic aneurysms or dissection should be sufficient to make the diagnosis of LDS1,8.

EDS

  • Clinical evaluation and presence of characteristic clinical features (for each EDS subtype).
  • Collagen typing based on the skin biopsy
  • Imaging studies including CT, MRI, angiography and ultrasound
  • A pathogenic variant in EDS-associated genes.

There is currently no cure for Marfan syndrome, Loeys-Dietz syndrome or related disorders. Ongoing medical management is required and guidelines and treatments specific to each disorder and subtype are available1,2,8,10.

  • Echocardiography, CT or MRI to detect and monitor aortic root, ascending aorta, and heart valves
  • Prophylactic surgical repair to the aorta and other vasculature
  • Aortic root replacement
  • Blood pressure medication, β-blockers or Angiotensin II receptor blockers
  • Pain-relief (acetaminophen, ibuprofen, naproxen and others)
  • Physical and occupational therapy.

  • MASS syndrome (a connective tissue disorder related to Marfan syndrome but with milder cardiovascular findings)
  • Mitral valve prolapse syndrome
  • Familial aortic aneurism
  • Ectopia lentis syndrome
  • Shprintzen-Goldberg syndrome
  • Congenital contractural arachnodactyly
  • Lujans syndrome
  • Stickler syndrome

To confirm/establish the diagnosis, CENTOGENE offers the following tests:

  • Marfan, Loeys-Dietz syndrome and related disorders NGS Panel which includes sequencing of the genes COL3A1, COL5A1, COL5A2, EFEMP2, FBN1, FBN2, NOTCH1, SKI, SLC2A10, SMAD2, SMAD3, TGFB2, TGFB3, TGFBR1, TGFBR2
  • Marfan, Loeys-Dietz syndrome and related disorders  NGS Panel + CNV which includes sequencing and additionally detection of large deletions and duplications from the NGS data for the above genes
  • Individuals with a family history of disease and presentation of the most common symptoms.
  • Individuals without a positive family history, but with symptoms resembling this disease.
  • Individuals with a negative but suspected family history, to perform proper genetic counselling (prenatal analyses are offered in families with affected individuals).

Confirmation of a clinical diagnosis through genetic testing of Marfan syndrome, Loeys-Dietz syndrome and related disorders can allow for genetic counseling and may direct medical management.

Early and specific diagnosis and classification of a disorder is relevant for timely treatment and prevention of potentially fatal complications.


Table 1. Overview of the genes in CENTOGENE´s Marfan, Loeys-Dietz syndrome and related disorders panel:

Gene OMIM (Gene) Associated diseases (OMIM) Inheritance CentoMD® exclusive variant numbers (++)
ACTA2 102620 Aortic aneurysm, familial thoracic 6; Multisystemic smooth muscle dysfunction syndrome; Moyamoya disease 5 AD 6
ADAMTS2 604539 Ehlers-Danlos syndrome dermatosparaxis type AR 5
ALDH18A1 138250 Cutis laxa, autosomal recessive, type IIIA; Spastic paraplegia 9A, autosomal dominant; spastic paraplegia 9B; Cutis laxa, autosomal dominant 3 AD, AR 10
ATP6V0A2 611716 autosomal recessive cutis laxa type IIA; Wrinkly skin syndrome AR 1
ATP7A 300011 X-linked distal spinal muscular atrophy type 3; Occipital horn syndrome; Menkes disease XLR 19
B3GALT6 615291 Spondyloepimetaphyseal dysplasia with joint laxity, type 1, with or without fractures; Ehlers-Danlos syndrome spondylodysplastic type 2 AR 8
B3GAT3 606374 Multiple joint dislocations, short stature, craniofacial dysmorphism, and congenital heart defects AR 5
B4GALT7 604327 Ehlers-Danlos syndrome spondylodysplastic type 1 AR 3
BGN 301870 Meester-Loeys syndrome XL, XLR 2
CBS 613381 homocystinuria with or without response to pyridoxine AR 26
CHST14 608429 Ehlers-Danlos syndrome musculocontractural type 1 AR 2
COL12A1 120320 Ullrich congenital muscular dystrophy 2; Bethlem myopathy 2 AD 20
COL1A1 120150 Caffey disease; Ehlers-Danlos syndrome arthrochalasia type 1; osteogenesis imperfecta type 1; osteogenesis imperfecta type 2; osteogenesis imperfecta type 4; OSTEOPOROSIS; osteogenesis imperfecta type 3 AD 80
COL1A2 120160 osteogenesis imperfecta type 2; osteogenesis imperfecta type 4; OSTEOPOROSIS; Ehlers-Danlos syndrome, cardiac valvular form; osteogenesis imperfecta type 3; Ehlers-Danlos syndrome arthrochalasia type 2 AD, AR 63
COL3A1 120180 vascular-type Ehlers-Danlos syndrome AD, AR 43
COL5A1 120215 Ehlers-Danlos syndrome classic type 1 AD 115
COL5A2 120190 Ehlers-Danlos syndrome classic type 2 AD 45
DSE 605942 Ehlers-Danlos syndrome musculocontractural type 2 AR 2
EFEMP2 604633 Cutis laxa, autosomal recessive, type IB AR 2
ELN 130160 Cutis laxa, autosomal dominant 1, ADCL1; Supravalvar aortic stenosis AD 4
FBLN5 604580 Cutis laxa, autosomal recessive, type IA; hereditary neuropathy with or without age-related macular degeneration AD, AR 1
FBN1 134797 Marfan syndrome; stiff skin syndrome; Weill-Marchesani syndrome 2; geleophysic dysplasia 2 AD 75
FBN2 612570 congenital contractural arachnodactyly; early-onset macular degeneration AD 47
FKBP14 614505 Ehlers-Danlos syndrome kyphoscoliotic type 2 AR 4
FLNA 300017 Congenital short bowel syndrome; Heterotopia, periventricular / X-linked periventricular heterotopia; Terminal osseous dysplasia; FG syndrome 2; Otopalatodigital syndrome, type II; Frontometaphyseal dysplasia; Melnick-Needles syndrome; otopalatodigital syndrome type I; Cardiac valvular dysplasia, X-linked XL, XLD, XLR 34
FOXE3 601094 Anterior segment dysgenesis 2, multiple subtypes; Cataract 34, multiple types AD, AR 1
GORAB 607983 geroderma osteodysplasticum AR 1
LOX 153455 AD 1
LTBP4 604710 Cutis laxa, autosomal recessive, type IC AR 7
MAT2A 601468 0
MED12 300188 Opitz-Kaveggia syndrome /FG syndrome-1; Lujan-Fryns syndrome XLR 21
MFAP5 601103 AD 0
MYH11 160745 familial thoracic aortic aneurysm 4 AD 38
MYLK 600922 Aortic aneurysm, familial thoracic 7 AD 18
NOTCH1 190198 aortic valve disease type 1; Adams-Oliver syndrome 5 AD 9
PLOD1 153454 Ehlers-Danlos syndrome kyphoscoliotic type 1 AR 26
PRDM5 614161 Brittle Cornea Syndrome 2 AR 2
PRKG1 176894 familial thoracic aortic aneurysm type 8 AD 1
PYCR1 179035 autosomal recessive cutis laxa type 2B AR 2
RIN2 610222 MACS syndrome AR 1
SKI 164780 Shprintzen-Goldberg Craniosynostosis Syndrome AD 3
SLC2A10 606145 arterial tortuosity syndrome AR 10
SLC39A13 608735 Ehlers-Danlos syndrome spondylodysplastic type 3 AR 1
SMAD2 601366 1
SMAD3 603109 Loeys-Dietz syndrome 3 AD 8
SMAD6 602931 Aortic valve disease 2; Craniosynostosis type 7 AD 4
TGFB2 190220 Loeys-Dietz syndrome 4 AD 3
TGFB3 190230 Arrhythmogenic right ventricular dysplasia 1; Loeys-Dietz syndrome 5 AD 10
TGFBR1 190181 Multiple Self-Healing Squamous Epithelioma, Susceptibility To; Loeys-Dietz syndrome 1 AD 7
TGFBR2 190182 Esophageal cancer, somatic; Loeys-Dietz syndrome 2; Colorectal cancer, hereditary nonpolyposis, type 6 AD 8
TNXB 600985 classic-like Ehlers-Danlos syndrome; Vesicoureteral reflux type 8 AD, AR 76
ZNF469 612078 Brittle cornea syndrome AR 6