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 (++)
COL3A1 120180 vascular-type Ehlers-Danlos syndrome AD 40
COL5A1 120215 Ehlers-Danlos syndrome classic type 1 AD 114
COL5A2 120190 Ehlers-Danlos syndrome classic type 2 AD 42
EFEMP2 604633 Cutis laxa, autosomal recessive, type IB AR 2
FBN1 134797 Marfan syndrome; Weill-Marchesani syndrome 2; geleophysic dysplasia 2 AD 71
FBN2 612570 congenital contractural arachnodactyly AD 47
NOTCH1 190198 aortic valve disease type 1; Adams-Oliver syndrome 5 AD 8
SKI 164780 Shprintzen-Goldberg Craniosynostosis Syndrome AD 3
SLC2A10 606145 arterial tortuosity syndrome AR 9
SMAD2 601366 1
SMAD3 603109 Loeys-Dietz syndrome 3 AD 8
TGFB2 190220 Loeys-Dietz syndrome 4 AD 3
TGFB3 190230 Arrhythmogenic right ventricular dysplasia 1; Loeys-Dietz syndrome 5 AD 9
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
COL3A1 120180 vascular-type Ehlers-Danlos syndrome AD 40
COL5A1 120215 Ehlers-Danlos syndrome classic type 1 AD 114
COL5A2 120190 Ehlers-Danlos syndrome classic type 2 AD 42
EFEMP2 604633 Cutis laxa, autosomal recessive, type IB AR 2
FBN1 134797 Marfan syndrome; Weill-Marchesani syndrome 2; geleophysic dysplasia 2 AD 71
FBN2 612570 congenital contractural arachnodactyly AD 47
NOTCH1 190198 aortic valve disease type 1; Adams-Oliver syndrome 5 AD 8
SKI 164780 Shprintzen-Goldberg Craniosynostosis Syndrome AD 3
SLC2A10 606145 arterial tortuosity syndrome AR 9
SMAD2 601366 1
SMAD3 603109 Loeys-Dietz syndrome 3 AD 8
TGFB2 190220 Loeys-Dietz syndrome 4 AD 3
TGFB3 190230 Arrhythmogenic right ventricular dysplasia 1; Loeys-Dietz syndrome 5 AD 9
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